Untitled

Issue Overview
Autonomic Disorders, Volume 26, Number 1, February 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
Downloaded from https://journals.lww.com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4XujbhandYgtxzwDDEmi4+C4jUIt7ueXEh+6w4esS99ZNkQ= on 02/06/2020
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Autonomic Disorders
issue, participants will be able to:
 Describe the anatomic and functional organization of the sympathetic and
parasympathetic systems, the central mechanisms of autonomic controls, and the
pathophysiologic basis of the manifestations of autonomic failure
 Use a structured approach to the clinical evaluation of patients with disorders of the
autonomic nervous system, including the history, examination, and autonomic laboratory
evaluation
 Describe the clinical features and management of autoimmune autonomic disorders,
including autoimmune autonomic ganglionopathy and immune-mediated autonomic
neuropathies
 Describe the clinical features, differential diagnosis, diagnostic approach, and natural
history of the autonomic peripheral neuropathies
 Discuss the defining autonomic and clinical features, pathophysiology, and management
of the α-synucleinopathy disorders of pure autonomic failure, multiple system atrophy,
dementia with Lewy bodies, and Parkinson disease
 Diagnose and manage postural tachycardia syndrome and neurally mediated syncope
 Describe the clinical and laboratory features of hyperhidrotic and anhidrotic sweating
disorders due to central and peripheral autonomic nervous system causes
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Describe the spectrum of disorders of autonomic hyperactivity in acute neurologic
disease and principles for their safe management
 Diagnose orthostatic hypotension and implement nonpharmacologic and pharmacologic
strategies for its management
 Discuss the approach to and management of bladder and bowel symptoms reported by
patients with neurologic disorders
 Discuss the role of skin biopsy in the evaluation of autonomic disorders
Core Competencies
This Continuum: Lifelong Learning in Neurology Autonomic 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
Eduardo E. Benarroch, MD, FAAN, Guest Editor

Professor of Neurology; Consultant, Department of Neurology, Mayo Clinic, Rochester,
Minnesota
Relationship Disclosure: Dr Benarroch serves as a section editor for Neurology, has received personal compensation
for speaking engagements from Lundbeck, and receives publishing royalties from Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Benarroch reports no disclosure.
Marta Campagnolo, MD
Neurologist, Department of Neurosciences, University of Padova, Padova, Italy
Relationship Disclosure: Dr Campagnolo reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Campagnolo reports no disclosure.
William P. Cheshire Jr, MD, FAAN

Professor of Neurology, Mayo Clinic, Jacksonville, Florida
Relationship Disclosure: Dr Cheshire serves as an associate editor for Clinical Autonomic Research and on the
editorial boards of Autonomic Neuroscience: Basic & Clinical and Parkinsonism & Related Disorders. Dr Cheshire
has received personal compensation for travel from Biohaven and for speaking engagements for Trinity Graduate
School.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Cheshire discusses the unlabeled/investigational use
of alizarin red and starch iodine for the visualization of sudomotor responses and the unlabeled/investigational use
of amitriptyline, clonidine, endoscopic transthoracic sympathotomy, gabapentin, glycopyrrolate, morphine, and
steroids for the treatment of sweating disorders.
Elizabeth A. Coon, MD
Assistant Professor of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Coon reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Coon discusses the unlabeled/investigational use of
pyridostigmine for orthostatic hypotension and clonazepam and melatonin for dream enactment behavior and the
unlabeled/investigational use of amitriptyline, clonidine, endoscopic transthoracic sympathotomy, gabapentin,
glycopyrrolate, morphine, and steroids for the treatment of sweating disorders.
Jeremy K. Cutsforth-Gregory, MD
Assistant Professor of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Cutsforth-Gregory receives publishing royalties from Mayo Clinic

Scientific Press and Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Cutsforth-Gregory discusses the

unlabeled/investigational use of droxidopa, fludrocortisone, ivabradine, midodrine, propranolol,
and pyridostigmine.
Roy Freeman, MBChB

Professor of Neurology, Harvard Medical School; Director, Center for Autonomic and Peripheral
Nerve Disorders, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Relationship Disclosure: Dr Freeman has received personal compensation and/or stock options for serving on
scientific advisory boards of Abide Therapeutics; Applied Therapeutics, Inc; Aptinyx, Inc; Astellas Pharma; Biogen;
Biohaven Pharmaceuticals; Chromocell; Cutaneous Neurodiagnostics, LLC; GW Pharmaceuticals, plc; Ironwood
Pharmaceuticals; Lundbeck; Mundipharma; NeuroBo Pharmaceuticals; Novartis; Pfizer, Inc; Regenacy
Pharmaceuticals; Spinifex Pharmaceuticals; Theravance Biopharma; Toray Medical Co, Ltd; and Vertex
Pharmaceuticals. Dr Freeman has received personal compensation for serving as editor-in-chief of Autonomic
Neuroscience: Basic & Clinical.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Freeman reports no disclosure.
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
Theravance Biopharma and Lundbeck and as an associate editor for Autonomic Neuroscience: Basic & 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.
Horacio Kaufmann, MD
Professor of Neurology, Medicine, and Pediatrics; Director, Dysautonomia Center, New York
University School of Medicine, New York, New York
Relationship Disclosure: Dr Kaufmann serves as editor-in-chief of Clinical Autonomic Research and as a consultant
for and on the scientific advisory boards of Biogen, Biohaven Pharmaceuticals, Lundbeck, and Pfizer Inc. Dr
Kaufmann receives research/grant support from the Familial Dysautonomia Foundation, Inc; the Michael J. Fox
Foundation for Parkinson's Research; the Multiple System Atrophy Coalition; the National Institutes of Health
(R01HL103988, U54NS065736); Theravance Biopharma; and the US Food and Drug Administration (FDR3731-
01) and publishing royalties from UpToDate, Inc. Dr Kaufmann has served as an expert witness for the Department
of Justice regarding the alleged relationship between human papilloma virus vaccination and autonomic disorders.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kaufmann discusses the unlabeled/investigational use
of acarbose, ampreloxetine, atomoxetine, erythropoietin, fludrocortisone, octreotide, and pyridostigmine for the
treatment of orthostatic hypotension.
Jee Young Kim, MD

Clinical Associate Professor, Myongji Hospital/Hanyang University College of
Medicine/Goyang-si, Gyeonggi-do, Republic of Korea
Relationship Disclosure: Dr Kim reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kim reports no disclosure.
Jose-Alberto Palma, MD, PhD

Associate Professor of Neurology, New York University School of Medicine, New York, New
York
Relationship Disclosure: Dr Palma serves as managing editor for Clinical Autonomic Research and as a consultant
for Biogen, Dr Reddy’s Laboratories Ltd, Lundbeck, and PTC Therapeutics. Dr Palma receives research/grant
support from the Familial Dysautonomia Foundation, Inc; the Michael J. Fox Foundation for Parkinson’s Research;
the Multiple System Atrophy Coalition; and the National Institute of Neurological Disorders and Stroke
(R01NS107596, U54NS065736).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Palma discusses the unlabeled/investigational use of
acarbose, ampreloxetine, atomoxetine, erythropoietin, fludrocortisone, octreotide, and pyridostigmine for the
treatment of orthostatic hypotension.

Jalesh N. Panicker, MD, DM, FRCP
Consultant Neurologist and Clinical Lead Reader in Uro-Neurology and Clinical Neurology, the
National Hospital for Neurology and Neurosurgery, University College London Queen Square
Institute of Neurology, London, United Kingdom
Relationship Disclosure: Dr Panicker has received personal compensation for speaking engagements from Astellas
Pharma Inc and Wellspect HealthCare and receives research/grant support from the United Kingdom’s Department
of Health National Institute of Health Research Biomedical Research Centres funding scheme and publishing
royalties from Cambridge University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Panicker reports no disclosure.
Alejandro A. Rabinstein, MD, FAAN

Professor of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Rabinstein serves as an associate editor of Neurocritical Care and on the editorial board
of Continuum and receives publishing royalties from Elsevier and Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rabinstein reports no disclosure.
Ryuji Sakakibara, MD, PhD, FAAN

Professor of Neurology and Internal Medicine, Sakura Medical Center, Toho University, Sakura,
Japan
Relationship Disclosure: Dr Sakakibara reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Sakakibara reports no disclosure.
Wolfgang Singer, MD
Consultant; Associate Professor of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Singer serves on the editorial board of Autonomic Neuroscience: Basic & Clinical, as an
associate editor for Clinical Autonomic Research, as a consultant for Biohaven Pharmaceuticals, and on an advisory
board for Lundbeck. Dr Singer receives research/grant support from Dysautonomia International, the National
Institutes of Health (R01 NS092625, U54 NS65736) and the US Food and Drug Administration (R01 FD4789).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Singer discusses the unlabeled/investigational use of
pyridostigmine for orthostatic hypotension and clonazepam and melatonin for dream enactment behavior.
Steven Vernino, MD, PhD, FAAS, FAAN

Distinguished Teaching Professor; Dr. Bob and Jean Smith Foundation Distinguished Chair in
Neuromuscular Disease Research, University of Texas Southwestern Medical Center, Dallas,
Texas
Relationship Disclosure: Dr Vernino serves on the board of directors of the American Autonomic Society; the
scientific advisory boards of Argenx, Dysautonomia International, and the Multiple System Atrophy Coalition; and
the editorial boards of Autonomic Neuroscience: Basic & Clinical and Clinical Autonomic Research. Dr Vernino
receives research/grant support from Dysautonomia International; Genentech, Inc; Grifols, SA; the Rex Griswold
Foundation; and Theravance and licensing fees to support his laboratory from Quest Diagnostics Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Vernino discusses the unlabeled/investigational use
of immunomodulatory treatments for autoimmune disorders.
Ningshan Wang, MD, PhD

Instructor of Neurology, Harvard Medical School, Boston, Massachusetts
Relationship Disclosure: Dr Wang reports no disclosure.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Wang reports no disclosure.
Self-Assessment and CME Test Writers

Allison L. Weathers, MD, FAAN
Associate Chief Medical Information Officer, Cleveland Clinic; Assistant Professor, Cleveland
Clinic Lerner College of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Weathers serves on the editorial board of Continuum and as chair of the adult
neurosciences specialty steering board for Epic.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Weathers reports no disclosure.
Allyson R. Zazulia, MD
Professor of Neurology and Radiology, Associate Dean for Continuing Medical Education,
Washington University, St. Louis, Missouri
Relationship Disclosure: Dr Zazulia reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Zazulia 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
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The text can be reviewed and digested most effectively by establishing a regular schedule of
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can be met.

FEBRUARY 2020
VOL. 26 NO. 1 Autonomic Disorders
Guest Editor: Eduardo E. Benarroch, MD, FAAN
10 Editor’s Preface
Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
12 Physiology and Pathophysiology of the Autonomic

Nervous System
Eduardo E. Benarroch, MD, FAAN
25 Autonomic History, Examination, and Laboratory Evaluation

William P. Cheshire Jr, MD, FAAN
44 Autoimmune Autonomic Disorders

Steven Vernino, MD, PhD, FAAS, FAAN
58 Autonomic Peripheral Neuropathy

Roy Freeman, MBChB
72 Synucleinopathies
Elizabeth A. Coon, MD; Wolfgang Singer, MD
93 Postural Tachycardia Syndrome and Neurally

Mediated Syncope
Jeremy K. Cutsforth-Gregory, MD
116 Sweating Disorders

Elizabeth A. Coon, MD; William P. Cheshire Jr, MD, FAAN
DENOTES CONTINUUM
138 Autonomic Hyperactivity
AUDIO INTERVIEW
Alejandro A. Rabinstein, MD, FAAN
154 Management of Orthostatic Hypotension

Jose-Alberto Palma, MD, PhD; Horacio Kaufmann, MD, FAAN

178 Lower Urinary Tract and Bowel Dysfunction
in Neurologic Disease
Jalesh N. Panicker, MD, DM, FRCP; Ryuji Sakakibara, MD, PhD, FAAN
200 Skin Biopsy in Evaluation of Autonomic Disorders

Christopher H. Gibbons, MD, MMSc, FAAN; Ningshan Wang, MD, PhD;
Jee Young Kim, MD; Marta Campagnolo, MD; Roy Freeman, MBChB
SELF-ASSESSMENT AND CME
4 Learning Objectives and Core Competencies
213 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
215 Postreading Self-Assessment and CME Test
228 Postreading Self-Assessment and CME Test—Preferred Responses
240 Erratum
241 Index
List of Abbreviations (Back Cover)

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives Core Competencies

Upon completion of this Continuum: Lifelong This Continuum: Lifelong Learning in Neurology
Learning in Neurology Autonomic Disorders issue, Autonomic Disorders issue covers the following
participants will be able to: core competencies:
◆ Describe the anatomic and functional organization ◆ Patient Care

of the sympathetic and parasympathetic systems,
the central mechanisms of autonomic controls, ◆ Medical Knowledge
and the pathophysiologic basis of the manifestations
of autonomic failure ◆ Practice-Based Learning and Improvement
◆ Use a structured approach to the clinical evaluation ◆ Interpersonal and Communication Skills
of patients with disorders of the autonomic nervous
system, including the history, examination, and ◆ Professionalism
autonomic laboratory evaluation
◆ Systems-Based Practice
◆ Describe the clinical features and management
of autoimmune autonomic disorders, including
autoimmune autonomic ganglionopathy
and immune-mediated autonomic neuropathies
◆ Describe the clinical features, differential diagnosis,

diagnostic approach, and natural history
of the autonomic peripheral neuropathies
◆ Discuss the defining autonomic and clinical features,

pathophysiology, and management of the
α-synucleinopathy disorders of pure autonomic
failure, multiple system atrophy, dementia
with Lewy bodies, and Parkinson disease
◆ Diagnose and manage postural tachycardia syndrome

and neurally mediated syncope
◆ Describe the clinical and laboratory features

of hyperhidrotic and anhidrotic sweating disorders
due to central and peripheral autonomic nervous
system causes
◆ Describe the spectrum of disorders of autonomic

hyperactivity in acute neurologic disease and
principles for their safe management
◆ Diagnose orthostatic hypotension and implement

nonpharmacologic and pharmacologic strategies
for its management
◆ Discuss the approach to and management of bladder

and bowel symptoms reported by patients with
neurologic disorders
◆ Discuss the role of skin biopsy in the evaluation

of autonomic disorders
4 F EB R UA R Y 2 0 2 0

CONTRIBUTORS
Eduardo E. Benarroch, MD, FAAN Elizabeth A. Coon, MD

Guest Editor Assistant Professor of

Professor of Neurology; Neurology, Mayo Clinic,
Consultant, Department Rochester, Minnesota
of Neurology, Mayo Clinic,
Relationship Disclosure: Dr Coon reports
Rochester, Minnesota no disclosure.
Relationship Disclosure: Dr Benarroch Unlabeled Use of Products/Investigational

serves as a section editor for Neurology, Use Disclosure: Dr Coon discusses
has received personal compensation the unlabeled/investigational use
for speaking engagements from Lundbeck, of pyridostigmine for orthostatic
and receives publishing royalties from hypotension and clonazepam and
Oxford University Press. melatonin for dream enactment behavior
and the unlabeled/investigational use
Unlabeled Use of Products/Investigational of amitriptyline, clonidine, endoscopic
Use Disclosure: Dr Benarroch reports transthoracic sympathotomy, gabapentin,
no disclosure. glycopyrrolate, morphine, and steroids
for the treatment of sweating disorders.
Marta Campagnolo, MD
Neurologist, Department Jeremy K. Cutsforth-Gregory, MD
of Neurosciences, University Assistant Professor of Neurology,
of Padova, Padova, Italy Mayo Clinic, Rochester,
Minnesota
Relationship Disclosure: Dr Campagnolo
reports no disclosure. Relationship Disclosure: Dr Cutsforth-
Gregory receives publishing royalties
Unlabeled Use of Products/Investigational from Mayo Clinic Scientific Press and Oxford
Use Disclosure: Dr Campagnolo reports no University Press.
disclosure.
Unlabeled Use of Products/Investigational
Use Disclosure: Dr Cutsforth-Gregory
discusses the unlabeled/investigational use
William P. Cheshire Jr, MD, FAAN of droxidopa, fludrocortisone, ivabradine,
Professor of Neurology, Mayo midodrine, propranolol, and pyridostigmine.
Clinic, Jacksonville, Florida
Relationship Disclosure: Dr Cheshire serves
as an associate editor for Clinical Autonomic
Research and on the editorial boards of
Autonomic Neuroscience: Basic & Clinical
and Parkinsonism & Related Disorders.
Dr Cheshire has received personal
compensation for travel from Biohaven
and for speaking engagements for Trinity
Graduate School.

Use Disclosure: Dr Cheshire discusses the
unlabeled/investigational use of alizarin
red and starch iodine for the visualization of
sudomotor responses and the unlabeled/
investigational use of amitriptyline,
clonidine, endoscopic transthoracic
sympathotomy, gabapentin, glycopyrrolate,
morphine, and steroids for the treatment of
sweating disorders.
6 F EB R UA R Y 2 0 2 0

Roy Freeman, MBChB Horacio Kaufmann, MD
Professor of Neurology, Harvard Professor of Neurology,
Medical School; Director, Center Medicine, and Pediatrics;
for Autonomic and Peripheral Director, Dysautonomia Center,
Nerve Disorders, Beth Israel New York University School of
Deaconess Medical Center, Medicine, New York, New York
Boston, Massachusetts
Relationship Disclosure: Dr Kaufmann serves
as editor-in-chief of Clinical Autonomic
Relationship Disclosure: Dr Freeman Research and as a consultant for and on
has received personal compensation the scientific advisory boards of Biogen,
and/or stock options for serving on Biohaven Pharmaceuticals, Lundbeck,
scientific advisory boards of Abide and Pfizer Inc. Dr Kaufmann receives
Therapeutics; Applied Therapeutics, Inc; research/grant support from the Familial
Aptinyx, Inc; Astellas Pharma; Biogen; Dysautonomia Foundation, Inc; the
Biohaven Pharmaceuticals; Chromocell; Michael J. Fox Foundation for Parkinson's
Cutaneous Neurodiagnostics, LLC; Research; the Multiple System Atrophy
GW Pharmaceuticals, plc; Ironwood Coalition; the National Institutes of Health
Pharmaceuticals; Lundbeck; Mundipharma; (R01HL103988, U54NS065736); Theravance
NeuroBo Pharmaceuticals; Novartis; Pfizer, Biopharma; and the US Food and Drug
Inc; Regenacy Pharmaceuticals; Spinifex Administration (FDR3731-01) and publishing
Pharmaceuticals; Theravance Biopharma; royalties from UpToDate, Inc. Dr Kaufmann
Toray Medical Co, Ltd; and Vertex has served as an expert witness for the
Pharmaceuticals. Dr Freeman has received Department of Justice regarding the alleged
personal compensation for serving as relationship between human papilloma virus
editor-in-chief of Autonomic Neuroscience: vaccination and autonomic disorders.
Basic & Clinical.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kaufmann discusses the
Use Disclosure: Dr Freeman reports unlabeled/investigational use of acarbose,
no disclosure. ampreloxetine, atomoxetine, erythropoietin,
fludrocortisone, octreotide, and pyridostigmine
for the treatment of orthostatic hypotension.
Christopher H. Gibbons, MD,

MMSc, FAAN Jee Young Kim, MD
Associate Professor Clinical Associate Professor,
of Neurology, Harvard Medical Myongji Hospital/Hanyang
School, Boston, Massachusetts University College of Medicine/
Relationship Disclosure: Dr Gibbons Goyang-si, Gyeonggi-do,
has received personal compensation Republic of Korea
for serving as a scientific advisor for
Theravance Biopharma and Lundbeck Relationship Disclosure: Dr Kim reports
and as an associate editor for Autonomic no disclosure.
Neuroscience: Basic & Clinical, research/
grant support from Grifols, and publishing Unlabeled Use of Products/Investigational
royalties from UpToDate, Inc. Dr Gibbons Use Disclosure: Dr Kim reports no disclosure.
has held stock/stock options in Cutaneous
Neurodiagnostics, LLC, and has given expert
medical testimony.

Use Disclosure: Dr Gibbons reports
no disclosure.
C O N T I N U U M J O U R N A L .C O M 7

CONTRIBUTORS (CONTINUED)
Jose-Alberto Palma, MD, PhD Alejandro A. Rabinstein, MD,

Associate Professor FAAN
of Neurology, New York Professor of Neurology, Mayo
University School of Medicine, Clinic, Rochester, Minnesota
New York, New York
Relationship Disclosure: Dr Rabinstein
Relationship Disclosure: Dr Palma serves serves as an associate editor of
as managing editor for Clinical Autonomic Neurocritical Care and on the editorial
Research and as a consultant for Biogen, board of Continuum and receives publishing
Dr Reddy’s Laboratories Ltd, Lundbeck, royalties from Elsevier and Oxford University
and PTC Therapeutics. Dr Palma receives Press.
research/grant support from the Familial
Dysautonomia Foundation, Inc; the Michael Unlabeled Use of Products/Investigational
J. Fox Foundation for Parkinson’s Research; Use Disclosure: Dr Rabinstein reports
the Multiple System Atrophy Coalition; no disclosure.
and the National Institute of Neurological
Disorders and Stroke (R01NS107596,
U54NS065736).
Ryuji Sakakibara, MD, PhD,
Unlabeled Use of Products/Investigational FAAN
Use Disclosure: Dr Palma discusses the
unlabeled/investigational use of acarbose,
Professor of Neurology
ampreloxetine, atomoxetine, erythropoietin, and Internal Medicine, Sakura
fludrocortisone, octreotide, and Medical Center, Toho University,
pyridostigmine for the treatment
of orthostatic hypotension.
Sakura, Japan
Relationship Disclosure: Dr Sakakibara
reports no disclosure.
Jalesh N. Panicker, MD, DM, Unlabeled Use of Products/Investigational
FRCP Use Disclosure: Dr Sakakibara reports
Consultant Neurologist and no disclosure.
Clinical Lead Reader in

Uro-Neurology and Clinical
Neurology, the National Hospital Wolfgang Singer, MD
for Neurology and Neurosurgery, Consultant; Associate
University College London Professor of Neurology, Mayo
Queen Square Institute of Clinic, Rochester, Minnesota
Neurology, London, Relationship Disclosure: Dr Singer serves
United Kingdom on the editorial board of Autonomic
Neuroscience: Basic & Clinical, as an
Relationship Disclosure: Dr Panicker associate editor for Clinical Autonomic
has received personal compensation Research, as a consultant for Biohaven
for speaking engagements from Astellas Pharmaceuticals, and on an advisory
Pharma Inc and Wellspect HealthCare board for Lundbeck. Dr Singer receives
and receives research/grant support research/grant support from Dysautonomia
from the United Kingdom’s Department International, the National Institutes of
of Health National Institute of Health Health (R01 NS092625, U54 NS65736), and
Research Biomedical Research Centres the US Food and Drug Administration
funding scheme and publishing royalties (R01 FD4789).
from Cambridge University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Singer discusses
Use Disclosure: Dr Panicker reports the unlabeled/investigational use of
no disclosure. pyridostigmine for orthostatic hypotension
and clonazepam and melatonin for dream
enactment behavior.
8 F EB R UA R Y 2 0 2 0

Steven Vernino, MD, PhD, Ningshan Wang, MD, PhD
FAAS, FAAN Instructor of Neurology,
Distinguished Teaching Harvard Medical School,
Professor; Dr. Bob and Jean Boston, Massachusetts
Smith Foundation Distinguished
Relationship Disclosure: Dr Wang reports
Chair in Neuromuscular Disease no disclosure.
Research, University of Texas
Southwestern Medical Center,
Use Disclosure: Dr Wang reports no
Dallas, Texas disclosure.
Relationship Disclosure: Dr Vernino serves

on the board of directors of the American
Autonomic Society; the scientific advisory
boards of Argenx, Dysautonomia International,
and the Multiple System Atrophy Coalition;
and the editorial boards of Autonomic
Neuroscience: Basic & Clinical and Clinical
Autonomic Research. Dr Vernino receives
research/grant support from Dysautonomia
International; Genentech, Inc; Grifols, SA;
the Rex Griswold Foundation; and Theravance
and licensing fees to support his laboratory
from Quest Diagnostics Inc.

Use Disclosure: Dr Vernino discusses
the unlabeled/investigational use
of immunomodulatory treatments
for autoimmune disorders.
Self-Assessment and CME Test Writers
Allison L. Weathers, MD, FAAN Allyson R. Zazulia, MD

Associate Chief Medical Professor of Neurology and
Information Officer, Cleveland Radiology, Associate Dean for
Clinic; Assistant Professor, Continuing Medical Education,
Cleveland Clinic Lerner College Washington University,
of Medicine, Cleveland, Ohio St. Louis, Missouri
Relationship Disclosure: Dr Weathers serves Relationship Disclosure: Dr Zazulia reports
on the editorial board of Continuum and as no disclosure.
chair of the adult neurosciences specialty
steering board for Epic. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Zazulia reports
Unlabeled Use of Products/Investigational no disclosure.
Use Disclosure: Dr Weathers reports
no disclosure.

EDITOR’S PREFACE
Diagnosing and Managing

Autonomic Disorders With
No Sweat
This issue of Continuum is devoted to the diagnosis and management
of our patients with disorders that involve the autonomic nervous
system. It has been more than 12 years since the last issue devoted to
this important but often poorly understood topic. I am therefore so
pleased that Dr Eduardo E. Benarroch accepted my invitation to be
the guest editor of this issue, and I extend my sincere thanks to him for inviting such
an outstanding team of renowned experts to contribute to this much-needed issue in
the Continuum curriculum.
The issue starts with the article by Dr Benarroch, autonomic peripheral neuropathies, including those
who provides his overview of the physiology and associated with diabetes mellitus, the amyloid
pathophysiology of the autonomic nervous system, polyneuropathies, the inherited autonomic
laying the groundwork for understanding the neuropathies, and toxic autonomic neuropathies.
pathophysiologic issues that underlie the specific In the next article, Drs Elizabeth A. Coon and
disorders that are discussed in the articles that follow. Wolfgang Singer review the α-synucleinopathies,
In the next article, Dr William P. Cheshire Jr extends including pure autonomic failure, multiple system
this introduction to the rest of the issue by providing atrophy, dementia with Lewy bodies, and Parkinson
his practical approach to the autonomic history, disease, degenerative conditions that include varying
examination, and laboratory evaluation of patients degrees and manifestations of autonomic dysfunction
with possible autonomic nervous system disorders. that may be presenting features of the diseases. Dr
Even those (many) neurologists without access to Jeremy K. Cutsforth-Gregory then reviews the
formal autonomic testing will gain so much by definitions, clinical features, diagnostic investigation,
understanding the theory behind this testing and and management of disorders of orthostatic intolerance,
recognizing how much information can be gained by including postural tachycardia syndrome and neurally
a careful and honed history, a penlight for the pupils, mediated syncope.
and a stethoscope to personally check for orthostatic Drs Coon and Cheshire review the clinical
hypotension in the clinic. phenomenology and management of disorders of
Dr Steven Vernino discusses the clinical features, sweating, both hyperhidrosis and hypohidrosis,
diagnosis, and management of autoimmune conditions that may be less familiar to many
autonomic disorders, including autoimmune neurologists but can be distressing or embarrassing to
autonomic ganglionopathy and the autonomic patients and may be clues to significant underlying
syndromes that may occur in association with other neurologic disorders. Dr Alejandro A. Rabinstein
autoimmune disorders. Dr Roy Freeman then next provides an overview of the syndromes of
discusses the diagnosis and management of the autonomic hyperactivity, such as paroxysmal
10 FEBRUARY 2020

sympathetic hyperactivity and autonomic and Roy Freeman describe the current role of skin
dysreflexia, that can occur as a consequence of biopsy in the evaluation of autonomic disorders and
traumatic brain injury and spinal cord injury, show a glimpse of a possible future role of this
respectively, and the dysautonomia that can occur minimally invasive technique in the diagnosis of
with peripheral nerve dysfunction, such as in α-synucleinopathies.
Guillain-Barré syndrome. After reading the issue and taking the Postreading
Drs Jose-Alberto Palma and Horacio Kaufmann Self-Assessment and CME Test written by Drs
provide their review of the management of patients Allison L. Weathers and Allyson R. Zazulia, you may
with orthostatic hypotension, emphasizing the earn up to 20 AMA PRA Category 1 CreditsTM toward
importance of nonpharmacologic measures, self-assessment CME or, for Canadian participants, a
including lifestyle modifications, while delineating maximum of 20 hours toward the Self-Assessment
the role and indications for the various pharmacologic Program (Section 3) of the Maintenance of
options. Drs Jalesh N. Panicker and Ryuji Sakakibara Certification Program of the Royal College of
then review the pathophysiology and management Physicians and Surgeons of Canada. Additional
of lower urinary tract and bowel dysfunction in credit can be obtained by listening to Continuum
neurologic disease, symptoms that complicate the Audio interviews associated with this and other
daily lives of so many of our patients with neurologic Continuum issues, available to all subscribers, and
disorders and for which the neurologist can play an completing tests on the Continuum Audio web
important role, including in collaboration with platform or mobile app. Continuum Audio is also
urologists or gastroenterologists. In the final review accredited by the Royal College of Physicians and
article of the issue, Drs Christopher H. Gibbons, Surgeons of Canada.
Ningshan Wang, Jee Young Kim, Marta Campagnolo, I would like to offer my deepest appreciation to
Dr Benarroch for his expert guest editorship of this
important issue in our curriculum, including his
great attention to critical details in each step of
planning and producing such an issue. I would also
like to thank Dr Benarroch for enlisting such expert
neurologic colleagues in the autonomic field to give
I would like to thank Dr Benarroch us a “heads-up” of what we need to know as we
for enlisting such expert neurologic diagnose (even with just the standard bedside tools
colleagues in the autonomic field to we all have) and manage the patients who present
give us a “heads-up” of what we with autonomic dysfunction due to any of the myriad
central or peripheral neurologic disorders that can
need to know as we diagnose (even affect the autonomic nervous system.
with just the standard bedside tools
we all have) and manage the patients —STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
who present with autonomic
dysfunction… © 2020 American Academy of Neurology.
CONTINUUMJOURNAL.COM 11

REVIEW ARTICLE

Physiology and
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
Pathophysiology of
the Autonomic
Nervous System
By Eduardo E. Benarroch, MD, FAAN
ABSTRACT
PURPOSE OF THE REVIEW: This
article reviews the anatomic, functional, and
neurochemical organization of the sympathetic and parasympathetic
outputs; the effects on target organs; the central mechanisms controlling
autonomic function; and the pathophysiologic basis for core symptoms of
autonomic failure.
RECENT FINDINGS: Functional neuroimaging studies have elucidated the areas

involved in central control of autonomic function in humans. Optogenetic
and other novel approaches in animal experiments have provided new
insights into the role of these areas in autonomic control across behavioral
states, including stress and the sleep-wake cycle.
SUMMARY: Control of the function of the sympathetic, parasympathetic, and
CITE AS: enteric nervous system functions depends on complex interactions at all
C O N T I N U U M ( M I N N E AP M I N N ) levels of the neuraxis. Peripheral sympathetic outputs are critical for
2020;26(1, AUTONOMIC DISORDERS):
maintenance of blood pressure, thermoregulation, and response to stress.
12–24.
Parasympathetic reflexes control lacrimation, salivation, pupil response to
Address correspondence to light, beat-to-beat control of the heart rate, gastrointestinal motility,
Dr Eduardo E. Benarroch, micturition, and erectile function. The insular cortex, anterior and
200 First St SW, Rochester,
MN 55905, benarroch@
midcingulate cortex, and amygdala generate autonomic responses to
mayo.edu. behaviorally relevant stimuli. Several nuclei of the hypothalamus generate
coordinated patterns of autonomic responses to internal or social
RELATIONSHIP DISCLOSURE:
Dr Benarroch serves as a section stressors. Several brainstem nuclei participate in integrated control of
editor for Neurology, has autonomic function in relationship to respiration and the sleep-wake
received personal compensation
cycle. Disorders affecting the central or peripheral autonomic pathways,
for speaking engagements from
Lundbeck Pharmaceuticals, and or both, manifest with autonomic failure (including orthostatic
receives publishing royalties hypotension, anhidrosis, gastrointestinal dysmotility, and neurogenic
from Oxford University Press.
bladder or erectile dysfunction) or autonomic hyperactivity, primary
UNLABELED USE OF hypertension, tachycardia, and hyperhidrosis.
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Benarroch reports no
disclosure.
© 2020 American Academy of

Neurology.
12 FEBRUARY 2020

KEY POINTS
INTRODUCTION
E
valuation and management of the autonomic manifestations of ● The sympathetic nervous
neurologic disorders require a basic understanding of the anatomy, system mediates patterns
physiology, and pathophysiology of the autonomic nervous system. of responses critical for
maintenance of blood
The initial section of this article focuses on the anatomic organization
pressure, local regulation
and neurotransmission of the peripheral autonomic system; this is of blood flow,
followed by a review of forebrain and brainstem areas controlling autonomic thermoregulation, and
function and the mechanisms involved in control of blood pressure, heart rate, response to exercise
and stress.
body temperature, bladder, and gastrointestinal function. The aim is to provide
the basis for understanding the pathophysiology and management of autonomic ● Autonomic dysreflexia
disorders discussed in other articles of this issue of Continuum. results from interruption of
supraspinal pathways
coordinating the activity of
ANATOMY, NEUROTRANSMISSION, AND FUNCTIONS OF THE preganglionic sympathetic
AUTONOMIC NERVOUS SYSTEM neurons.
The peripheral control of visceral organs is exerted by the sympathetic and
parasympathetic systems, enteric nervous system, and visceral afferents. The
sympathetic and parasympathetic outputs consist of preganglionic neurons
located in the brainstem or spinal cord and autonomic ganglion neurons that
innervate the target organ. Preganglionic neurons have small myelinated axons
and use acetylcholine (ACh) as their neurotransmitter. ACh elicits fast excitation
of all autonomic ganglion and enteric neurons via ganglion type (α3/β4) nicotinic
receptors. Autoantibodies directed against the α3 subunit produce autoimmune
autonomic ganglionopathy, resulting in sympathetic, parasympathetic, and
enteric nervous system failure, in several combinations.1 Neurons of autonomic
ganglia contain unmyelinated axons and primarily use either ACh or
norepinephrine as their neurotransmitter.
Sympathetic System
The sympathetic preganglionic neurons are located in the thoracolumbar spinal cord
at the T1 to L2 segments, primarily in lamina VII forming the intermediolateral
column (FIGURE 1-1). These preganglionic neurons form functional units that are
activated in a selective manner in response to orthostatic stress, exposure to heat or
cold, hypoglycemia, hemorrhage, exercise, or emotion.2,3 Whereas these neurons
may be individually activated by segmental visceral or somatic afferents (primarily
via local interneurons), in normal conditions the preganglionic sympathetic
subunits are differentially recruited to mediate distinct patterns of sympathetic
responses coordinated by descending inputs from the medulla and hypothalamus.4
The sympathetic output is critical for maintenance of blood pressure, local regulation
of blood flow, thermoregulation, and responses to exercise and internal or
external stressors. Interruption of supraspinal descending autonomic pathways
above the spinal T5 level results in massive, unpatterned reflex activation of
sympathetic preganglionic neurons in response to segmental inputs such as
visceral distension or nociceptor stimulation. This constitutes autonomic
dysreflexia, which manifests primarily with severe hypertension.5
The preganglionic sympathetic axons terminate on paravertebral, prevertebral,
and terminal ganglia as well as the adrenal medulla (FIGURE 1-1).6 Paravertebral
ganglia innervate all tissues and organs except those in the abdomen, pelvis, and
perineum; prevertebral ganglia innervate the viscera and blood vessels of the
abdomen and pelvis. The adrenal medulla releases epinephrine to the bloodstream.

PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
FIGURE 1-1
General organization of the sympathetic system.
The primary neurotransmitter in sympathetic ganglion neurons is norepinephrine;

the exception is sympathetic ganglion neurons innervating the sweat glands,
which are cholinergic. Norepinephrine and epinephrine act via different subtypes
of α1, α2, and β adrenoceptors. The α1 receptors mediate excitation of the smooth
muscle in blood vessels, iris (pupil dilator), vas deferens, bladder neck, and
internal sphincter of the rectum. The α2 receptors are located mostly in presynaptic
terminals, and their main effect is presynaptic inhibition of the release of
norepinephrine from sympathetic terminals (inhibitory autoreceptors) or other
neurotransmitters from parasympathetic or afferent terminals. The β1 receptors
are present in the heart and stimulate automatism of the sinus node, excitability of
the His-Purkinje system, and contractility of the myocardium. The β2 receptors
elicit smooth muscle relaxation, including vasodilation, bronchodilation, and
relaxation of smooth muscle in the bladder and uterus.
Parasympathetic System
The preganglionic parasympathetic neurons are located in the general visceral
efferent column of the brainstem or at the sacral spinal cord segments S2 through
S4 (FIGURE 1-2). From the functional standpoint, the parasympathetic output can
be subdivided into outputs to cranial effectors; outputs mediated by the vagus
nerve to the thoracic and abdominal viscera; and sacral preganglionic outputs to
the bladder, rectum, and sexual organs. Preganglionic axons innervate target
ganglia located just outside or within the wall of the target organ. Thus, each
parasympathetic output mediates organ-specific reflexes. The oculomotor nerve
(cranial nerve III) provides inputs to the ciliary ganglion, which mediates pupil
14 FEBRUARY 2020

FIGURE 1-2
General organization of the parasympathetic system.
constriction and accommodation reflexes. The facial nerve (cranial nerve VII)
provides inputs to the pterygopalatine (sphenopalatine) ganglion to elicit
lacrimation and cranial vasodilation and to submaxillary and submandibular
ganglia to elicit salivation. The glossopharyngeal nerve (cranial nerve IX)
innervates the otic ganglion that promotes parotid gland secretion. The vagus
nerve (cranial nerve X) provides the preganglionic innervation to autonomic
ganglia in the thorax and abdomen.
Vagal preganglionic neurons located in the dorsal motor nucleus of the vagus
nerve innervate ganglia of the cardiac, pulmonary, and enteric nervous system
plexuses, whereas neurons of the nucleus ambiguus provide vagal output to
cardiac ganglion neurons controlling the sinus node. Vagal reflexes are critical for
beat-to-beat control of the heart rate and activation of upper gastrointestinal
motility. The sacral preganglionic nucleus controls micturition, defecation, and
erectile function.
Acetylcholine (ACh) is the primary neurotransmitter of most parasympathetic
ganglion and enteric nervous system neurons. In target organs, the effects of
ACh are primarily mediated by muscarinic receptors, including excitatory M1-like
(M1 and M3 subtypes) and inhibitory M2 receptors. The M3 subtype mediates most
of the excitatory effects of ACh on the visceral targets of parasympathetic neurons,
including smooth muscle contraction, exocrine gland secretion, and endothelial
synthesis of nitric oxide. The M3 receptors also mediate the excitatory action
of cholinergic sympathetic neurons on the sweat gland. The M2 receptors mediate
the inhibitory effects of the vagus by decreasing the automatism of the sinus

node and atrioventricular conduction. Activation of presynaptic M2 receptors

inhibit neurotransmitter release in most organs. The parasympathetic output is
also mediated by noncholinergic neurons that release nitric oxide and vasoactive
intestinal polypeptide. These neurons elicit smooth muscle relaxation, secretory
function, and vasodilation; nitric oxide is the major mediator for cranial
vasodilation and penile erection.
The main effects of the sympathetic and parasympathetic system on target organs
and the neurochemical mediators and receptors are summarized in TABLE 1-1.
Disorders affecting the peripheral autonomic nerves may result in a variety of
symptoms of combined sympathetic and parasympathetic failure (CASE 1-1).
TABLE 1-1 Effects of the Sympathetic and Parasympathetic Systems on Different

Targets
Sympathetic
Target (Receptor) Parasympathetic (Receptor)
Pupil Dilation (α1) Constriction (M3)
Ciliary muscle NA Accommodation (M3)
Salivary and lacrimal glands Inhibition (α2?) Stimulation (M3, vasoactive

intestinal polypeptide receptors)
Heart Stimulation (β1) Inhibition (M2)
Bronchi Dilation (β2) Constriction (M3)
Skeletal muscle vessels Constriction (α1) NA

Dilation (β2)
Skin vessels Constriction (α1) NA

Dilation? (nitric oxide?)
Cranial and visceral vessels Constriction (α1) Dilation (nitric oxide, vasoactive
intestinal polypeptide)
Sweat glands Stimulation (M3) NA
Gastrointestinal motility Inhibition (β2) Contraction (M3)

Relaxation (nitric oxide, vasoactive
Gastrointestinal secretion Inhibition (α2) Gastric acid secretion (M1);

intestinal secretion (M3, vasoactive
Bladder detrusor Inhibition (β2, β3) Stimulation (M3)
Bladder neck Stimulation (α1) Inhibition (nitric oxide)
Rectal smooth muscle Inhibition (β2) Stimulation (M3)
Erectile tissue Constriction (α1) Dilation (nitric oxide)
Vas deferens Contraction (α1) NA
NA = not applicable.
16 FEBRUARY 2020

Central Control of Autonomic Function
The central control of the autonomic output involves several interconnected
areas distributed throughout the forebrain and brainstem that control the activity
of preganglionic sympathetic and parasympathetic neurons (FIGURE 1-3). This
central autonomic network is involved in moment-to-moment modulation of
visceral functions, maintenance of homeostasis, and adaptation to internal or
external challenges.7,8
FOREBRAIN AREAS. The primary forebrain autonomic areas identified in both

animals and humans are the insular cortex, anterior and midcingulate cortex,
amygdala, and hypothalamus.9–18 The posterior insular cortex receives and
integrates visceral, pain, and temperature sensations, which together are
referred to as interoception, or bodily sensation. The dorsal posterior insula
contains a sensory representation of all these modalities and is therefore the
primary interoceptive cortex.19 The posterior insula projects to the anterior
insula, which integrates interoceptive signals with emotional and cognitive
processing and is involved in conscious experience of bodily sensation,19
A 42-year-old man with a 7-year-history of non–insulin-dependent CASE 1-1

diabetes mellitus presented for evaluation of a 2-year history of bilateral
foot pain and numbness and a 1-year history of episodes of dizziness upon
standing. He also described increased intolerance to heat, early satiety,
constipation, difficulty emptying his bladder, and erectile dysfunction.
He was taking glyburide and simvastatin and had stopped taking his
antihypertensive medication because of his orthostatic symptoms.
Neurologic examination showed difficulty walking on his heels, absent
ankle jerks, and sensory loss to all modalities in the feet, which were
red and dry. His blood pressure in the supine position was 150/90 mm Hg
with a heart rate of 98 beats/min; in the standing position, his blood
pressure was 90/60 mm Hg and heart rate was 102 beats/min. An autonomic
reflex screen showed length-dependent sudomotor impairment, blunted
heart rate responses to deep breathing and Valsalva maneuver,
exaggerated fall of blood pressure with impaired recovery during the Valsalva
maneuver, and orthostatic fall of arterial pressure of 40 mm Hg with no
compensatory increase in heart rate. Postvoid residual volume was 300 mL
(normal <100 mL).
This case illustrates a typical example of autonomic neuropathy affecting COMMENT

sympathetic, parasympathetic, and enteric nervous system functions and
associated with distal sensorimotor peripheral neuropathy. Common
causes are diabetes mellitus and amyloidosis. In this case, sympathetic
failure manifested with orthostatic hypotension and heat intolerance, vagal
failure manifested with impaired upper gastrointestinal motility and
blunted heart responses to deep breathing, enteric nervous system failure
manifested with constipation, and sacral parasympathetic failure
manifested with bladder and erectile dysfunction.

FIGURE 1-3
Areas of the central nervous system involved in autonomic control.
including timing of the heartbeat.14 The anterior cingulate cortex includes

subgenual and pregenual portions that are primarily involved in emotional
processing.20 The subgenual portion projects to the autonomic areas involved in
parasympathetic control of the heart,21–24 and its stimulation results in a decrease
in blood pressure.25 The midcingulate cortex is involved in goal-directed
allocation of effort for control of behavior. Its anterior portion is typically
coactivated with the anterior insula in response to pain and tasks that involve
awareness, attention, and behavioral engagement. These two areas are part of the
so-called salience network,26 and their resting-state activity correlates with
sympathetic muscle activity.13 These visceromotor cortices play a major role in
interoception by issuing prediction signals about the expected state of the body
based on previous experience; these interoceptive predictions are then compared
to current visceral sensations as a mechanism to correct autonomic output.27
The amygdala provides affective or emotional value to incoming sensory
information.28 The central nucleus of the amygdala initiates autonomic,
neuroendocrine, and motor responses to emotion and stress via its widespread
connections with the hypothalamus and brainstem.29 The hypothalamus initiates
specific patterns of autonomic, endocrine, and arousal responses to internal or
external stressors.3,30 The main hypothalamic autonomic outputs originate from
18 FEBRUARY 2020

the paraventricular nucleus, the dorsomedial nucleus, and the perifornical area KEY POINTS
of the lateral hypothalamus; these regions contain neurons that project to autonomic
● Norepinephrine elicits
nuclei of the brainstem and spinal cord. The paraventricular nucleus triggers vascular and visceral
responses to internal stressors such as pain, hypoglycemia, hypovolemia, and smooth muscle contraction
inflammatory cytokines. The dorsomedial nucleus is involved in responses to social via α1 receptors, presynaptic
stressors and in thermoregulatory responses to cold. The perifornical area and the inhibition of neurotransmitter
release via α2 receptors,
dorsomedial nucleus contain orexin/hypocretin neurons that orchestrate autonomic
cardiac stimulation via β1
responses in the setting of behavioral arousal and reward-driven behavior.30 receptors, and vasodilation
and smooth muscle
BRAINSTEM AREAS. Several areas of the brainstem participate in integrated relaxation via β2 and β3
autonomic control. The midbrain periaqueductal gray has an important role in receptors.
coordinated autonomic, somatomotor, and pain modulatory responses to stress ● The parasympathetic
and in control of the micturition reflex.31 The parabrachial nucleus located in the nervous system is critical
dorsolateral pons is involved in cardiovascular, respiratory, and gastrointestinal for lacrimation, salivation,
reflexes; thermoregulation; and control of food intake.32 The parabrachial pupil reaction to light,
beat-to-beat control of the
nucleus is also a critical component of the arousal system via its projections to the
heart rate, gastrointestinal
basal forebrain. The nucleus of the solitary tract is the first relay station for motility and secretion,
visceral afferents triggering medullary reflexes regulating cardiovascular micturition, and erectile
function, respiration, and gastrointestinal motility.33 The reticular formation of function.
the rostral ventrolateral medulla contains premotor sympathoexcitatory neurons
● Parasympathetic neurons
that project to the intermediolateral column and are the key effectors for releasing acetylcholine
sympathetic regulation of peripheral resistance in response to the baroreceptor activate smooth muscle
reflex (baroreflex). This reflex is a feedback mechanism critical for the contraction, exocrine gland
moment-to-moment control of blood pressure. They include the C1 group, secretion, and vasodilation
via M3 receptors and inhibit
which also mediates sympathoexcitatory responses to hypoxia, pain, and other cardiac function via M2
stressors. The rostral ventromedial medulla, including the medullary raphe, receptors; neurons releasing
mediates sympathoexcitatory response to external stressors (such as social nitric oxide and vasoactive
stressors) and responses to cold, including skin vasoconstriction. intestinal polypeptide elicit
vasodilation and smooth
muscle relaxation.
Mechanisms of Autonomic Control and Pathophysiologic Correlations
Several areas of the central nervous system participate in the control of autonomic ● The insula is the primary
functions via integration of visceral afferent inputs and descending influences viscerosensory cortex and
contributes to conscious
from forebrain areas involved in emotion, homeostasis, and other survival responses. bodily sensation.
BAROREFLEX CONTROL OF THE ARTERIAL BLOOD PRESSURE AND HEART RATE. ● The anterior midcingulate
Arterial blood pressure is primarily regulated by the sympathetic noradrenergic cortex and the anterior
insular cortex are part of the
input to skeletal muscle and mesenteric blood vessels, mediated by α1 receptors
so-called salience network
and driven by premotor neurons in the rostral ventrolateral medulla. The vagal and are activated during
output to the heart, originating in the nucleus ambiguus, exerts beat-to-beat tasks associated with
control of the heart rate. The baroreflex is the principal mechanism for short- increased sympathetic
term, moment-to-moment control of blood pressure. It provides a continuous activity.
buffering of acute fluctuations of blood pressure in response to orthostatic ● The central nucleus of
changes, stress, and other stimuli by separately controlling the sympathetic the amygdala triggers
vasomotor and cardiovagal outputs. The arterial baroreceptors are located in the autonomic, endocrine, and
wall of the carotid sinus (innervated by the glossopharyngeal nerve) and aortic motor response to
emotionally salient stimuli.
arch (innervated by the vagus nerve) and respond to stretch elicited by pulse
pressure; their afferents synapse on neurons of the nucleus of the solitary tract.
Barosensitive neurons of the nucleus of the solitary tract initiate a sympathoinhibitory
response that reduces the output to the resistance blood vessels via inhibition
of premotor sympathetic neurons of the rostral ventrolateral medulla; this

inhibition is mediated by neurons in the caudal ventrolateral medulla and is the

primary mechanism for beat-to-beat control of arterial blood pressure. Neurons
of the nucleus of the solitary tract also activate the cardiovagal neurons of the
nucleus ambiguus, eliciting bradycardia in response to an increase in arterial
pressure. In contrast, in response to a decrease in pulsatile blood pressure (as
occurs upon standing from a supine or sitting position [orthostatic stress]),
decreased baroreceptor afferent input triggers reflex increase in sympathetic
vasomotor activity (and thus peripheral resistance) and tachycardia. The
increase in sympathetic output to splanchnic and skeletal muscle vessels
prevents venous pooling in the abdomen and lower limbs and is the primary
mechanism to prevent orthostatic hypotension.
Orthostatic hypotension, the most disabling manifestation of sympathetic
failure, may result from lesions affecting the rostral ventrolateral medulla, its
projections to the intermediolateral column, the preganglionic sympathetic
neurons, the sympathetic ganglia, postganglionic axons, or noradrenergic
neurotransmission (including the effects of α1 blocking drugs) leading to
baroreflex efferent failure. In contrast, loss of baroreceptor inputs, or baroreflex
CASE 1-2 A 52-year-old-woman presented for evaluation of fluctuating

hypertension. She had undergone neck radiation therapy for
nasopharyngeal carcinoma 12 years earlier and had been followed yearly
with no evidence of cancer recurrence. Two years earlier, she had
developed episodes of severe hypertension with a sensation of head
pressure, face flushing, and palpitations, typically triggered by stressful
situations, such as speaking in public. She was started on amlodipine,
which resulted in orthostatic dizziness and was therefore discontinued.
Neurologic examination showed a mild flaccid dysarthria and impaired
elevation of the palate but was otherwise normal. During the interview,
she had the sensation of head pressure and developed flushing of the
face. At that time, her blood pressure in the sitting position was 180/
110 mm Hg with a heart rate of 60 beats/min. Upon standing, her blood
pressure was 130/80 mm Hg with a heart rate of 62 beats/min. The
autonomic reflex screen showed normal ability to sweat, blunted heart
rate responses to deep breathing, a severe fall of blood pressure during
the Valsalva maneuver with blunted heart rate response, and a 40 mm Hg
fall of arterial pressure with a 5 beats/min increase in heart rate during
head-up tilt.
COMMENT This case illustrates a typical example of baroreflex failure, which most
commonly occurs following bilateral neck surgery or radiation therapy,
leading to loss of baroreceptor inputs from the carotid sinus. Baroreflex
failure may also be a manifestation of Guillain-Barré syndrome or familial
dysautonomia and may result in hypertensive encephalopathy, posterior
reversible encephalopathy syndrome (PRES), or takotsubo cardiomyopathy.
Management is typically difficult as these patients are extremely sensitive to
both antihypertensive and vasoconstrictor drugs.
20 FEBRUARY 2020

afferent failure (referred to as baroreflex failure), manifests with hypertensive KEY POINTS
crisis, fluctuating hypertension, and, more rarely, orthostatic tachycardia or
● The hypothalamus
hypotension and bradycardia (CASE 1-2). initiates specific patterns of
autonomic responses to
CONTROL OF THE HEART RATE. Under normal resting conditions, heart rate is internal or external stressors
primarily influenced by a tonic vagal activity from the nucleus ambiguus, via projection from the
paraventricular and
which exerts beat-to-beat control on the automatism of the sinus node under
dorsomedial nuclei and
baroreceptor influence. In addition, the cardiovagal output is modulated by orexin/hypocretin neurons.
respiration; it decreases during inspiration and increases during expiration,
leading to respiratory sinus arrhythmia. Respiratory sinus arrhythmia is the ● The periaqueductal gray
most reliable index of the integrity of cardiovagal output. The sympathetic coordinates autonomic,
somatomotor, and pain
noradrenergic input to the heart, mediated primarily by β1 receptors, is critical modulatory responses
for maintenance of cardiac output during exercise. Sympathetically mediated to stress.
orthostatic tachycardia may be exaggerated in the setting of venous pooling
in the lower limbs, as may occur in peripheral neuropathies selectively ● The parabrachial nucleus
is involved in arousal,
affecting the sympathetic input to blood vessels in the lower limbs. Typical respiratory control,
contributory factors are physical deconditioning, and hypersympathetic states and modulation of
such as anxiety. When symptomatic, this constitutes the postural tachycardia cardiovascular and
syndrome. For more information on postural tachycardia syndrome, refer gastrointestinal reflexes.
to the article “Postural Tachycardia Syndrome and Neurally Mediated
● The nucleus of the
Syncope” by Jeremy K. Cutsforth-Gregory, MD,34 in this issue of solitary tract is the first relay
Continuum. station for medullary
cardiovascular, respiratory,
THERMOREGULATION. Maintenance of body core temperature depends on the and gastrointestinal
reflexes.
sympathetic innervation of the skin. Thermoregulatory responses critically
involve neurons in the preoptic region of the hypothalamus. Afferent inputs ● Sympathoexcitatory
from peripheral thermoreceptors relay on neurons in the superficial layers of the neurons of the rostral
dorsal horn that project to the parabrachial nucleus. The parabrachial nucleus ventrolateral medulla,
including the C1 group,
contains cold- or heat-sensitive neurons that convey inputs from the mediate the baroreflex and
thermoreceptors to separate groups of neurons in the median preoptic area. responses to hypoxia and
The medial preoptic area contains heat-sensitive neurons that sense blood other internal stressors.
temperature (representing core temperature) and integrates this information
● Neurons of the rostral
with information from peripheral thermoreceptors conveyed via the median
ventromedial medulla and
preoptic area. Heat-sensitive neurons tonically inhibit cold-sensitive neurons in nucleus raphe pallidus
the dorsomedial nucleus of the hypothalamus. Cold inputs relayed via the mediate sympathoexcitatory
median preoptic area inhibit these warm-sensitive neurons and directly activate responses to external
cold-sensitive hypothalamic neurons. These neurons initiate cold-defense stressors and exposure
to cold.
responses via projections to the nucleus raphe pallidus in the ventromedial
medulla.35–38 Sympathetic responses to cold are triggered by inputs from the ● Arterial blood pressure is
dorsomedial hypothalamic nucleus to the nucleus raphe pallidus and include primarily regulated by the
skin vasoconstriction via α1 receptors and thermogenesis via β2 receptors in sympathetic noradrenergic
input to skeletal muscle and
brown fat tissue. The descending pathways involved in responses to heat are mesenteric blood vessels,
still poorly defined but may originate from neurons in the medial preoptic mediated by α1 receptors
area via a relay in the rostral medulla projecting to the intermediolateral cell and driven by premotor
column. Activation of heat-sensitive neurons elicits sympathetic cholinergic neurons in the rostral
ventrolateral medulla.
activation of the sweat glands via M3 receptors as well as skin vasodilation.
Interruption of the heat-defense pathway, by either central or peripheral
lesions, results in anhidrosis, which manifests with heat intolerance. Either
abnormal activation of the heat-dissipation pathway or interruption of the
heat-conservation pathway may result in severe hypothermia.

KEY POINTS CONTROL OF BLADDER FUNCTION. The bladder detrusor and sphincter muscles
receive parasympathetic, sympathetic, and somatic innervation.39 The sacral
● The baroreceptor reflex is
the principal mechanism for
parasympathetic cholinergic output is critical for normal voiding. The
short-term, moment-to- micturition reflex is triggered by high-frequency discharge of bladder afferents,
moment control of blood which relay in sacral cord neurons that project to the ventrolateral
pressure, buffering acute periaqueductal gray; this area sends inputs to the pontine micturition center
fluctuations in response to
(also known as the pelvic organ coordinating center or Barrington nucleus). This
orthostatic changes or
stress. pontine region sends descending inputs that activate the sacral preganglionic
neurons innervating the bladder detrusor and inhibit, via local interneurons, the
● Baroreflex-triggered Onuf nucleus motor neurons (S2-S3 segments) innervating the external urethral
sympathetic vasoconstriction sphincter. Sympathetic output from the L1-L2 spinal segments triggers relaxation
mediated by α1 receptors
and skeletal muscle and of the detrusor muscle via β2 and β3 receptors and contraction of the bladder neck
splanchnic vessels is critical via α1 receptors together with the output to the external sphincter; this reflex,
to prevent orthostatic which is called the storage reflex, is critical for maintenance of urinary continence.
hypotension, which may be For more information on bladder reflexes, refer to the article “Lower Urinary
a manifestation of disorders
affecting every step of the
Tract and Bowel Dysfunction in Neurologic Disease” by Jalesh N. Panicker, MD,
efferent baroreflex DM, FRCP, and Ryuji Sakakibara, MD, PhD, FAAN,40 in this issue of Continuum.
sympathoexcitatory
pathway. GASTROINTESTINAL MOTILITY. Motility and secretion in the gastrointestinal tract
are controlled by the enteric nervous system, extrinsic parasympathetic and
● Baroreflex afferent
failure manifests with sympathetic inputs, and visceral afferents.41 Sensory neurons, interneurons, and
fluctuating hypertension excitatory motor neurons in the enteric nervous system are cholinergic and elicit
and hypotension. smooth muscle contraction; inhibitory motor neurons use vasoactive intestinal
polypeptide or nitric oxide and elicit smooth muscle relaxation; and secretomotor
● Impaired heart rate
response to deep breathing neurons utilize ACh and vasoactive intestinal polypeptide.42 The dorsal motor
is a reliable index of nucleus of the vagus nerve provides cholinergic input to all neurons of the enteric
cardiovagal failure. nervous system. Vagal influence is most prominent in the esophagus and stomach
and is critical for vagovagal reflexes integrated at the level of the nucleus of the
● The sympathetic output
to the sweat glands and skin
solitary tract and for regulating esophageal and gastric motility.43 The sacral
blood vessels is critical for parasympathetic output activates cholinergic enteric nervous system neurons that
thermoregulation. promote propulsive activity of the rectum during defecation and inhibitory
neurons that initiate colonic relaxation. Anal relaxation induced by rectal
● Peripheral autonomic
distension (the rectoanal inhibitory reflex) is mediated by nitric oxide.
denervation results in
exaggerated responsiveness
of target organs to DENERVATION SUPERSENSITIVITY. Denervation supersensitivity is the
cholinergic or adrenergic exaggerated response of autonomic effectors in the setting of peripheral
agonists (denervation denervation. This reflects upregulation of adrenergic or cholinergic receptors
supersensitivity).
due to loss of tonic modulation of receptor kinetics by its ligand. The typical
example is the exaggerated constrictor response of the Adie pupil to low doses of
the muscarinic agonist pilocarpine owing to loss of its cholinergic innervation by
the ciliary ganglion. One potential serious consequence of denervation
supersensitivity is hypertension due to exaggerated vasoconstrictor responses to
low-dose sympathomimetic agents (such as over-the-counter decongestants
containing pseudoephedrine) caused by upregulation of vascular α1receptors in
patients with autonomic neuropathies.
CONCLUSION
The control of autonomic function includes interconnected forebrain and
brainstem areas that regulate the activity of the sympathetic and parasympathetic
22 FEBRUARY 2020

systems. The sympathetic systems mediate patterns of responses and are critical
for maintenance of arterial pressure and thermoregulation; sympathetic failure
manifests primarily with orthostatic hypotension and anhidrosis. The
parasympathetic system mediates local reflexes regulating individual organs;
parasympathetic failure manifests with impaired reaction to light, dry mouth and
dry eyes, gastrointestinal dysmotility, hypotonic bladder, and erectile dysfunction.
REFERENCES
1 Vernino S, Hopkins S, Wang Z. Autonomic ganglia, 12 Shoemaker JK, Norton KN, Baker J, Luchyshyn T.
acetylcholine receptor antibodies, and autoimmune Forebrain organization for autonomic
ganglionopathy. Auton Neurosci 2009;146(1–2):3–7. cardiovascular control. Auton Neurosci 2015;188:
doi:10.1016/j.autneu.2008.09.005. 5–9. doi:10.1016/j.autneu.2014.10.022.
2 Janig W, Häbler HJ. Neurophysiological analysis 13 Taylor KS, Kucyi A, Millar PJ, et al. Association
of target-related sympathetic pathways—from between resting-state brain functional
animal to human: similarities and differences. connectivity and muscle sympathetic burst
Acta Physiol Scand 2003;177(3):255–274. incidence. J Neurophysiol 2016;115(2):662–673.
doi:10.1046/j.1365-201X.2003.01088.x. doi:10.1152/jn.00675.2015.
3 Saper CB. The central autonomic nervous 14 Schulz SM. Neural correlates of heart-focused
system: conscious visceral perception and interoception: a functional magnetic resonance
autonomic pattern generation. Annu Rev imaging meta-analysis. Philos Trans R Soc Lond B
Neurosci 2002;25:433–469. doi:10.1146/ Biol Sci 2016;371(1708). doi:10.1098/rstb.2016.0018.
annurev.neuro.25.032502.111311.
15 Macefield VG, Henderson LA. “Real-time”
4 Deuchars SA, Lall VK. Sympathetic preganglionic imaging of cortical and subcortical sites of
neurons: properties and inputs. Compr Physiol cardiovascular control: concurrent recordings of
2015;5(2):829–869. doi:10.1002/cphy.c140020. sympathetic nerve activity and fMRI in awake
subjects. J Neurophysiol 2016;116(3):1199–1207.
5 Eldahan KC, Rabchevsky AG. Autonomic
doi:10.1152/jn.00783.2015.
dysreflexia after spinal cord injury: Systemic
pathophysiology and methods of management. 16 Stern ER, Grimaldi SJ, Muratore A, et al.
Auton Neurosci 2018;209:59–70. doi:10.1016/j. Neural correlates of interoception: effects of
autneu.2017.05.002. interoceptive focus and relationship to
dimensional measures of body awareness.
6 McLachlan EM. Transmission of signals through
Hum Brain Mapp 2017;38(12):6068–6082.
sympathetic ganglia—modulation, integration or
doi:10.1002/hbm.23811.
simply distribution? Acta Physiol Scand 2003;
177(3):227–235. doi:10.1046/j.1365-201X.2003.01075.x. 17 Kimmerly DS. A review of human neuroimaging
investigations involved with central autonomic
7 Dampney RA. Central neural control of the
regulation of baroreflex-mediated cardiovascular
cardiovascular system: current perspectives.
control. Auton Neurosci 2017;207:10–21. doi:10.1016/
Adv Physiol Educ 2016;40(3):283–296.
j.autneu.2017.05.008.
doi:10.1152/advan.00027.2016.
18 Fontes MAP, Filho ML, Santos Machado NL, et al.
8 McDougall SJ, Münzberg H, Derbenev AV,
Asymmetric sympathetic output: The
Zsombok A. Central control of autonomic
dorsomedial hypothalamus as a potential link
functions in health and disease. Front Neurosci
between emotional stress and cardiac
2015;8:440. doi:10.3389/fnins.2014.00440.
arrhythmias. Auton Neurosci 2017;207:22–27.
9 Critchley HD. Neural mechanisms of autonomic, doi:10.1016/j.autneu.2017.01.001.
affective, and cognitive integration. J Comp
19 Craig AD. Interoception: the sense of the
Neurol 2005;493(1):154–166. doi:10.1002/
physiological condition of the body. Curr Opin
cne.20749.
Neurobiol 2003;13(4):500–505. doi:10.1016/
10 James C, Macefield VG, Henderson LA. Real-time S0959-4388(03)00090-4.
imaging of cortical and subcortical control of
20 Vogt BA, Vogt L, Farber NB, Bush G. Architecture
muscle sympathetic nerve activity in awake
and neurocytology of monkey cingulate gyrus.
human subjects. Neuroimage 2013;70:59–65.
J Comp Neurol 2005;485(3):218–239. doi:10.1002/
doi:10.1016/j.neuroimage.2012.12.047.
cne.20512.
11 Beissner F, Meissner K, Bär KJ, Napadow V.
21 Terreberry RR, Neafsey EJ. The rat medial frontal
The autonomic brain: an activation likelihood
cortex projects directly to autonomic regions of
estimation meta-analysis for central processing
the brainstem. Brain Res Bull 1987;19(6):639–649.
of autonomic function. J Neurosci 2013;33(25):
doi:10.1016/0361-9230(87)90050-5.
10503–10511. doi:10.1523/JNEUROSCI.1103-13.2013.

22 Hurley KM, Herbert H, Moga MM, Saper CB. 34 Cutsforth-Gregory JK. Postural tachycardia
Efferent projections of the infralimbic cortex of syndrome and neurally mediated syncope.
the rat. J Comp Neurol 1991;308(2):249–276. Continuum (Minneap Minn) 2020;26(1, Autonomic
doi:10.1002/cne.903080210. Disorders):93–115.
23 Verberne AJ, Owens NC. Cortical modulation of 35 Boulant JA. Neuronal basis of Hammel’s model
the cardiovascular system. Prog Neurobiol 1998; for set-point thermoregulation. J Appl Physiol
54(2):149–168. doi:10.1016/S0301-0082(97)00056-7. (1985) 2006;100(4):1347–1354. doi:10.1152/
japplphysiol.01064.2005.
24 Critchley HD, Harrison NA. Visceral influences on
brain and behavior. Neuron 2013;77(4):624–638. 36 McAllen RM. The cold path to BAT. Am J Physiol
doi:10.1016/j.neuron.2013.02.008. Regul Integr Comp Physiol 2007;292(1):R124–R126.
doi:10.1152/ajpregu.00651.2006.
25 Lacuey N, Hampson JP, Theeranaew W, et al.
Cortical structures associated with human blood 37 Dimicco JA, Zaretsky DV. The dorsomedial
pressure control. JAMA Neurol 2018;75(2): hypothalamus: a new player in thermoregulation.
194–202. doi:10.1001/jamaneurol.2017.3344. Am J Physiol Regul Integr Comp Physiol 2007;
292(1):R47–R63. doi:10.1152/ajpregu.00498.2006.
26 Margulies DS, Kelly AM, Uddin LQ, et al. Mapping
the functional connectivity of anterior cingulate 38 Nakamura K, Morrison SF. Central efferent
cortex. Neuroimage 2007;37(2):579–588. pathways mediating skin cooling-evoked
doi:10.1016/j.neuroimage.2007.05.019. sympathetic thermogenesis in brown adipose
tissue. Am J Physiol Regul Integr Comp Physiol
27 Barrett LF, Simmons WK. Interoceptive
2007;292(1):R127–R136. doi:10.1152/ajpregu.
predictions in the brain. Nat Rev Neurosci 2015;
00427.2006.
16(7):419–429. doi:10.1038/nrn3950.
39 Fowler CJ, Griffiths D, de Groat WC. The neural
28 LeDoux J. The amygdala. Curr Biol 2007;17(20):
control of micturition. Nat Rev Neurosci 2008;9:
R868–874. doi:10.1016/j.cub.2007.08.005.
453–466. doi:10.1038/nrn2401.
29 Ulrich-Lai YM, Herman JP. Neural regulation of
40 Panicker JN, Sakakibara R. Lower urinary tract
endocrine and autonomic stress responses.
and bowel dysfunction in neurologic disease.
Nat Rev Neurosci 2009;10(6):397–409.
Continuum (Minneap Minn) 2020;26(1, Autonomic
doi:10.1038/nrn2647.
Disorders):178–199.
30 Dampney RA. Central mechanisms regulating
41 Cersosimo MG, Benarroch EE. Neural control of
coordinated cardiovascular and respiratory
the gastrointestinal tract: implications for
function during stress and arousal. Am J Physiol
Parkinson disease. Mov Disord 2008;23(8):
Regul Integr Comp Physiol 2015;309(5):
1065–1075. doi:10.1002/mds.22051.
R429–R443. doi:10.1152/ajpregu.00051.2015.
42 Anlauf M, Schäfer MK, Eiden L, Weihe E.
31 Benarroch EE. Periaqueductal gray: an interface
Chemical coding of the human gastrointestinal
for behavioral control. Neurology 2012;78(3):
nervous system: cholinergic, VIPergic, and
210–217. doi:10.1212/WNL.0b013e31823fcdee.
catecholaminergic phenotypes. J Comp Neurol
32 Benarroch EE. Parabrachial nuclear complex: 2003;459(1):90–111. doi:10.1002/cne.10599.
Multiple functions and potential clinical
43 Travagli RA, Hermann GE, Browning KN, Rogers
implications. Neurology 2016;86(7):676–683.
RC. Brainstem circuits regulating gastric function.
doi:10.1212/WNL.0000000000002393.
Annu Rev Physiol 2006;68:279–305. doi:10.1146/
33 Cutsforth-Gregory JK, Benarroch EE. Nucleus of annurev.physiol.68.040504.094635.
the solitary tract, medullary reflexes, and clinical
implications. Neurology 2017;88(12):1187–1196.
doi:10.1212/WNL.0000000000003751.
24 FEBRUARY 2020

Autonomic History, REVIEW ARTICLE

Examination, and 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
Laboratory Evaluation
By William P. Cheshire Jr, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: Autonomic disorders offer a fascinating view of the
complexity of the nervous system. Their impact on human health ranges
from benign to severe. Deciphering autonomic symptoms and signs draws
on the cognitive skills and personal interest in the plight of patients that
first attracted many physicians to the field of neurology. This article
provides tools to sharpen those skills.
RECENT FINDINGS:Autonomic neuroscience and accumulated clinical

knowledge have led to the categorization of autonomic disorders into
specific syndromes that can be identified on the basis of clinical
phenotypes and physiologic responses to standardized stimuli in the CITE AS:
CONTINUUM (MINNEAP MINN)
autonomic laboratory. A key development has been the ability to 2020;26(1, AUTONOMIC DISORDERS):
distinguish neurogenic orthostatic hypotension from other causes of 25–43.
hypotension. Quantification of sudomotor responses has proven valuable

Address correspondence to
in the diagnosis of thermoregulatory disorders and small fiber Dr William P. Cheshire Jr, Mayo
neuropathies such as those related to diabetes mellitus. Increasing Clinic, 4500 Mellish Dr,
attention has focused on autonomic failure as a defining feature of Jacksonville, FL 32224,
cheshire@mayo.edu.
neurodegenerative α-synucleinopathies, especially multiple system
atrophy. As awareness of autonomic disorders has increased, the once RELATIONSHIP DISCLOSURE:
obscure term dysautonomia has entered into common parlance. Dr Cheshire serves as an
associate editor for Clinical
Autonomic Research and on the
SUMMARY: With appropriate knowledge and experience, neurologists can editorial boards of Autonomic
diagnose autonomic dysfunction accurately and with confidence. The Neuroscience: Basic & Clinical
and Parkinsonism & Related
opportunity to play an important role in caring for patients with autonomic Disorders. Dr Cheshire has
disorders is worth the effort. received personal
compensation for travel from
Biohaven and for speaking
engagements for Trinity
Graduate School.
INTRODUCTION
I
nnervating every organ system in the body, the autonomic nervous system UNLABELED USE OF
sustains biological homeostasis at rest and in response to stress through
USE DISCLOSURE:
an intricate network of central and peripheral neurons that function Dr Cheshire discusses the
automatically. Autonomic disorders are frequently encountered in clinical unlabeled/investigational use of
alizarin red and starch iodine for
practice. Their presentations are diverse, ranging from common to rare, from the visualization of sudomotor
benign to severe, from localized to generalized, from episodic to continuous, responses.
from transient to progressive. They can manifest in a number of ways.
Deafferentation of central autonomic centers can disrupt the magnitude or © 2020 American Academy
timing of peripheral autonomic effectors. Lesions of autonomic efferent of Neurology.

AUTONOMIC HISTORY, EXAMINATION, AND LABORATORY EVALUATION
neurons can reduce or nullify autonomic responses. Drugs or antibodies that

act on receptors on autonomic neurons can produce a variety of physiologic
phenomena from hyperfunction to hypofunction or loss of function. The
complex clinical manifestations of autonomic disorders may at first
seem enigmatic.
To make sense of autonomic disorders, the clinical evaluation of the patient
with autonomic symptoms requires an organized approach. It cannot be
overstated that the most important element of the autonomic evaluation is a
careful, detailed, nonhurried medical history. Second is the autonomic
component of the neurologic examination, and third is laboratory evaluation
directed toward the individual patient’s presentation. The goals of evaluation are
to identify whether an autonomic disorder is present, to localize and define its
distribution, and to gauge its severity. Of particular importance is to detect
serious and treatable disorders.
AUTONOMIC MEDICAL HISTORY

Taking the autonomic history is a sophisticated cognitive service that, to be
done properly, requires knowledge of neuroanatomy, neurophysiology,
neuropharmacology, neurologic diseases, and related general medical
conditions. As the autonomic nervous system is integrative, the clinical approach
to autonomic disorders should be holistic, not only in its consideration of the
complexity of the body but also in its understanding of the patient as a person.
Seldom does the patient with an autonomic concern present with a single,
clearly articulated symptom of a readily identified diagnosis that can be easily
TABLE 2-1 Common Categories of Medication That Affect Autonomic Function
Heart Rate
Blood Pressure Heart Rate Variability Sweating Peristalsis
Increase Nicotine, α1- Sympathomimetics, Unknown Opioids, serotonin Acetylcholinesterase

receptor agonists, M2 anticholinergics, norepinephrine inhibitors
mineralocorticoids, alcohol withdrawal reuptake inhibitors
ergots, alcohol (SNRIs),
withdrawal, sodium acetylcholinesterase
chloride inhibitors, cholinergic
agonists
Decrease α1-receptor β-receptor Anticholinergics, M3 anticholinergics, Opioids, M3

antagonists, α2- antagonists sympathomimetics carbonic anhydrase anticholinergics,
receptor agonists, inhibitors, tricyclic calcium channel
nitrates, calcium antidepressants, antagonists
channel neuroleptics,
antagonists, antihistamines,
diuretics, antiemetics,
angiotensin- botulinum toxin
converting enzyme
inhibitors,
phosphodiesterase
5 antagonists,
tricyclic
antidepressants
26 FEBRUARY 2020

reversed with treatment. Patients come to the neurologist with nonlinear KEY POINTS
narratives of multiple symptoms entwined with compelling personal stories. The
● Autonomic disorders are
skillful neurologist will listen attentively, remaining alert to subtle clues, common and diverse in
questioning the patient for additional information, and placing the details into character and can present
context in order to organize the facts into a coherent framework that makes sense with sustained or episodic
out of what may begin as a jumble of experiences. hypofunction or
hyperfunction of
The art of taking an autonomic history includes taking a full review of
sympathetic or
autonomic systems and identifying relevant details while knowing which parasympathetic systems.
incidental minutiae to exclude.1 Taking an autonomic history can resemble a
dance in which the neurologist and the patient gather information in partnership. ● A thoughtful autonomic
Skillful in history taking, the neurologist knows when to direct the discussion so history is the most important
component of the
that important areas of inquiry are covered. Expert in the art of medicine, the evaluation of the patient
neurologist also knows when to allow the patient to lead, telling the story in his or with autonomic symptoms.
her unique way. Patients recall their medical symptoms biographically and The art of the history
subjectively in narratives that should not be expected to conform to the outline of consists in taking a jumble of
clues and formulating a
a medical textbook. The adroit neurologist is able to distill disjointed historical coherent set of questions
fragments into a logical collection of facts, some of which explain, whereas others and conclusions.
lead to further questions. When taking notes, it can be helpful to organize the
history into sections on a page rather than constrain the patient to follow the ● Key aspects of the
autonomic history are timing
neurologist’s sequence of thought or the electronic medical record’s structure for
of onset, temporal course,
data entry. If the patient digresses as another symptom comes to mind, the associated illness or
neurologist’s pen (or keystrokes) should be nimble enough to move back and context, modifying factors,
forth across categories, filling in details as they emerge. At the end, it may be and use of medications and
dietary supplements.
helpful to summarize key elements of the history back to the patient to ensure
they have been understood correctly.
Discerning the Context

As when taking any neurologic history, it is important to define the context in
which symptoms occur. Additionally, knowledge of the anatomy, functional
organization, and biochemistry of the autonomic nervous system can, like a lens,
bring fuzzy facts into sharper focus.
A crucial part of taking the history is to delineate the temporal course of the
patient’s symptoms. Did the symptoms begin at a specific point in time, did they
evolve gradually, or have they always been present? How rapidly did they
develop? If they began suddenly, what else was happening at the time? Was a
new medication started? Did the patient have an antecedent viral illness,
potential toxic exposure, dietary change, or stressful life event? As time goes on,
are the symptoms improving or worsening?
Further questions explore modifying factors. Are the symptoms more
pronounced in the early morning or evening, while standing, during or after
meals or exercise, or when the weather is cold or hot? How long can the patient
stand without discomfort, and of what does the discomfort consist? With
continued standing, do the symptoms improve or worsen? Patients with
orthostatic intolerance may have difficulty standing for more than a few minutes
at a kitchen sink, in a warm shower, or in a waiting line. Some patients will report
being able to continue standing only if they shift their weight back and forth
from one leg to the other.
The history should explore the complete list of prescribed and over-the-
counter medications as well as dietary supplements, as these frequently can
affect autonomic function (TABLE 2-1). Because of individual genetic differences

in metabolic enzymes, some patients are exquisitely sensitive to certain drugs.

Interactions between drugs also can produce unexpected and occasionally serious
adverse effects. Which treatments have helped and which have not, at what
doses, and for how long? What, if any, side effects were encountered?
Also important is defining the impact of symptoms on the patient’s quality of
life. What activities can the patient no longer perform, or, if ability is limited, for
how long can the patient perform them? Has transient loss of consciousness
resulted in physical injury? Has impaired thermoregulation led to heat
intolerance? Has increased sweating led to social withdrawal? Has autonomic
impairment created obstacles to relationships, education, or employment? Does
the severely debilitated patient have access to adequate social and financial
resources for care?
Discerning Patterns
Dysautonomias are syndromic, depending on the part of the autonomic nervous
system involved (TABLE 2-2). Specific clinical syndromes can be recognized as
they cluster into patterns of presentation, which are described in the next few
sections. These patterns reflect the organization of the peripheral autonomic
nervous system, which consists of sympathetic, parasympathetic, and enteric
divisions.2 Specific autonomic disorders can affect these systems selectively or
in combination.
The sympathetic nervous system comprises noradrenergic, adrenergic,
and cholinergic systems, in which the primary chemical messengers are
norepinephrine, epinephrine, and acetylcholine, respectively. Sympathetic
noradrenergic and cholinergic neurons, which are nonmyelinated and slowly
conducting, derive from thoracolumbar chain ganglia. Sympathetic adrenergic
neurons are myelinated and rapidly conducting and pass through the
sympathetic ganglia without synapsing to innervate the adrenal medulla.
Parasympathetic neurons arise from the brainstem or sacral spinal cord and
are myelinated, rapidly conducting, and cholinergic. Their ganglia are near or
embedded in their target organs.
TABLE 2-2 Autonomic Syndromes
Sympathetic Parasympathetic
Function Noradrenergic Adrenergic Cholinergic Cranial Sacral
Decreased Orthostatic Fatigue, hypoglycemia Decreased Dry mouth, Urinary retention,

hypotension, lack of sweating mydriasis, male erectile failure
tachycardia, Horner constipation
syndrome
Increased Palpitations, increased Palpitations, increased Increased Salivation, Nausea, urinary

systolic blood pressure, systolic blood pressure, sweating bradycardia, frequency,
tachycardia, mydriasis, tachycardia, mydriasis, bronchial increased
sweating, cold hands, pallor, cold hands, slowed constriction, gastrointestinal
salivation, piloerection gastrointestinal transit, miosis, transit
anxiety, tachypnea, lacrimation
bronchial dilation,
hyperglycemia
28 FEBRUARY 2020

Enteric neurons, which derive from neural crest cells, are embedded in the KEY POINTS
lining of the gastrointestinal tract and consist of two types of ganglia. The
● The impact of autonomic
myenteric plexus, which controls gastrointestinal motility, receives symptoms on daily
parasympathetic innervation from the vagus nerve and sympathetic innervation functioning and quality of
from postganglionic neurons. The submucous plexus, which provides life is important. Standing
secretomotor innervation, receives parasympathetic innervation only. Both can activities may be limited,
and tolerance of heat or
function independently of the brain, spinal cord, and sympathetic and
cold may be impaired. Social
parasympathetic nerves, although are influenced by them. and job-related function
may also be impaired.
Sympathetic Noradrenergic Disorders
Failure of the sympathetic noradrenergic system presents with orthostatic ● Dysautonomias are
syndromic and cluster into
hypotension, which can be disabling. Upon standing, gravity pulls intravascular recognizable patterns of
fluid downward, causing 500 mL to 800 mL of blood to be displaced to presentation that help to
splanchnic and proximal lower extremity vascular beds (FIGURE 2-1). In organize the history and
healthy people, the autonomic nervous system promptly compensates for this. examination.
The unloading of carotid sinus baroreceptors initiates an increase in sympathetic ● Sympathetic
noradrenergic outflow, causing an increase in peripheral vasoconstrictor tone noradrenergic failure causes
and cardiac output that compensates for the displacement of blood, thereby neurogenic orthostatic
sustaining blood pressure and cerebral blood flow. When neurotransmission of hypotension, which is often
worse in the morning, in hot
norepinephrine at sympathetic postganglionic nerve terminals innervating
environments, after
peripheral blood vessels is deficient, blood pressure drops upon standing. The exercise, or after meals.
patient may report dizziness, lightheadedness, weakness, fatigue, graying or
dimming of vision, difficulty focusing thoughts, or no symptoms.3 Severe
sympathetic noradrenergic
failure is among the neurologic
deficits that characterizes
multiple system atrophy
(CASE 2-1).
A surprising aspect of
orthostatic hypotension is that
some patients do not report
symptoms despite profound
drops in blood pressure,
although they will usually insist
on sitting down, which promptly
restores blood pressure adequate
for cerebral perfusion. The
absence of expressed symptoms
may reflect accommodation to a
chronic condition or a reduced
ability of the hypoperfused brain
to register or describe symptoms.
What is important to appreciate
is that symptoms alone are FIGURE 2-1
unreliable in the diagnosis of Schema of orthostatic venous blood
orthostatic hypotension. redistribution. Upon standing, the force of gravity
Orthostatic hypotension is pulls 500 mL to 800 mL of blood downward. If
unopposed by the autonomic nervous system,
defined not by symptoms but by thoracic venous blood is redistributed toward the
an abnormal change in blood abdomen, pelvis, and proximal lower extremities,
pressure. and venous return to the heart declines.

The history should explore relationship with factors such as heat exposure,
exercise, and meals, as they can transiently exacerbate orthostatic hypotension.
Symptoms tend to be worse during the morning hours when patients may be
relatively dehydrated. Clarifying the history of medications is also important,
as vasodilators, diuretics, and alpha-blockers can unmask or worsen
orthostatic hypotension.
CASE 2-1 A 63-year-old man presented with the recent onset of hoarseness,
lightheadedness after exercising, and urinary incontinence. On further
questioning, he reported he had also experienced a gradual decline in
mobility, with slowness of gait, loss of balance when turning, and
occasional falling; urinary urgency; erectile failure; loss of fine motor
hand coordination; and dream enactment behavior. His blood pressure
while seated during check-in was reported to be normal at 150/78 mm Hg.
On examination, his blood pressure taken by the neurologist with the
patient supine was 190/94 mm Hg and his heart rate was 70 beats/min;
after 1 minute of standing, his blood pressure was 84/62 mm Hg and his
heart rate was 76 beats/min. Despite the drop in blood pressure, the
patient reported that he had no symptoms while standing, although he
insisted on sitting down. Other findings included facial hypomimia,
hypophonia with admixed dysphonia and ataxia of speech, hypometric
saccades, postural instability, anterocollis, poor tandem gait, cogwheel
rigidity, and intact tendon reflexes and primary sensory modalities.
Autonomic testing demonstrated failure of sudomotor, cardiovagal, and
noradrenergic responses.
COMMENT This case exemplifies the sporadic, neurodegenerative, and fatal α-

synucleinopathy multiple system atrophy, which is characterized by
progressive autonomic failure in combination with parkinsonian or
cerebellar features.4 Its variable presentations may mimic Parkinson
disease or late-onset cerebellar ataxia. Multiple system atrophy may be
distinguished from dementia with Lewy bodies, in most cases, by the more
severe degree of autonomic failure and absence of dementia or visual
hallucinations in multiple system atrophy. The hallmark neuropathologic
finding is proteinaceous oligodendroglial cytoplasmic inclusions. Brain MRI
may disclose atrophy of the pons, cerebellum, or striatum. Nocturnal
inspiratory stridor, if present, should be treated as it can lead to
sudden death.
Measures to treat neurogenic orthostatic hypotension include
hydration, avoidance of triggers such as rapid postural changes or large
meals, elimination of medications that can worsen hypotension, physical
countermaneuvers to increase muscle pumping of venous blood, waist-
high compressive garments to reduce venous pooling, or an abdominal
binder to compress splanchnic vessels. Medications effective for
neurogenic orthostatic hypotension include the α-adrenoceptor agonist
midodrine and the norepinephrine prodrug droxidopa.3
30 FEBRUARY 2020

When evaluating the patient who has difficulty standing, the neurologist KEY POINTS
should keep in mind a differential diagnosis that includes orthostatic hypotension
● Sympathetic
as well as nonautonomic conditions such as vertigo, postural instability, ataxia, noradrenergic hyperactivity
weakness of leg muscles that support the body against gravity, and osteoarthritis causes hypertension,
with weight-bearing musculoskeletal pain. Unlike orthostatic hypotension, tachycardia, palpitations,
vertigo manifests as a sensation of movement that is typically rotational and may pupillary dilatation, and
piloerection.
occur not only when standing but also when the patient turns over while
reclining in bed. Postural instability and ataxia, unlike orthostatic hypotension, ● Sympathetic adrenergic
improve if the patient touches furniture or leans against a wall to restore balance. failure occurs in adrenal
Lower extremity muscle weakness may be more evident during leg exertion, failure and presents with
such as rising from a chair or ascending stairs, than when standing still. Other fatigue. Sympathetic
adrenergic hyperactivity
manifestations of sympathetic noradrenergic failure can include male ejaculatory causes palpitations, dilated
failure, eyelid ptosis, and lack of piloerection in response to cold. pupils, facial pallor, palmar
Sympathetic noradrenergic hyperactivity, on the other hand, can cause sweating, and decreased
palpitations, increased blood pressure and heart rate, pupillary dilatation, or intestinal motility.
piloerection. Pallor may occur due to cutaneous blood vessel constriction. The ● Sympathetic cholinergic
history should explore any use of stimulant medications, including agents used to failure causes hypohidrosis
promote weight loss or increase mental energy. When evaluating the patient who or anhidrosis. When severe
has episodic and highly labile hypertension, the neurologist should inquire about or widespread, patients may
be at risk for heat-related
any past history of irradiation to the neck (eg, in the treatment of cancer), as
illness, including heatstroke.
damage to the carotid baroreceptors can cause disinhibition of central Anticholinergic medications
sympathetic outflow. Sympathetic noradrenergic episodic hyperactivity is also a or carbonic anhydrase
hallmark of autonomic dysreflexia (CASE 2-2). inhibitors can contribute to
anhidrosis.
Sympathetic Adrenergic Disorders

Failure of the sympathetic adrenergic system, which causes epinephrine
(adrenaline) to be released from the adrenal medulla, can result in seemingly
nonspecific symptoms of fatigue. Sympathetic adrenergic hyperactivity is
manifested by palpitations, pallor, a queasy stomach due to inhibition of peristalsis,
and dilated pupils. Circulating epinephrine also activates palmar and plantar
eccrine and axillary apocrine glands and plays a role in emotional sweating.
Sympathetic Cholinergic Disorders

Failure of the sympathetic cholinergic system causes hypohidrosis or anhidrosis,
which can impair thermoregulatory sweating, as acetylcholine is the primary
neurochemical messenger at eccrine neuroeffector junctions. When anhidrosis is
extensive, patients do not tolerate hot weather, especially when exercising, and
will report feeling hot, lightheaded, and tired. They may report headache or
prickling paresthesia in hot environments. Under conditions of heat stress,
patients who do not sweat may experience cutaneous flushing as a secondary
mechanism to release heat. These patients can be at increased risk for heat
exhaustion or the potentially serious condition of heatstroke.6 Compensatory
hyperhidrosis may occur in body regions that retain sweat function. Involvement
of postganglionic sudomotor neurons in diabetic autonomic neuropathy causes
sympathetic cholinergic deficits that may be distal, radicular, or global in
distribution (CASE 2-3).
It is important to ask about medications that can inhibit sweating,9 which
fall into two classes. Anticholinergic drugs, of which there are many, reduce
sweating by inhibiting the release of acetylcholine. Dry mouth is a common side
effect in patients taking anticholinergic medications. Carbonic anhydrase

inhibitors such as topiramate and acetazolamide may block sweat production in

the eccrine secretory coil.
Sympathetic cholinergic hyperactivity causes hyperhidrosis (increased
sweating), which is more often noticed by patients than is hypohidrosis.
Hyperhidrosis may be focal, involving the palms and soles, or it may be
generalized, often concentrated in the head, neck, and upper chest. Here also the
medication history is important, as hyperhidrosis is a common side effect of
opioids, selective serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs). Heavy sweating along with
confusion, agitation, muscle twitching, dilated pupils, increased blood pressure,
tachycardia, and diarrhea can signify serotonin syndrome in a patient who has
increased the dose of a serotonergic agent.
Parasympathetic Nervous System Disorders

Failure of the cranial component of the parasympathetic nervous system can
result in dry mouth, pupillary dilatation, increased heart rate, decreased heart
CASE 2-2 A 38-year-old man with C7 paraplegia resulting from a motor vehicle
collision 1 year earlier was hospitalized for the sudden onset of left face
and arm weakness with headache. His blood pressure was 200/110 mm Hg
and heart rate was 55 beats/min. Head CT disclosed an acute right
thalamic lacunar infarction. The onset of symptoms occurred during one
of many episodes he had experienced over the past 3 months consisting
of hypertension, bradycardia, facial flushing, blurry vision, sweating in
the face and arms, cold hands, and piloerection in the trunk and legs.
Urinary bladder catheterization obtained 500 mL of cloudy, blood-
tinged urine, after which his blood pressure subsided to 140/76 mm Hg.
Following a course of antibiotics for urinary tract infection and a daily
program of intermittent self-catheterization to prevent bladder
distension, no further episodes of hypertension occurred.
COMMENT This case illustrates the condition of autonomic dysreflexia, which occurs
to some degree in 90% of patients with severe spinal cord injuries above
the level of T6.5 Autonomic dysreflexia can rise to the level of a medical
emergency that, if not treated, may lead to myocardial infarction, stroke, or
cerebral hemorrhage. These patients lack descending neural inhibition of
spinal cord reflexes and peripheral receptors. Sudden episodes of
noradrenergic hyperfunction are triggered by sensory stimuli such as
bladder distension, urinary tract infection, kidney stones, constipation,
fecal impaction, ingrown toenail, or pressure sores. Medical procedures
can also trigger this response. The hypertension activates the carotid
baroreceptors, causing vagally mediated bradycardia. Treatment consists
of removal of the noxious stimulus, which may be mild or initially
inapparent. Short-acting antihypertensive agents such as nifedipine or
captopril may be required if blood pressure remains elevated after removal
of the offending stimulus.
32 FEBRUARY 2020

rate variability, and constipation. Failure of the sacral component can result
in urinary bladder retention or male erectile failure. Parasympathetic failure
occurs along with sympathetic noradrenergic failure in multiple system atrophy
(CASE 2-1).
Parasympathetic hyperactivity can manifest as increased salivation, slower
heart rate, nausea, and urinary frequency or urgency. Following injury to the
A 51-year-old woman presented with dizziness that occurred when CASE 2-3
standing, particularly first thing in the morning when she took a shower or
stood to dress. Her dizziness also occurred when she stood up after
exercising and, on several occasions, led to momentary collapse without
loss of consciousness. She did not endorse any sensation of rotation. Her
past medical history was significant for a 10-year history of type 2
diabetes mellitus, and her medications included amitriptyline 50 mg at
bedtime for burning feet.
Neurologic examination was notable for absent Achilles tendon jerks,
decreased sensation to pinprick below the midcalves, normal strength,
and no sign of nystagmus. Her blood pressure was 140/86 mm Hg
supine, 132/84 mm Hg seated, and 90/62 mm Hg standing, with her
heart rate in the low 80s in all postures.
Her fingerstick glucose levels during symptoms were not low; rather,
her diabetic control had been suboptimal with a recent hemoglobin A1c of
8.0%. Autonomic testing disclosed quantitative sudomotor axon reflex
test (QSART) responses that were reduced in volume at distal sites. Heart
rate variability to deep breathing was subnormal for age. Beat-to-beat
blood pressure responses to the Valsalva maneuver demonstrated
prolonged pressure recovery and absent overshoot.
This case typifies the cause of autonomic neuropathy that is most common COMMENT
in the developed world and increasing in prevalence in the developing
world. This patient has a diabetic peripheral neuropathy with evidence of
sensory, motor, and autonomic involvement. Her greatest symptoms, in
addition to acral neuropathic pain, are caused by neurogenic orthostatic
hypotension. Autonomic neuropathy occurs in approximately 70% of
patients with long-term diabetes mellitus, and 20% will develop a clinically
consequential cardiovascular autonomic neuropathy,7 which is associated
with a twofold increased risk of silent myocardial ischemia and mortality.8
Treatment of orthostatic hypotension should begin with hydration, each
morning replacing water lost during the night and, unless contraindicated
by hypertension or renal disease, sodium supplementation to expand
intravascular volume. Medications such as amitriptyline that can worsen
orthostatic hypotension should be discontinued; in this case, gabapentin
would be a reasonable alternative. Symptomatic orthostatic hypotension
refractory to conservative measures may be treated with an abdominal
binder, waist-high compressive stockings, or the α-adrenergic agonist
midodrine 5 mg to 10 mg 2 to 3 times a day during upright activities.

facial nerve from Bell’s palsy or parotid gland surgery, the patient may
experience focal gustatory sweating over the cheek as the result of aberrant
reinnervation of facial eccrine glands by parasympathetic fibers that formerly
innervated the salivary glands.
Enteric Nervous System Disorders

Disturbances of the enteric nervous system encompass a range of clinical
presentations that can include nausea, bloating, early satiety, or reflux in the
patient with gastroparesis. The patient with esophageal achalasia may report
difficulty swallowing, regurgitation, or chest pain. Constipation is a common
symptom with many potential causes; when severe, intestinal hypomotility
should be considered. Colonic pseudoobstruction from myenteric plexus
denervation, for example, causes severe constipation and abdominal distension
in the absence of mechanical obstruction.
AUTONOMIC PHYSICAL EXAMINATION

The ascertainment of objective neurologic examination findings is an
indispensable part of the evaluation of autonomic disorders. As with other
neurologic subspecialties, the autonomic neurologic examination has areas of
emphasis to be explored in detail (TABLE 2-3). The physical examination should
be informed by an intelligently gathered autonomic history.
Orthostatic Vital Signs

When evaluating the patient who develops symptoms upon standing that are
relieved by sitting down, the physical examination is incomplete without
measurement of blood pressure and heart rate while standing and comparison to
baseline values obtained seated or supine. Orthostatic hypotension cannot be
diagnosed on the basis of symptoms any more than hypertension can be.
Orthostatic hypotension is defined not by subjective symptoms, which are
frequently nonspecific or even absent, but objectively by a sustained reduction in
systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least
10 mm Hg within 3 minutes of standing.10 The condition that the reduction be
TABLE 2-3 Areas of Emphasis in the Autonomic Neurologic Examination
Autonomic
◆ Blood pressure and heart rate, supine and standing
◆ Pupillary size, symmetry, reactivity
◆ Skin coloration of the face, hands, feet
◆ Sweating, presence or absence and symmetry
Collateral
◆ Distal sensory loss
◆ Tendon reflexes
◆ Parkinsonism
◆ Cerebellar ataxia
34 FEBRUARY 2020

sustained is intended to exclude the transient reduction in blood pressure that KEY POINTS
can occur in healthy people during the first 20 to 30 seconds of standing and then
● Sympathetic cholinergic
recovers. For this reason, it is best to measure the standing blood pressure after hyperactivity causes
the patient has been standing for at least 1 minute. When the patient is unable to increased sweating.
stand for a full minute, it may be necessary to measure the blood pressure Opioids, selective serotonin
more quickly. reuptake inhibitors, and
serotonin norepinephrine
The neurologic assessment seeks to distinguish whether orthostatic
reuptake inhibitors may
hypotension is neurogenic. The systolic blood pressure drop from supine to contribute to sweating.
standing is frequently greater and the heart rate increase is less pronounced when Consider serotonin
orthostatic hypotension is neurogenic. One reason for this is that neurogenic syndrome in the patient who
has increased the dose of a
orthostatic hypotension is often accompanied by supine hypertension, defined as
serotonergic agent.
systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg
measured after at least 5 minutes of rest in the supine position.11 These factors ● Orthostatic hypotension
were taken into account in the development of the diagnostic criteria for multiple is a sustained reduction in
system atrophy, which assigns greater diagnostic confidence to a reduction in systolic blood pressure of
>20 mm Hg within 3 minutes
systolic blood pressure of at least 30 mm Hg or diastolic blood pressure of at least of standing, with or without
15 mm Hg in the context of other phenotypic features such as parkinsonism or symptoms. Orthostatic
cerebellar ataxia.12 hypotension cannot be
Some patients with orthostatic intolerance who do not have orthostatic diagnosed by symptoms
alone but requires
hypotension will exhibit an excessive increase in heart rate when standing. The measurement of blood
postural tachycardia syndrome (POTS) is defined as a sustained heart rate pressure.
increment of ≥30 beats/min within 10 minutes of standing or head-up tilt in the
absence of orthostatic hypotension.10 Transient acceleration of heart rate during ● Postural tachycardia
syndrome is a sustained
the first 15 to 30 seconds of standing is normal.2,13 For patients younger than
increase in heart rate during
20 years of age, a heart rate increment of ≥40 beats/min is required to diagnose standing or head-up tilt
postural tachycardia syndrome.14 ≥30 beats/min above
When obtaining orthostatic vital signs, the patient should rest in the supine baseline, or, for patients
posture for at least 2 minutes before baseline measurements are taken. Standing younger than 20 years of
age, ≥40 beats/min
measurements are best taken after at least 1 minute of standing, as the autonomic above baseline. The
response to standing takes 20 to 30 seconds to equilibrate.15 If orthostatic tachycardia must not be in
hypotension is not present but, on the basis of the history, is strongly suspected, response to orthostatic
then repeating standing measurements at 2 to 5 minutes may be informative.2 hypotension.
In addition to blood pressure and heart rate, further physical signs may be ● About one-third of
present upon standing. The patient with profound orthostatic hypotension orthostatic hypotension is
(eg, systolic blood pressure <80 mm Hg) may begin to lean forward, which neurogenic, as recognized
decreases the vertical distance between the heart and the circle of Willis, thereby by impaired blood pressure
responses to the Valsalva
increasing blood flow to the brain. The patient with orthostatic intolerance may
maneuver and by deficient
shift weight from one leg to the other, activating the muscle pump as contracting reflex tachycardia. Blood
the skeletal muscles compresses veins and assists venous return to the heart. pressure drops in
A key diagnostic distinction is whether orthostatic hypotension is neurogenic. neurogenic orthostatic
hypotension can also be
The majority of orthostatic hypotension occurs in patients with a normally
more profound than
functioning autonomic nervous system and is due to factors such as dehydration, orthostatic hypotension
cardiac pump failure, deconditioning, or vasoactive drugs.3 Approximately that does not have a
one-third of persistent orthostatic hypotension is neurogenic,16 resulting from neurogenic basis.
the deficient neurotransmission of norepinephrine, which is the primary
neurotransmitter released at sympathetic postganglionic nerve terminals.
Patients with neurogenic orthostatic hypotension may lack the reflex tachycardia
that occurs in other causes of orthostatic hypotension17 and, as discussed
below, have impaired blood pressure responses to the Valsalva maneuver.18
Further, systolic blood pressure changes correlate more closely with noradrenergic

failure than diastolic blood pressure changes, measurement of which can be

less accurate.13,19
Pupillomotor Signs
Pupillary light reflexes should be examined in a darkened room with the patient
gazing into the distance to avoid the pupillary constriction that occurs during
convergence. An oculosympathetic deficit decreases pupillary size and is more
apparent in dim light, whereas an oculoparasympathetic deficit increases
pupillary size and is more apparent in bright light.
A unilateral oculosympathetic deficit comprising ptosis, miosis, and facial
anhidrosis (Horner syndrome) can be an important clue to an apical lung tumor,
carotid artery dissection, cervical myelopathy, or lateral medullary stroke.
Oculoparasympathetic deficits cause an enlarged, tonic pupil. A unilateral or
bilateral tonic pupil may occur as an isolated finding (Adie pupil), with tendon
hyporeflexia (Holmes-Adie syndrome), or with tendon hyporeflexia and
anhidrosis (Ross syndrome).
Vasomotor Signs
Facial flushing occurs in many conditions, including emotional arousal,
menopause, rosacea, sunburn, anticholinergic or antiestrogen medication use,
mastocytosis, carcinoid syndrome, polycythemia vera, or niacin use, or as a
constitutional trait. Patients with global anhidrosis who are unable to sweat will
flush in response to heat stress as a way of liberating heat.6 Facial pallor is a
distinctive sign often preceding neurally mediated syncope.
Hemifacial flushing in response to heat stress, exercise, or sudden emotion in
the patient with a contralateral sympathetic deficit is known as harlequin
syndrome. The asymmetry of color across the face can be quite striking with a
vertical line demarcating red from white (FIGURE 2-2). The patient may regard
the flushing side as abnormal, but it is the sympathetically denervated pale and
dry half of the face that is truly abnormal.20
Distal arteriolar vasoconstriction may manifest as cold hands or feet in some
patients with autonomic neuropathies. Vasomotor instability leading to venous
pooling may cause red or purple erythema in the distal lower extremities.
Secretomotor Signs
Dryness of the eyes may cause slight redness of the conjunctivae and inability of
contact lenses to remain in place. This frequently occurs in Sjögren syndrome,
which is one of the causes of autonomic neuropathy. Decreased eye blinking in
Parkinson disease can also lead to dry eyes. Sjögren syndrome also causes
deficient salivation, although the most common cause of dry mouth is
anticholinergic medication. The tongue may appear dry and the lips cracked.
Sudomotor Signs
Dryness of areas of the skin that do not sweat is more easily detected by palpation
than visualization. When gently stroked, anhidrotic skin (unless lubricated with
lotion) feels rough as compared to smooth skin in which normal baseline
sweating is present. Asymmetries can be defined by palpation analogous to
mapping sensory deficits.
Focal hyperhidrosis is most easily visualized in a dimly lit room by shining a
bright light positioned just above the examiner’s eyes perpendicularly to the
36 FEBRUARY 2020

patient’s skin. Sweat droplets reflecting KEY POINT
the light will render the skin shiny. Sweat
● Harlequin syndrome
droplets can be inspected more closely consists of strikingly
with a magnifying glass or otoscope. unilateral facial flushing
provoked by heat stress.
AUTONOMIC LABORATORY The opposite side of the
face, which remains pale, is
EVALUATION
abnormal and lacks
The patient suspected of having an sympathetic vasomotor
autonomic neuropathy should undergo innervation.
routine laboratory investigations for
peripheral neuropathy. Tests to consider in
the routine evaluation of orthostatic
hypotension include serum electrolytes,
glucose, hemoglobin A1c, complete blood
cell count, serum protein electrophoresis,
morning cortisol, thyroid-stimulating
hormone (TSH), vitamin B12, and supine
and standing catecholamines (drawn
through an indwelling IV catheter or
FIGURE 2-2
needle after 30 minutes of supine rest and
A patient with harlequin syndrome. For after 10 minutes of standing). When
the past 10 years, whenever the patient neurologic examination discloses sensory
exercises in hot weather, the right side or motor deficits, nerve conduction studies
of her face flushes and sweats while
the left side remains pale and dry. No
and EMG are useful in diagnosing a
Horner syndrome is present (in some peripheral neuropathy that may also
cases, Horner syndrome may be involve autonomic fibers.
evident on the dry side). Neurologic Further tests to consider in special
examination and MRI of the brain and
cases include α3-ganglionic nicotinic
cervical spine were normal in this
patient. Quantitative sudomotor axon acetylcholine receptor antibodies
reflex testing (QSART) demonstrated (autoimmune autonomic ganglionopathy),
absent sudomotor responses in the left α-galactosidase (Fabry disease),
forearm, proximal leg, and foot,
subcutaneous fat pad biopsy or genetic
whereas sudomotor responses were
normal on the right side, consistent testing (transthyretin amyloid
with a left-sided sympathetic neuropathy), SSA and SSB antibodies
postganglionic sudomotor deficit. (Sjögren syndrome), plasma free
metanephrines (pheochromocytoma),
24-hour urine 5-hydroxyindoleacetic
acid (carcinoid syndrome), or plasma histamine (mast cell degranulation
disorder). A Schirmer test to measure tear production and the rose bengal test
of conjunctival integrity are helpful in evaluating dry eyes. Gastrointestinal
motility studies are useful in evaluating gastroparesis and colonic inertia.
Urinary bladder denervation (neurogenic bladder) can be quickly assessed
by measuring postvoid residual volumes by straight catheterization or
suprapubic ultrasound, whereas more detailed information can be obtained by
urodynamic studies.
The development of noninvasive autonomic function tests has considerably
enhanced the neurologic evaluation of autonomic disorders beyond what the
history and physical examination achieve. The types of testing vary among
centers, which may emphasize physiologic, neurochemical, or neuroimaging
batteries of tests. Most neurology practices that perform autonomic testing

focus on standard tests of sudomotor (sympathetic cholinergic), cardiovagal

(parasympathetic), and noradrenergic (sympathetic cardiovascular) function.
In 2014, the American Academy of Neurology published a position statement
on autonomic testing, including the recommendation that physicians who
interpret autonomic test results have appropriate training in autonomic
disorders.21 The United Council of Neurologic Subspecialties has established
an autonomic disorders board examination as a method to certify such
expertise (www.ucns.org).
Sudomotor Testing
A number of tests have been developed for assessing sudomotor dysfunction.
Well-established normative values and clinical guidelines exist for the quantitative
sudomotor axon reflex test (QSART), which evaluates sudomotor nerves at four
standard sites in a quantitative and reproducible manner.22 The test involves
iontophoresis of acetylcholine at the skin surface, which activates an axon reflex
mediated by the postganglionic sympathetic sudomotor axon. The impulse
generated travels antidromically, reaching a branch point in the peripheral nerve,
and from there travels orthodromically to evoke a sudomotor response in adjacent
eccrine glands. The evoked response is measured by the moisture detected over
time in a capsule placed over the skin. QSART and variations thereof are a
sensitive method for detecting small fiber peripheral neuropathies23 and are
recommended in the evaluation of autonomic neuropathy in diabetes mellitus.21
The thermoregulatory sweat test evaluates the anatomic distribution of sweating
as the patient’s body is gradually heated under conditions of controlled temperature
and humidity. Whereas an abnormal QSART localizes to the postganglionic
sudomotor neuron or eccrine sweat gland, an abnormal thermoregulatory sweat
test results from a lesion anywhere along the thermoregulatory pathway from
the brain to the spinal cord, to preganglionic nerves, to sympathetic ganglia, and
to postganglionic nerves. Visualization of sweating patterns is aided by topical
application of a dye that changes color when wet, such as alizarin red mixed in
cornstarch and sodium carbonate. Starch iodine is sometimes used to evaluate
focal sudomotor disorders. Some laboratories use the sympathetic skin response,
which detects emotional rather than thermoregulatory sweating, or silicone
impression techniques, which evaluate localized sweating.
It is important to perform sudomotor tests in the absence of medications that
inhibit sweating, which is mediated by M3 acetylcholine receptors. Otherwise a
medication effect may be indistinguishable from an autonomic neuropathy. Among
M3 receptor antagonists are numerous medications, the most potent of which
include atropine, hyoscyamine, oxybutynin, glycopyrrolate, amitriptyline,
diphenhydramine, and tolterodine. Carbonic anhydrase inhibitors, including
topiramate, zonisamide, and acetazolamide, may also inhibit sweating, particularly
in children. Patients vary in the degree to which drugs alter sudomotor responses.
A reasonable practice is to withhold these medications for three to five elimination
half-lives, when safe to do so, in preparation for sudomotor testing.6
Cardiovagal Testing
The parasympathetic (vagus nerve) influence on heart rate is assessed by the
heart rate response to deep breathing or by the Valsalva ratio. The R-R intervals
on a single-lead ECG tracing are converted to beat-to-beat heart rate, which is
traced along with respiration. Heart rate response to deep breathing is measured
38 FEBRUARY 2020

by having the patient inspire and expire deeply at a frequency of 6 breaths/min. KEY POINTS
The mean of a series of differences in maximum and minimum heart rate is a
● Physicians who perform
sensitive index of cardiovagal function. Its magnitude declines with advancing autonomic testing should be
age, and it is suppressed by sympathetic activation. Sensitivity is greatest when knowledgeable about the
the patient is supine and relaxed. autonomic nervous system
For the Valsalva maneuver, the recumbent patient is asked to exhale against and its disorders.
resistance and maintain a column of mercury at 30 mm Hg to 40 mm Hg for
● The quantitative
15 seconds. The Valsalva ratio is derived from the beat-to-beat heart rate tracing sudomotor axon reflex
and consists of the maximum heart rate divided by the lowest heart rate within test evaluates distal
30 seconds of peak heart rate. postganglionic sudomotor
Power spectrum analysis of ECG signals has also been used to estimate neurons innervating eccrine
glands. This test is a
cardiovagal function. Heart period (the reciprocal of heart rate) oscillations at sensitive method for
approximately 0.25 Hz correlate with parasympathetic function, and patients detecting small fiber
with cardiovagal failure will show attenuation of the power spectrum at this peripheral neuropathies,
frequency. Alterations are sometimes reported in conjunction with low- but the results can be
confounded by medications
frequency power spectra as an index of “sympathovagal balance,” which is an that inhibit sweating. Such
oversimplified concept that is not universally accepted, as the meaning of the medications should be
low-frequency power spectrum remains unclear. withheld in advance of testing
when it is safe to do so.
Vasomotor Adrenergic Testing
● A sensitive test of
Dynamic changes in blood pressure during the Valsalva maneuver are a valuable cardiovagal function is the
index of baroreflex-sympathoneural function. These changes occur too quickly variation in heart rate with
to capture by arm cuff sphygmomanometry but require a finger cuff that tracks sinusoidal deep breathing,
which assesses respiratory
beat-to-beat blood pressure noninvasively. Whereas the term “adrenergic”
sinus arrhythmia. Another
function is often applied, baroreflex-sympathoneural function is noradrenergic method is the Valsalva ratio,
(TABLE 2-2) and should be distinguished from adrenomedullary adrenergic which is the maximum heart
function. rate divided by the minimum
The Valsalva maneuver is a key test for distinguishing neurogenic orthostatic heart rate in response to
straining.
hypotension from other causes of orthostatic hypotension.3,18 In patients with
neurogenic orthostatic hypotension, the blood pressure responses to the Valsalva ● The Valsalva maneuver
maneuver are impaired. consists of four phases.
The Valsalva maneuver is divided into four phases (FIGURE 2-3). In phase I, Phases I and III are
mechanical and occur
increased intrathoracic pressure at the onset of straining causes a brief at the beginning
mechanical rise in arterial pressure as the aorta is compressed. In early phase II, and end of straining.
the thoracic pressure gradient reduces cardiac filling, leading to a decline in Baroreflex-sympathoneural
stroke volume and cardiac output. The sympathetic response is first seen in late (noradrenergic
cardiovascular) function is
phase II, as the progressive decline in beat-to-beat blood pressure unloads carotid
assessed by how quickly
baroreceptors, which signal the brainstem to drive sympathetic noradrenergic and completely the blood
outflow. This causes an increase in peripheral vasoconstrictor tone, cardiac rate, pressure recovers during
and inotropic force. In a healthy person, blood pressure recovers nearly to phases II and IV and
overshoots in phase IV in
baseline, but in baroreflex-sympathoneural failure, late phase II blood pressure
response to the drop in
recovery is deficient or absent. In phase III, release of straining and normalization blood pressure early in
of intrathoracic pressure causes a brief mechanical fall in blood pressure. In phase II that occurs in
phase IV, cardiac filling returns to normal, but in the context of reflexively response to straining.
constricted peripheral vasculature, an overshoot in blood pressure occurs. The
patient with baroreflex-sympathoneural failure lacks this blood pressure
overshoot, and the time for blood pressure to recover to baseline (the pressure
recovery time) is delayed.
Another measure of vasomotor adrenergic testing is the tilt-table test, which is
useful in the assessment of orthostatic hypotension, orthostatic intolerance,

FIGURE 2-3
Beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver. A, In a
healthy individual, the decrease in blood pressure during early phase II (IIE) recovers during
late phase II (IIL) as the heart rate gradually increases, as indications of noradrenergic
sympathetic outflow. During phase IV, blood pressure returns rapidly to baseline and then
overshoots as cardiac output increases in the presence of peripheral vasoconstriction.
Parasympathetic vagal activation causes a decrease in heart rate. B, In a patient with multiple
system atrophy with autonomic failure, the decrease in blood pressure during phase IIE
persists without recovery during IIL. During phase IV, a long delay of 20 seconds for blood
pressure to return to baseline is seen and no overshoot is seen. Very little sympathic
cardioacceleration or parasympathetic bradycardia is seen.
and unexplained syncope.13 The methodology should include continuous

beat-to-beat monitoring of blood pressure and heart rate. The conditions and
duration of tilt-table testing are determined by the clinical question being
asked. During passive head-up tilting to 70 degrees, a transient decrease in
blood pressure and increase in heart rate normally occurs and recovers to
baseline within 30 seconds. In patients with baroreflex-sympathoneural
failure, blood pressure does not recover but may decline further, and the heart
rate response is decreased. A tilt duration of 5 minutes is sufficient to establish
neurogenic orthostatic hypotension, but in the evaluation of disorders of
delayed orthostatic intolerance, including syncope, a longer duration of tilt is
often necessary.13
Tilt-table testing differs significantly from active standing. The table supports
the patient in maintaining an upright posture, thus reducing activation of leg
muscles that, when contracted, compress or pump the veins and facilitate return
of blood to the heart. Its value lies in the ability to assess autonomic responses to
orthostatic stress independently of skeletal muscle activation.
By contrast, active standing in healthy persons causes a larger transient
decrease in blood pressure and increase in heart rate as compared to passive
40 FEBRUARY 2020

head-up tilt. The decrease in blood pressure during active standing is driven by KEY POINTS
reflex peripheral vasodilatation in response to activation of low-pressure
● Not all tilt-table tests are
cardiopulmonary baroreflexes as muscle contraction enables venous blood in the the same, but the duration
abdomen and lower extremities to return to the heart.13 and conditions of the test
are adjusted to the goals of
Trends the test. A duration of
5 minutes is sufficient to
Access to personal autonomic nervous system data is no longer within the
establish neurogenic
exclusive purview of clinicians and scientists. Increasingly, portable or wearable orthostatic hypotension.
nonmedical devices are displaying heart rate or blood pressure data to patients in Longer durations of tilt are
their daily lives. These devices can be useful diagnostically as they allow patients needed when assessing
orthostatic intolerance and
to correlate their symptoms with real-time cardiovascular data and in
syncope.
management as an indicator of their response to treatment. They also introduce
potential problems for the patient who, lacking medical knowledge, ● Personal health devices
misinterprets normal physiologic variations or artifacts as a dysautonomia. that display autonomic data
Frequent checking of heart rate or blood pressure values may exacerbate anxiety such as heart rate and blood
pressure are increasingly
in patients predisposed to somatic hypervigilance. available to patients. Such
In the medical office setting, a number of simplified automated testing devices data have become part of
have entered the market with claims of evaluating the autonomic nervous system the autonomic evaluation.
without physician interpretation. Some of these devices include software that The numbers can be useful,
but they can also be
automatically generates a diagnosis or even treatment recommendations. misinterpreted.
Neurologists should be aware that such devices have not been scientifically
validated, omit necessary components of testing, and are known to generate ● Dysautonomia is not a
erroneous results.21 specific diagnosis but rather
a broad category. No one
universal treatment exists
EXPLAINING THE DIAGNOSIS for “dysautonomia.”
Drawing from knowledge about the autonomic nervous system to provide the Treatment decisions must
patient with an explanation for baffling symptoms can be quite rewarding. It is be directed to the patient’s
crucial to understand the patient’s expectations. Establishing an autonomic specific diagnosis and
condition.
diagnosis can potentially obviate the need for further medical testing in the
search for other disorders. Whether symptoms can be explained or not, there is
value in listening to patients and letting them know they have been heard and
their symptoms have been taken seriously. Such discussions require not only
knowledge but also the ability to express complex neurologic phenomena in plain
language with humility and a nonjudgmental attitude.
Medical terminology can be confusing, particularly when practitioners use it
differently. It must be remembered that orthostatic hypotension is a physical
sign, not a symptom, and should be based on objective measurements of blood
pressure. Further, the term dysautonomia is not a specific diagnosis, but rather a
category, as is weakness or gait unsteadiness. An accurate diagnosis on which to
base appropriate treatment decisions requires further clarification.
A multitude of symptoms does not necessarily mean that the patient’s
symptoms are always psychological. Also, physiologic symptoms mediated
through autonomic nerves or that arouse autonomic responses in the patient with
an intact and normally functioning autonomic nervous system do not necessarily
indicate a dysautonomia.
CONCLUSION
The approach to evaluating the patient with an autonomic disorder has never
before been as scientifically grounded and diagnostically fruitful as it is today.

Characterization of distinct autonomic disorders has led to the recognition of

specific disease patterns in clinical practice. The availability of noninvasive
autonomic reflex testing has provided objective measures of autonomic
phenomena that can be difficult to discern on physical examination or to define
adequately on the basis of a subjective history.
Despite these gains, each neurologic discovery has led to more questions to
be answered. There remains an educational gap to be bridged so that more
neurologists and other health care professionals can recognize autonomic
disorders and know how to evaluate and manage them appropriately. Much
remains to be done also in the development of more effective treatments for
patients with autonomic disorders.
USEFUL WEBSITES
AMERICAN AUTONOMIC SOCIETY THE MULTIPLE SYSTEM ATROPHY COALITION
The American Autonomic Society is a The Multiple System Atrophy Coalition is a volunteer
multidisciplinary professional society that brings organization dedicated to education, research
together clinicians and researchers who share an funding, and advocacy for patients with multiple
interest in the structure and function of the system atrophy and their families.
autonomic nervous system and in the pathology, multiplesystematrophy.org/
treatment, and prevention of its disorders.
americanautonomicsociety.org
REFERENCES
1 Goldstein DS, Cheshire WP Jr. The autonomic 9 Cheshire WP, Fealey RD. Drug-induced
medical history. Clin Auton Res 2017;27(4): hyperhidrosis and hypohidrosis: incidence,
223–233. doi:10.1007/s10286-017-0425-7. prevention, and management. Drug Saf 2008;
31(2):109–126. doi:10.2165/00002018-200831020-
2 Cheshire WP, Goldstein DS. The physical
00002.
examination as a window into autonomic
disorders. Clin Auton Res 2018;28(1):23–33. 10 Freeman R, Wieling W, Axelrod FB, et al.
doi:10.1007/s10286-017-0494-7. Consensus statement on the definition of
orthostatic hypotension, neurally mediated
3 Cheshire WP. Chemical pharmacotherapy for the
syncope and the postural tachycardia syndrome.
treatment of orthostatic hypotension. Expert
Clin Auton Res 2011;21:69–72. doi:10.1007/s10286-
Opin Pharmacother 2019;20(2):187–199. doi:
011-0119-5.
10.1080/14656566.2018.1543404.
11 Gilman S, Wenning GK, Low PA, et al. Second
4 Fanciulli A, Wenning GK. Multiple system atrophy.
consensus statement on the diagnosis of
N Engl J Med 2015;372:249–263. doi:10.1056/
multiple system atrophy. Neurology 2008;71(9):
NEJMra1311488.
670–676. doi:10.1212/01.wnl.0000324625.
5 Cragg J, Krassioukov A. Autonomic dysreflexia. 00404.15.
CMAJ 2012;184(1):66. doi:10.1503/cmaj.110859.
12 Fanciulli A, Jordan J, Biaggioni I, et al. Consensus
6 Cheshire WP. Thermoregulatory disorders and statement on the definition of neurogenic supine
illness related to heat and cold stress. Auton hypertension in cardiovascular autonomic failure
Neurosci 2016;196:91–104. doi:10.1016/j. by the American Autonomic Society (AAS) and
autneu.2016.01.001. the European Federation of Autonomic Societies
(EFAS): endorsed by the European Academy of
7 Zhou Y, Ke SJ, Ziu XP, et al. Prevalence, risk
Neurology (EAN) and the European Society of
factors, and prognosis of orthostatic hypotension
Hypertension (ESH). Clin Auton Res 2018;28(4):
in diabetic patients: a systematic review and
355–362. doi:10.1007/s10286-018-0529-8.
meta-analysis. Medicine (Baltimore) 2017;96:
e8004. doi:10.1097/MD.0000000000008004. 13 Cheshire WP, Goldstein DS. Autonomic uprising:
the tilt table test in autonomic medicine. Clin
8 Maser RE, Mitchell BD, Vinik AI, Freeman R. The
Auton Res 2019;29(2):215–230. doi:10.1007/
association between cardiovascular autonomic
s10286-019-00598-9.
neuropathy and mortality in individuals with
diabetes: a meta-analysis. Diabetes Care 2003;
26:1895–1901. doi:10.2337/diacare.26.6.1895.
42 FEBRUARY 2020

14 Singer W, Sletten DM, Opfer-Gehrking TL, et al. 19 Fedorowski A, Hamrefors V, Sutton R, et al. Do
Postural tachycardia in children and adolescents: we need to evaluate diastolic blood pressure in
what is abnormal? J Pediatr 2012;160(2):222–226. patients with suspected orthostatic hypotension?
doi:10.1016/j.jpeds.2011.08.054. Clin Auton Res 2017;27(3):167–173. doi:10.1007/
s10286-017-0409-7.
15 Soysal P, Aydin AE, Okudur SK, Isik AT. When
should orthostatic blood pressure changes be 20 Cheshire WP Jr, Low PA. Harlequin syndrome: still
evaluated in elderly: 1st, 3rd, or 5th minute? Arch only half understood. J Neuroophthalmol 2008;
Gerontol Geriatr 2016;65:199–203. doi:10.1016/j. 28(3):169–170. doi:10.1097/WNO.0b013e318183c1a0.
archger.2016.03.022.
21 Gibbons CH, Cheshire WP. Fife TD. American
16 Goldstein DS, Sharabi Y. Neurogenic orthostatic Academy of Neurology model coverage policy
hypotension: a pathophysiological approach. autonomic testing. aan.com/siteassets/home-
Circulation 2009;119(1):139–146. doi:10.1161/ page/tools-and-resources/practicing-
CIRCULATIONAHA.108.805887. neurologist–administrators/billing-and-coding/
model-coverage-policies/14autonomicmodel_tr.
17 Norcliffe-Kaufmann L, Palma JA, Kaufmann H.
pdf. Published October 2014. Accessed
A validated test for neurogenic orthostatic
November 22, 2019.
hypotension at the bedside. Ann Neurol 2018;
84(6):959–960. doi:10.1002/ana.25362. 22 Illigens BM, Gibbons CH. Sweat testing to
evaluate autonomic function. Clin Auton Res
18 Goldstein DS, Cheshire WP. Beat-to-beat blood
2009;19(2):79–87. doi:10.1007/s10286-008-0506-8.
pressure and heart rate responses to the
Valsalva maneuver. Clin Auton Res 2017;27(6): 23 Low VA, Sandroni P, Fealey RD, Low PA.
361–367. doi:10.1007/s10286-017-0474-y. Detection of small-fiber neuropathy by
sudomotor testing. Muscle Nerve 2006;34:57–61.
doi:10.1002/mus.20551.

REVIEW ARTICLE

Autoimmune Autonomic
ONLINE
Disorders
By Steven Vernino, MD, PhD, FAAS, FAAN
ABSTRACT
PURPOSE OF REVIEW:Autonomic disorders sometimes occur in the context of
systemic autoimmune disease or as a direct consequence of autoimmunity
against the nervous system. This article provides an overview of autonomic
disorders with potential autoimmune etiology.
RECENT FINDINGS: Recent evidence highlights a close association between the

autonomic nervous system and inflammation. The autonomic nervous
CITE AS: system regulates immune function, and autonomic manifestations may
occur in a number of systemic autoimmune diseases. In a few instances,
44–57. autoimmunity directly influences autonomic function. Autoimmune
autonomic ganglionopathy is the prototypic antibody-mediated autonomic
Address correspondence to disorder. Over time, a better understanding of the clinical spectrum of
Dr Steven Vernino, University
of Texas Southwestern autoimmune autonomic ganglionopathy, the significance of ganglionic
Department of Neurology and nicotinic acetylcholine receptor antibodies, other immune-mediated
Neurotherapeutics, 5323 Harry
autonomic neuropathies, and autonomic manifestations of other systemic
Hines Blvd, Dallas, TX 75390,
steven.vernino@utsouthwestern. or neurologic autoimmune disorders has emerged.
edu.
SUMMARY: Autoimmune autonomic disorders may be challenging, but
Dr Vernino serves on the board correct identification of these conditions is important. In some cases,
of directors of the American potential exists for effective immunomodulatory treatment.
Autonomic Society; the scientific
advisory boards of Argenx,
Dysautonomia International, and
The Multiple System Atrophy INTRODUCTION
Coalition; and the editorial
I
boards of Autonomic mpairment of autonomic function occurs in a number of clinical contexts.
Neuroscience: Basic & Clinical Etiologies of autonomic failure discussed elsewhere in this issue include
and Clinical Autonomic Research.
Dr Vernino receives
neurodegenerative disorders and acquired peripheral autonomic neuropathies,
research/grant support from such as diabetes mellitus. Autonomic dysfunction can also occur in the context
Dysautonomia International; of systemic autoimmune or inflammatory conditions, and, in some cases, the
Genentech, Inc; Grifols, SA; the
Rex Griswold Foundation; and
autonomic nervous system is the primary target for autoimmunity. This article
Theravance and licensing fees to highlights the interaction between the immune system and the autonomic nervous
support his laboratory from system and discusses autonomic disorders with proven or putative autoimmune
Quest Diagnostics Inc.
etiology (TABLE 3-1). Some autoimmune autonomic disorders may benefit from
UNLABELED USE OF immunomodulatory treatment. Additionally, awareness of autonomic
manifestations in other autoimmune neurologic disorders or systemic
USE DISCLOSURE:
Dr Vernino discusses the rheumatologic disorders is important for effective clinical care.
unlabeled/investigational use of
immunomodulatory treatments
for autoimmune disorders. THE INTERPLAY BETWEEN THE AUTONOMIC NERVOUS SYSTEM AND
IMMUNE FUNCTION
© 2020 American Academy
The principal role of the autonomic nervous system is to maintain homeostasis and
of Neurology. optimize the physiologic state of the body. Over the past decade, understanding
44 FEBRUARY 2020

of the influence of the autonomic nervous system on immune function has
increased. Cross talk between the autonomic and immune systems is critical for
regulating host defense against injury or infection; however, dysregulation in this
neuroimmune interaction could perpetuate chronic inflammatory/autoimmune
disorders.
The vagus nerve provides a bidirectional communication pathway between the
brain and immune system (FIGURE 3-1). The vagal cholinergic anti-inflammatory
pathway reduces inflammation through activation of α7-type acetylcholine (ACh)
receptors on splenic macrophages.1 Sympathetic nerve activity also modulates
inflammation, but in a more complex way. Circulating norepinephrine and
epinephrine tend to accentuate local inflammation, whereas sympathetic
innervation of the spleen via the splenic nerve may contribute to the anti-
inflammatory reflex.2 In the setting of chronic systemic inflammation (as in
systemic autoimmune diseases, hypertension, chronic infection, or malignancy),
persistent activation of the sympathetic nervous system may contribute
to symptoms.3
Over the past few decades, recognition of neurologic disorders caused by
specific neurologic autoimmunity has been increasing. The prototypical example
of an antibody-mediated neurologic disorder is myasthenia gravis caused by
antibodies against the muscle-type ACh receptor. Antibodies against antigens
associated with the peripheral autonomic nervous system have also been
identified, as described in the following section.
AUTOIMMUNE AUTONOMIC GANGLIONOPATHY

The first cases of probable autoimmune autonomic failure were published in
the early 1970s.4 For many years, these rare cases were thought to be cases of
“pure autonomic” Guillain-Barré syndrome or instances of exposure to an
unidentified autonomic toxin. A larger case series of idiopathic autonomic
Autoimmune Autonomic Disorders TABLE 3-1
Autonomic Disorders With Definite Autoimmune Etiology

◆ Autoimmune autonomic ganglionopathy
◆ Paraneoplastic autonomic/enteric neuropathy
◆ Lambert-Eaton myasthenic syndrome
Autonomic Disorders With Possible Autoimmune Etiology
◆ Immune-mediated sensory and autonomic neuropathies
◆ Postural tachycardia syndrome
Other Autoimmune Disorders With Prominent Autonomic Features
◆ Guillain-Barré syndrome
◆ N-methyl-D-aspartate (NMDA) receptor encephalitis
◆ Leucine-rich glioma inactivated protein 1 (LGI1) and contactin-associated proteinlike 2
(CASPR2) antibody disorders (including Morvan syndrome)
◆ Dipeptidyl-peptidase–like protein 6 (DPPX)–associated encephalitis
◆ Sjögren syndrome

AUTOIMMUNE AUTONOMIC DISORDERS
FIGURE 3-1
The interplay between the autonomic nervous system and inflammation. The parasympathetic
and sympathetic nervous systems provide important regulation of immune function. The
best characterized pathway is the cholinergic anti-inflammatory reflex involving the vagus
nerve. Autonomic innervation of the spleen (and other immune organs) by the vagus and
sympathetic splenic nerves downregulate inflammation. Conversely, inflammatory cytokines
and visceral afferents provide information to the central nervous system (CNS) about
inflammation in the body. The autonomic responses are complex. Chronic inflammation
can promote an activation of sympathetic activity as well as activation of the cholinergic
anti-inflammatory reflex.
IL-6 = interleukin 6; TNF-α = tumor necrosis factor-α.
neuropathy in 1994 suggested the possibility of an immune-mediated neuropathy

restricted to the autonomic nerves.5
Autoantibodies specific for the ganglionic nicotinic ACh receptor are
identified in association with some cases of subacute panautonomic failure; this
entity has been called autoimmune autonomic ganglionopathy. About 50% of
patients with autoimmune autonomic ganglionopathy have high levels of
ganglionic nicotinic ACh receptor antibodies.6 The ganglionic nicotinic ACh
receptor mediates synaptic transmission in all autonomic ganglia. Antibodies
against the ganglionic nicotinic ACh receptor have been proven to cause
autonomic failure in both active immunization and passive transfer animal
models.7–9 Transient neonatal autoimmune autonomic ganglionopathy has also
been described due to placental transfer of maternal antibodies.10
Patients with autoimmune autonomic ganglionopathy typically present in the
fifth to seventh decades of life, although cases in children or the elderly have
been identified. The disease classically follows an acute or subacute course,
but some cases show a slow insidious onset that can suggest the diagnosis of a
neurodegenerative autonomic disorder. Characteristic features of autoimmune
autonomic ganglionopathy include orthostatic hypotension and lower
gastrointestinal symptoms (constipation) in 70% of patients.11 Prominent
cholinergic failure (dry mouth and dry eyes, urinary retention, and impaired
pupil responses) are also commonly present and help differentiate autoimmune
autonomic ganglionopathy from peripheral autonomic neuropathy or
46 FEBRUARY 2020

neurodegenerative disorders. Ganglionic nicotinic ACh receptor antibody levels KEY POINTS
correlate with disease severity.6,12,13 Antibody levels greater than 1.0 nmol/L are
● The autonomic nervous
fairly specific for autoimmune autonomic ganglionopathy,14,15 and these high system regulates
antibody levels correlate with more severe orthostatic hypotension and with inflammation through a
characteristic pupillary constriction abnormalities (CASE 3-1).12,18 A minority of cholinergic anti-
patients with autoimmune autonomic ganglionopathy report sensory inflammatory reflex.
symptoms5; the frequency of paresthesia is reported to be as high as 46% in
● Some cases of
reports from Japan.19 However, objective evidence of sensory or motor nerve autoimmune autonomic
involvement is not found on clinical examination or neurophysiology. Cognitive failure are associated with
impairment has been reported in a minority of patients,14,20 and psychiatric antibodies against the
symptoms have been reported in case series from Japan.19 ganglionic nicotinic
acetylcholine receptor.
Autoimmune autonomic ganglionopathy is a rare disease. High levels of
ganglionic nicotinic ACh receptor antibody (greater than 1.0 nmol/L) are quite ● Synaptic transmission in
specific for autoimmune autonomic ganglionopathy. Intermediate antibody all autonomic ganglia
levels are seen in a variety of other scenarios, including chronic slowly requires acetylcholine and
the ganglionic nicotinic
progressive autoimmune autonomic ganglionopathy and restricted autonomic acetylcholine receptor.
failure such as isolated gastrointestinal dysmotility.14,21 Low levels of ganglionic
nicotinic ACh receptor antibody (less than 0.2 nmol/L) are quite nonspecific14,15; ● Autoimmune autonomic
low levels may be found in 2% to 4% of healthy controls and in patients with ganglionopathy is an
antibody-mediated disorder
unrelated neurologic diseases,22 including patients with peripheral neuropathy,
caused by antibodies to the
systemic autoimmune diseases, and postural tachycardia syndrome (POTS). ganglionic nicotinic
Since ganglionic nicotinic ACh receptor antibody testing has become widely acetylcholine receptor.
available, retrospective data indicate that the majority of low-positive ganglionic
nicotinic ACh receptor antibody results are not associated with neurologic ● Features of autoimmune
autonomic ganglionopathy
disorders.14,15 include prominent
In seropositive cases of autoimmune autonomic ganglionopathy, some cholinergic failure,
partial spontaneous remission may be seen, but immunotherapy appears to be orthostatic hypotension,
associated with more dramatic benefit. IV immunoglobulin (IVIg) and plasma and abnormal pupillary light
responses.
exchange have shown benefit in case reports and small series.17,23 Longer-term
benefit may be achieved by combining these acute therapies with oral ● Paresthesia (but not pain)
immunosuppressants.24 Rituximab has also been reported to produce good occurs in autoimmune
results in several individual case reports.25–27 Additionally, management of the autonomic ganglionopathy
without objective evidence
symptoms of autonomic failure should be included in the treatment program.
of sensory neuropathy.
This includes pharmacologic and nonpharmacologic management of orthostatic
hypotension, urinary retention, constipation, heat intolerance, and sicca ● Low levels of ganglionic
symptoms. nicotinic acetylcholine
receptor (<0.2 nmol/L)
antibody are nonspecific
LIMITED AUTOIMMUNE AUTONOMIC NEUROPATHY and should not be
AND GANGLIONOPATHY considered diagnostic of an
Limited presentations of autonomic failure have also been associated with autoimmune autonomic
ganglionic nicotinic ACh receptor antibodies, generally with intermediate disorder.
antibody levels ranging from 0.2 nmol/L to 1.0 nmol/L.11,14,28 Seropositivity has
● Immunotherapy may be
been documented in 10% of patients with idiopathic gastrointestinal dysmotility6 beneficial for autoimmune
and as many as 50% of patients with chronic intestinal pseudoobstruction (bowel autonomic ganglionopathy.
dilation and impaired motility without mechanical obstruction).29 Patients with
chronic orthostatic hypotension, clinically similar to pure autonomic failure, may
have positive antibodies and respond to immunotherapy.11,17
Other limited forms of presumed autoimmune autonomic failure have also
been described. Although typically a manifestation of Lambert-Eaton myasthenic
syndrome (LEMS) or Sjögren syndrome, isolated cholinergic neuropathy without

evidence of sympathetic vasomotor dysfunction has been reported.30 These

patients are occasionally positive for ganglionic nicotinic ACh receptor antibodies
at low titers.28 Idiopathic anhidrosis presents with heat intolerance due to
inadequate sweating, with symptoms including skin flushing, lightheadedness,
rash (cholinergic urticaria), and hyperhidrosis of areas with preserved sweat
function (face, axillae, palms, and soles). The condition may respond to steroids,
particularly if administered early in the course.31 This condition is not associated
with ganglionic nicotinic ACh receptor antibodies.21
CASE 3-1 A 76-year-old woman presented with chronic orthostatic

lightheadedness and frequent near-syncope. She related a long history
of dry mouth and dry eyes and had been given a clinical diagnosis of
Sjögren syndrome 20 years earlier. She reported severe constipation for
10 years; without medication, she had bowel movements only once every
4 to 5 days. Three years before presentation, she developed orthostatic
lightheadedness and frequent urinary tract infections. She was found to
have urinary retention with overflow incontinence. Medications for
urinary symptoms were not successful, and chronic intermittent urinary
catheterization was required. When symptomatic, her standing systolic
blood pressure was recorded at 60 mm Hg to 70 mm Hg. Fludrocortisone
and midodrine had been prescribed, but she did not tolerate them
because of side effects.
She denied numbness, paresthesia, or muscle weakness but reported a
general feeling of weakness when standing. She denied any history of
tremor, sleep disturbance, cognitive impairment, or loss of smell.
Aside from sluggish pupillary light reaction, the general neurologic
examination was normal. On autonomic testing, the quantitative
sudomotor axon reflex test (QSART) results were reduced at all sites.
Heart rate variability to deep breathing and Valsalva was markedly
impaired, and the adrenergic blood pressure response to Valsalva was
severely impaired with delayed pressure recovery time during phase IV
(FIGURE 3-2A). On tilt-table testing, her supine blood pressure was
162/79 mm Hg with a heart rate of 65 beats/min. After 5 minutes of head-up
tilt, her blood pressure fell to 95/59 mm Hg with a heart rate of 60 beats/
min. Quantitative pupillometry revealed premature pupillary dilation
(FIGURE 3-2B). Her composite autonomic severity score was 9 (out of 10).
Serum ganglionic nicotinic acetylcholine (ACh) receptor antibodies
were present at high levels (30.5; normal <0.05 nmol/L). Initial treatment
with plasma exchange was followed by maintenance therapy with
pyridostigmine, oral prednisone, and mycophenolate mofetil. Over time,
her orthostatic symptoms and sicca symptoms improved. Constipation and
urinary retention remained problematic. After several years, concerns over
recurrent pulmonary infections led to discontinuation of mycophenolate
mofetil. Her autonomic symptoms worsened, and her ganglionic nicotinic
ACh receptor antibody level continued to be highly elevated, so treatment
with anti-CD20 therapy was started. Again, her autonomic symptoms
improved, and she was able to resume nearly normal upright activity.
48 FEBRUARY 2020

IMMUNE-MEDIATED AUTONOMIC AND SENSORY NEUROPATHY
Other cases of idiopathic and subacute autonomic neuropathy are associated
with more definitive features of sensory neuropathy and generally are not
associated with ganglionic nicotinic ACh receptor antibodies. These seronegative
cases do not show the prominent cholinergic symptoms, urinary retention, and
pupillary abnormalities seen in patients with seropositive autoimmune
autonomic ganglionopathy.32 Sensory symptoms, including neuropathic pain,
are more commonly seen, along with objective evidence of small or large fiber
FIGURE 3-2
Autonomic testing in autoimmune autonomic ganglionopathy. A, Systolic and diastolic blood
pressure and heart rate response to 15-second Valsalva maneuver. Normal response shows
blood pressure recovery during late phase II and rapid recovery of blood pressure in phase IV,
with blood pressure overshoot. During Valsalva, a rise in heart rate also occurs, which falls
quickly as blood pressure recovers. In the patient with autoimmune autonomic ganglionopathy
(AAG), supine hypertension, a marked progressive fall in blood pressure during phase II, very
slow recovery of blood pressure in phase IV with no overshoot, and absence of heart rate
response are seen. B, Pupillary constriction response during a 2-second light stimulus (left
pupil, blue tracing; right pupil, red tracing). The normal pupil response shows brisk constriction
and persistent constriction throughout the light stimulus followed by redilation after removal
of the light stimulus. In the patient with autoimmune autonomic ganglionopathy, the initial
pupillary constriction is normal, but the pupils begin to redilate while the light stimulus is still
present. This premature redilation represents fatigue of the pupillary constriction response
and is characteristic of autoimmune autonomic ganglionopathy.
Autoimmune autonomic ganglionopathy associated with ganglionic nicotinic COMMENT

ACh receptor antibodies presents with a characteristic constellation of
severe autonomic symptoms affecting the sympathetic (orthostatic
hypotension), parasympathetic (sicca, urinary retention, pupils), and enteric
nervous systems. Autonomic testing shows diffuse severe autonomic failure,
and QSART responses are impaired.16 In some cases, the onset of symptoms
occurs over many years, which makes the diagnosis of an autoimmune
disorder more challenging.11 Immunotherapy can be beneficial even in
patients with long-standing symptoms.17

CASE 3-2 A 68-year-old man presented with a 2-month history of difficulty eating.
He noted loss of taste and loss of interest in smoking as well as a feeling
of early satiety and nausea even when eating a small amount of food. On
gastroenterologic evaluation, he was found to have poor esophageal
motility, delayed gastric emptying, and ileus of the small bowel without
obstruction. Because of his inability to maintain hydration and nutrition,
IV total parenteral nutrition was required. Additionally, he noted dry
mouth, lightheadedness on standing, and numbness and hypersensitivity
in the feet and hands.
On neurologic examination, his strength and coordination were normal.
He had distal loss of sensation to pinprick in the fingers and hands more
than the feet. Vibratory sensation was mildly reduced in the fingers and
toes. The patellar reflexes were reduced, and all other deep tendon
reflexes were absent. Supine blood pressure was 159/91 mm Hg with a
heart rate of 66 beats/min. After 3 minutes of standing, his blood
pressure was 149/86 mm Hg with a heart rate of 69 beats/min. Autonomic
testing showed impairment of heart rate variability to deep breathing and
Valsalva. The blood pressure response to Valsalva showed mildly
prolonged blood pressure recovery time.
Serologic testing was positive for antineuronal nuclear antibody type 1
(ANNA-1, anti-Hu) antibodies. CT of the chest was unremarkable, but
positron emission tomography (PET) imaging revealed a hypermetabolic
paratracheal mass that proved to be small cell carcinoma at biopsy.
Treatment with chemotherapy produced an excellent tumor response.
For his enteric neuropathy, pyridostigmine, corticosteroids, and oral
immunosuppression were initiated after chemotherapy was completed.
Over the course of 1 year after cancer remission, his gastrointestinal
function slowly improved and he regained weight. The symptoms of
peripheral neuropathy remained stable. Immunotherapy was
discontinued after 3 years, and he remained in long-term oncologic
remission for more than 5 years.
COMMENT This patient presented with typical features of paraneoplastic enteric

neuropathy (along with symptoms of autonomic and peripheral sensory
neuropathy). The paraneoplastic etiology was confirmed by positive anti-
Hu antibodies and discovery of small cell lung carcinoma. In patients with
paraneoplastic disorders, the prognosis with respect to malignancy is
often very favorable compared to similar stage tumors without neurologic
autoimmunity.38,39 Although paraneoplastic disorders may be associated
with neuronal loss, clinical stability and modest clinical improvement may
be seen if diagnosis and treatment are prompt. In patients with positive
paraneoplastic antibodies and cancer risk factors, PET/CT imaging has a
higher diagnostic yield than CT imaging alone.40
50 FEBRUARY 2020

sensory involvement. These cases therefore likely represent immune-mediated KEY POINTS
sensory and autonomic neuropathy rather than antibody-mediated autonomic
● Intermediate levels of
ganglionopathy.33 In a 2017 series of cases with seronegative autonomic failure, ganglionic nicotinic
orthostatic hypotension, gastrointestinal dysmotility, and painful sensory acetylcholine receptor
neuropathy were often seen.34 Some patients responded well to high-dose IV antibodies may be
steroids, even when antibody-targeted therapies (IVIg, plasma exchange, associated with chronic
cases of autoimmune
rituximab) were ineffective.34 Similar immune-mediated acute autonomic and
sensory neuropathies have been reported in the literature and are quite or with limited forms of
heterogeneous in terms of the extent of sensory involvement and autonomic autonomic failure such as
failure.30,35 It is unclear if these represent a single disorder or a variety of isolated gastrointestinal
dysmotility.
different conditions. In a large case series from Japan, characteristic features
included an acute onset, often with an antecedent upper respiratory infection.36 ● Chronic idiopathic
Initial symptoms of sensory disturbance and gastrointestinal issues were anhidrosis is suspected to
followed by more diffuse autonomic impairment, neuropathic pain, and be an autoimmune disorder
sensory ataxia in many patients. The reported response to immunotherapy but is not associated with
ganglionic nicotinic
was mixed. acetylcholine receptor
antibodies.
PARANEOPLASTIC AUTONOMIC OR ENTERIC NEUROPATHY
Immune-mediated autonomic neuropathy or ganglionopathy can also occur in the ● Acute autonomic and
sensory neuropathy differs
context of systemic malignancy. The onset of paraneoplastic neurologic syndromes
from autoimmune
usually precedes the diagnosis of cancer, and malignancies, when found, are autonomic ganglionopathy
often at an early and limited stage. A number of different paraneoplastic in clinical features and
antibodies have been identified in the context of paraneoplastic autonomic or response to treatment and is
not associated with
enteric neuropathy, including antineuronal nuclear antibody type 1 (ANNA-1,
ganglionic nicotinic
anti-Hu) or collapsin response mediator protein-5 (CRMP-5, CV 2). These acetylcholine receptor
antibodies are strongly associated with malignancy, most commonly small cell antibodies.
lung carcinoma.
Among patients with anti-Hu antibodies, 18% have features of autonomic ● The clinical features of
acute immune-mediated
neuropathy and 12% may present initially solely with enteric neuropathy.37 sensory and autonomic
These patients often present with severe nausea, anorexia, and weight loss. neuropathy are varied but
Clinical investigations may show impaired esophageal motility (including often include neuropathic
achalasia), delayed gastric emptying, and intestinal hypomotility (CASE 3-2). pain, orthostatic
hypotension, and
A paraneoplastic autonomic disorder may also present as diffuse autonomic gastrointestinal dysmotility.
failure similar to autoimmune autonomic ganglionopathy, with constipation,
orthostatic hypotension, anhidrosis, and pupillary involvement. Positive ● Paraneoplastic autonomic
ganglionic nicotinic ACh receptor antibodies may be seen in patients with lung neuropathy is most
commonly associated with
cancer or thymoma.6,41 Additional clinical features of limbic encephalitis,
small cell lung carcinoma
cerebral ataxia, or sensory neuronopathy should increase the suspicion for a and anti-Hu antibodies.
paraneoplastic etiology.42 Therapy for paraneoplastic autonomic/enteric
neuropathy is first directed at identification and treatment of the underlying ● Severe gastrointestinal
malignancy. Additional immunotherapy may be offered, but many of the dysmotility with
gastroparesis is the most
paraneoplastic neurologic syndromes are associated with cell-mediated neuronal common presentation of
injury that may be irreversible.43 LEMS and Morvan syndrome may also occur paraneoplastic autonomic/
as paraneoplastic phenomena with autonomic features and are discussed enteric neuropathy.
further below.
● Other clinical syndromes
such as limbic encephalitis
LAMBERT-EATON MYASTHENIC SYNDROME may coexist with
Although LEMS is recognized as a neuromuscular junction disorder presenting paraneoplastic autonomic
with proximal weakness, fatigability, and areflexia, autonomic symptoms are neuropathy.
commonly present. The majority of patients describe dry mouth, constipation,

and, in men, erectile dysfunction.44,45 These cholinergic autonomic symptoms

are likely related to impairment in cholinergic synaptic transmission within the
autonomic nervous system. LEMS is caused by an antibody-mediated impairment
in ACh release at peripheral synapses due to antibodies directed against the
P/Q-type voltage-gated calcium channel. Many cases of LEMS are associated
with lung cancer. Both the autonomic and motor symptoms may improve with
treatment of the underlying malignancy and immunotherapy.46
GUILLAIN-BARRÉ SYNDROME
Guillain-Barré syndrome is an acute inflammatory demyelinating neuropathy
presenting as progressive weakness. Some degree of autonomic dysfunction
may be present in up to two-thirds of cases, and these autonomic features are
quite varied.47 Labile blood pressure and heart rate may be present, with
episodes of sinus tachycardia or bradycardia or episodic severe hypertension
or hypotension that may require intervention. Visceral autonomic manifestations
can include paralytic ileus, urinary retention, or sweating changes. The
presence of autonomic dysfunction may be independent of the severity of motor
weakness. Treatment of Guillain-Barré syndrome includes immunotherapy
and supportive care for both the weakness and autonomic dysfunction. The
clinical autonomic dysfunction typically resolves over time in concert with
the other features.
AUTOIMMUNE ENCEPHALITIS
A number of distinct autoimmune encephalitides are now recognized, characterized
by the rapid onset of cognitive impairment, psychiatric symptoms, and
seizures. Autonomic features may be present with certain forms of
autoimmune encephalitis. In patients with antibodies against the voltage-gated
potassium channel complex proteins leucine-rich glioma inactivated protein 1
(LGI1) or contactin-associated proteinlike 2 (CASPR2), episodes of autonomic
hyperactivity may be seen. Hyperhidrosis or hypersalivation have been reported,
as have tachycardia, blood pressure lability, and urinary symptoms.48 In cases of
Morvan syndrome (a disorder of peripheral nerve hyperexcitability, encephalopathy,
and insomnia), dysautonomia is quite prominent, and autonomic testing may
reveal deficits in blood pressure control and thermoregulation.49 The
autonomic features of voltage-gated potassium channel complex antibody
encephalitis may be due to a combination of peripheral autonomic nerve
hyperexcitability and central impairments of autonomic function. Autonomic
deficits improve with immunotherapy in concert with the improvement
in encephalopathy.
Manifestations of central autonomic dysfunction can also be seen in
autoimmune encephalitis associated with N-methyl-D-aspartate (NMDA)
receptor antibodies. In addition to cognitive and psychiatric symptoms, these
patients may develop tachyarrhythmias, labile blood pressure, and even central
hypoventilation. These autonomic issues may contribute to the need for
management in the intensive care unit.50
More recently, a newly recognized form of autoimmune encephalitis has
been described in association with dipeptidyl-peptidase–like protein 6 (DPPX)
antibodies.51 DPPX is a regulatory protein associated with Kv4.2 potassium
channels that are expressed in the central nervous system and by enteric neurons
in the myenteric plexus. Patients typically present with severe symptoms of
52 FEBRUARY 2020

gastrointestinal dysmotility (profuse diarrhea and weight loss). Symptoms of KEY POINTS
encephalopathy (confusion, myoclonus, exaggerated startle, and psychosis)
● Patients with Lambert-
develop later.52 Both the encephalopathy and the enteric symptoms improve Eaton myasthenic syndrome
with immunotherapy. commonly report dry mouth,
constipation, and sexual
SJÖGREN SYDROME AND OTHER RHEUMATOLOGIC DISEASES dysfunction.
Primary Sjögren syndrome is characterized by sicca symptoms (dry mouth and
● Various autonomic
dry eyes) and lymphocytic infiltration of exocrine glands. Peripheral nerve disturbances can be seen in
involvement may occur, particularly sensory ganglionopathy and small fiber patients with Guillain-Barré
neuropathy. More than half of patients with Sjögren syndrome with neuropathy syndrome independent of
report symptoms of autonomic dysfunction (especially gastrointestinal the severity of muscle
weakness.
dysmotility and orthostatism).53 Impairment of pupillary constriction may also
be seen. Objective testing of autonomic function has yielded varying degrees of ● Autonomic hyperactivity
decreased cardiovagal function,54,55 impaired sympathetic vasomotor activity,56 (hypertension, tachycardia,
or tachycardic response to head-up tilt.57 Autonomic features may precede the hypersalivation) can be seen
in disorders associated with
diagnosis of Sjögren syndrome.57 The pathophysiology of autonomic dysfunction voltage-gated potassium
in Sjögren syndrome is not well understood but is presumed to be related to an channel complex antibodies
immune-mediated small fiber neuropathy affecting autonomic nerves. Some (leucine-rich glioma
patients may respond to immunotherapy.58 inactivated protein 1 [LGI1]
and contactin-associated
Autonomic function may be altered in other rheumatologic diseases as well.
proteinlike 2 [CASPR2]).
In systemic lupus erythematosus, decreased heart rate variability has been
reported, although these abnormalities do not correlate well with disease ● Central autonomic
severity.59 Similarly, patients with rheumatoid arthritis have been reported to dysfunction may be seen in
have increased sympathetic nerve activity, reduced cardiac baroreflex patients with N-methyl-D-
aspartate (NMDA) receptor
sensitivity, and a variety of other markers of autonomic dysfunction.60 These antibody encephalitis.
findings appear to be more closely associated with pain and deconditioning
rather than with severity of inflammation.61 Parasympathetic and ● Encephalitis associated
sympathetic dysfunction have also been described in scleroderma62 and with severe gastrointestinal
dysmotility has been
psoriatic arthritis.63 associated with dipeptidyl-
peptidase–like protein 6
POSTURAL TACHYCARDIA SYNDROME (DPPX) antibodies.
POTS is a very common autonomic disorder characterized by an excessive
● Autonomic dysfunction
increment in heart rate on standing associated with symptoms of
may be seen in patients with
lightheadedness. POTS is often associated with a number of other symptoms Sjögren syndrome.
that are unrelated to tachycardia, including gastrointestinal symptoms, cognitive
impairment, allergic symptoms, sensory symptoms, and others. The clinical ● Autonomic symptoms in
syndrome of POTS is likely heterogeneous. In some cases, clinical features and Sjögren syndrome are
mostly cholinergic. In
laboratory findings suggest that autoimmunity or chronic inflammation may addition to sicca symptoms,
contribute to the pathophysiology. The autoimmune basis of POTS is orthostatic intolerance
still debated.64 with tachycardia and
The majority of patients with POTS are young women similar to the gastrointestinal symptoms
are seen.
demographic seen in many systemic autoimmune diseases. A personal or family
history of autoimmunity may be present. A variety of autoantibodies have been
reported in association with POTS, although the pathologic significance of these
antibodies has not been established. As discussed earlier, chronic inflammatory
conditions may be associated with persistent activation of the sympathetic
nervous system; this appears to be present in at least a subset of patients with
POTS, in whom acute or subacute onset after an immunologic stimulus
(infection or physical stressor) is reported.65 About one-fifth of patients have
comorbid autoimmune disease (CASE 3-3), and a variety of autoantibodies

(including antinuclear, antiphospholipid, and Sjögren antibodies) have been

found.66,67 Autoantibodies against autonomic nervous system targets have also
been described, including those against α-adrenergic and β-adrenergic
receptors,68 angiotensin II type 1 receptors,69 and (in low titers) ganglionic
nicotinic ACh receptors.65 Despite the frequent association with autoimmunity,
however, a causative role has not been established, and immunomodulatory
therapy is not indicated for POTS at this time.
CONCLUSION
Peripheral autonomic neuropathies and ganglionopathies may be immune
mediated in some cases. Autonomic dysfunction may also be prominent in
systemic rheumatologic diseases and in autoimmune encephalopathies. An
appreciation of the interplay between the autonomic nervous system and
immune function and recognition of the underlying pathophysiology of these
autonomic disorders will facilitate the judicious use of immunotherapy in select
cases as well as appropriate management of autonomic symptoms.
CASE 3-3 A 45-year-old woman with no significant past medical history developed
palpitations and tachycardia associated with prolonged standing or heat.
Symptoms progressed and evolved over time. About 5 years after the
onset of the symptoms, she developed arthralgia, dry eyes, dry mouth,
and Raynaud phenomenon. She presented 8 years after the onset of her
symptoms reporting orthostatic lightheadedness, palpitations,
constipation, fatigue, nausea, and exercise intolerance.
The neurologic examination was normal. Autonomic testing revealed
normal cardiovagal and vasomotor reflexes, and her quantitative
sudomotor axon reflex test (QSART) was normal. Orthostatic testing
revealed postural tachycardia and hypertension. Supine blood pressure
was 116/61 mm Hg with a heart rate of 80 beats/min. After 7 minutes of
head-up tilt, her blood pressure was 140/73 mm Hg with a heart rate of
133 beats/min. Plasma norepinephrine increased from 305 pg/mL to 1208
pg/ml during head-up tilt. Serum Sjögren syndrome A (SSA) and Sjögren
syndrome B (SSB) antibodies were elevated, and minor salivary gland
biopsy revealed lymphocytic infiltration consistent with Sjögren
syndrome.
COMMENT This patient presented with clinical features of hyperadrenergic postural

tachycardia syndrome (POTS). This occurred in the context of a systemic
rheumatologic disorder meeting the criteria for Sjögren syndrome.57 In this
setting, the systemic autoimmune disease may precipitate dysautonomia
either through nonspecific effects of systemic inflammation or perhaps
through an inflammatory small fiber autonomic neuropathy or
ganglionopathy. Interestingly, although POTS commonly presents in
adolescents, the onset of POTS in this case was at an older age and in
association with rheumatologic features.
54 FEBRUARY 2020

KEY POINTS
REFERENCES
● Various degrees of
1 Tracey KJ. The inflammatory reflex. Nature 2002; 14 McKeon A, Lennon VA, Lachance DH, et al. autonomic dysfunction have
420(6917):853–859. doi:10.1038/nature01321. Ganglionic acetylcholine receptor autoantibody: been reported in systemic
oncological, neurological, and serological lupus erythematosus,
2 Pereira MR, Leite PE. The involvement of
accompaniments. Arch Neurol 2009;66(6):
parasympathetic and sympathetic nerve in the rheumatoid arthritis, and
735–741. doi:10.1001/archneurol.2009.78.
inflammatory reflex. J Cell Physiol 2016;231(9): scleroderma and may
1862–1869. doi:10.1002/jcp.25307. 15 Li Y, Jammoul A, Mente K, et al. Clinical experience represent effects of
of seropositive ganglionic acetylcholine receptor deconditioning and chronic
3 Carnagarin R, Matthews V, Zaldivia MTK, et al.
antibody in a tertiary neurology referral center. systemic inflammation
The bidirectional interaction between the
Muscle Nerve 2015;52(3):386–391. doi:10.1002/
sympathetic nervous system and immune rather than autonomic
mus.24559.
mechanisms in the pathogenesis of hypertension. neuropathy.
Br J Pharmacol 2019;176(12):1839–1852. doi:10.1111/ 16 Kimpinski K, Iodice V, Sandroni P, et al.
bph.14481. Sudomotor dysfunction in autoimmune autonomic ● An autoimmune basis for
ganglionopathy. Neurology 2009;73(18):1501–1506. postural tachycardia
4 Young RR, Asbury AK, Corbett JL, Adams RD. Pure
doi:10.1212/WNL.0b013e3181bf995f.
pan-dysautonomia with recovery. Brain 1975; syndrome has been
98(4):613–636. doi:10.1093/brain/98.4.613. 17 Schroeder C, Vernino S, Birkenfeld AL, et al. proposed but not yet
Plasma exchange for primary autoimmune proven.
5 Suarez GA, Fealey RD, Camilleri M, Low PA.
autonomic failure. N Engl J Med 2005;353(15):
Idiopathic autonomic neuropathy: clinical,
1585–1590. doi:10.1056/NEJMoa051719.
neurophysiologic, and follow-up studies on ● Various autoantibodies
27 patients. Neurology 1994;44(9):1675–1682. 18 Muppidi S, Scribner M, Gibbons CH, et al. A have been found in patients
doi:10.1212/WNL.44.9.1675. unique manifestation of pupillary fatigue in with postural tachycardia
autoimmune autonomic ganglionopathy. Arch syndrome.
6 Vernino S, Low PA, Fealey RD, et al. Autoantibodies
Neurol 2012;69(5):644–648. doi:10.1001/
to ganglionic acetylcholine receptors in
archneurol.2011.2143.
autoimmune autonomic neuropathies. N Engl J
Med 2000;343(12):847–855. doi:10.1056/ 19 Nakane S, Mukaino A, Maeda Y, et al. Extra-
NEJM200009213431204. autonomic manifestations in autoimmune
autonomic ganglionopathy: a Japanese survey.
7 Lennon VA, Ermilov LG, Szurszewski JH, Vernino S.
J Neurol Neurosurg Psychiatry 2017;88(4):
Immunization with neuronal nicotinic acetylcholine
367–368. doi:10.1136/jnnp-2016-314707.
receptor induces neurological autoimmune
disease. J Clin Invest 2003;111(6):907–913. 20 Baker SK, Morillo C, Vernino S. Autoimmune
doi:10.1172/JCI17429. autonomic ganglionopathy with late-onset
encephalopathy. Auton Neurosci 2009;146(1–2):
8 Vernino S, Ermilov LG, Sha L, et al. Passive transfer
29–32. doi:10.1016/j.autneu.2008.10.016.
of autoimmune autonomic neuropathy to mice.
J Neurosci 2004;24(34):7037–7042. doi:10.1523/ 21 Sandroni P, Low PA. Other autonomic neuropathies
JNEUROSCI.1485-04.2004. associated with ganglionic antibody. Auton
Neurosci 2009;146(1–2):13–17. doi:10.1016/j.autneu.
9 Vernino S, Low PA, Lennon VA. Experimental
2008.10.022.
autoimmune autonomic neuropathy.
J Neurophysiol 2003;90(3):2053–2059. 22 Lang K, Prüss H. Frequencies of neuronal
doi:10.1152/jn.00408.2003. autoantibodies in healthy controls: estimation
of disease specificity. Neurol Neuroimmunol
10 Baker SK, Chow BM, Vernino SA. Transient neonatal
Neuroinflamm 2017;4(5):e386. doi:10.1212/
autoimmune autonomic ganglionopathy. Neurol
NXI.0000000000000386.
Neuroimmunol Neuroinflamm 2014;1(3):e35.
doi:10.1212/NXI.0000000000000035. 23 Iodice V, Kimpinski K, Vernino S, et al. Efficacy of
immunotherapy in seropositive and seronegative
11 Klein CM, Vernino S, Lennon VA, et al. The spectrum
putative autoimmune autonomic ganglionopathy.
of autoimmune autonomic neuropathies.
Neurology 2009;72(23):2002–2008. doi:10.1212/
Ann Neurol 2003;53(6):752–758. doi:10.1002/
WNL.0b013e3181a92b52.
ana.10556.
24 Gibbons CH, Vernino SA, Freeman R. Combined
12 Gibbons CH, Freeman R. Antibody titers predict
immunomodulatory therapy in autoimmune
clinical features of autoimmune autonomic
autonomic ganglionopathy. Arch Neurol 2008;
ganglionopathy. Auton Neurosci 2009;146(1–2):
65(2):213–217. doi:10.1001/archneurol.2007.60.
8–12. doi:10.1016/j.autneu.2008.11.013.
25 Bouxin M, Schvartz B, Mestrallet S, et al. Rituximab
13 Cutsforth-Gregory JK, McKeon A, Coon EA, et al.
treatment in seronegative autoimmune autonomic
Ganglionic antibody level as a predictor of
neuropathy and autoimmune autonomic
severity of autonomic failure. Mayo Clin Proc
ganglionopathy: case-report and literature
2018;93(10):1440–1447. doi:10.1016/j.mayocp.
review. J Neuroimmunol 2019;326:28–32.
2018.05.033.
doi:10.1016/j.jneuroim.2018.11.009.

26 Gupta A, Harris S, Vernino S, Naina HV. 39 Wirtz PW, Lang B, Graus F, et al. P/Q-type calcium
Rituximab-based therapy and long-term control channel antibodies, Lambert-Eaton myasthenic
of autoimmune autonomic ganglionopathy. Clin syndrome and survival in small cell lung cancer.
Auton Res 2015;25(4):255–258. doi:10.1007/ J Neuroimmunol 2005;164(1–2):161–165. doi:10.1016/
s10286-015-0299-5. j.jneuroim.2005.04.001.
27 Imrich R, Vernino S, Eldadah BA, et al. Autoimmune 40 McKeon A, Apiwattanakul M, Lachance DH, et al.
autonomic ganglionopathy: treatment by plasma Positron emission tomography-computed
exchanges and rituximab. Clin Auton Res 2009; tomography in paraneoplastic neurologic
19(4):259–262. doi:10.1007/s10286-009-0012-7. disorders: systematic analysis and review. Arch
Neurol 2010;67(3):322–329. doi:10.1001/
28 Vernino S, Sandroni P, Singer W, Low PA. Invited
archneurol.2009.336.
article: autonomic ganglia: target and novel
therapeutic tool. Neurology 2008;70(20): 41 Vernino S, Lennon VA. Autoantibody profiles and
1926–1932. doi:10.1212/01.wnl.0000312280. neurological correlations of thymoma. Clin Cancer
44805.5d. Res 2004;10(21):7270–7275. doi:10.1158/1078-0432.
CCR-04-0735.
29 Mukaino A, Minami H, Isomoto H, et al. Anti-
ganglionic AChR antibodies in Japanese patients 42 Sharp L, Vernino S. Paraneoplastic neuromuscular
with motility disorders. J Gastroenterol 2018; disorders. Muscle Nerve 2012;46(6):841–850.
53(12):1227–1240. doi:10.1007/s00535-018-1477-8. doi:10.1002/mus.23502.
30 Koike H, Watanabe H, Sobue G. The spectrum of 43 Muppidi S, Vernino S. Paraneoplastic neuropathies.
immune-mediated autonomic neuropathies: Continuum (Minneap Minn) 2014;20(5 Peripheral
insights from the clinicopathological features. Nervous System Disorders):1359–1372. doi:10.1212/
J Neurol Neurosurg Psychiatry 2013;84(1):98–106. 01.CON.0000455876.53309.ec.
doi:10.1136/jnnp-2012-302833.
44 O’Suilleabhain P, Low PA, Lennon VA. Autonomic
31 Munetsugu T, Fujimoto T, Satoh T, et al. Evaluation dysfunction in the Lambert–Eaton myasthenic
of the correlation between severity of acquired syndrome: serologic and clinical correlates.
idiopathic generalized anhidrosis and quality of Neurology 1998;50(1):88–93. doi:10.1212/
life scores. J Dermatol 2017;44(7):747–752. WNL.50.1.88.
doi:10.1111/1346-8138.13785.
45 Titulaer MJ, Wirtz PW, Kuks JB, et al. The Lambert–
32 Sandroni P, Vernino S, Klein CM, et al. Idiopathic Eaton myasthenic syndrome 1988–2008: a clinical
autonomic neuropathy: comparison of cases picture in 97 patients. J Neuroimmunol 2008;
seropositive and seronegative for ganglionic 201–202:153–158. doi:10.1016/j.jneuroim.
acetylcholine receptor antibody. Arch Neurol 2008.05.025.
2004;61(1):44–48. doi:10.1001/archneur.61.1.44.
46 Kesner VG, Oh SJ, Dimachkie MM, Barohn RJ.
33 Goldstein DS, Holmes C, Sullivan P, et al. Lambert–Eaton myasthenic syndrome. Neurol
Autoimmunity-associated autonomic failure with Clin 2018;36(2):379–394. doi:10.1016/j.ncl.2018.
sympathetic denervation. Clin Auton Res 2017; 01.008.
27(1):57–62. doi:10.1007/s10286-016-0388-0.
47 Zaeem Z, Siddiqi ZA, Zochodne DW. Autonomic
34 Golden EP, Bryarly MA, Vernino S. Seronegative involvement in Guillain–Barré syndrome: an
autoimmune autonomic neuropathy: a distinct update. Clin Auton Res 2018. doi:10.1007/s10286-
clinical entity. Clin Auton Res 2018;28:115–123. 018-0542-y.
doi:10.1007/s10286-016-0388-0.
48 Vincent A, Buckley C, Schott JM, et al. Potassium
35 Colan RV, Snead OC 3rd, Oh SJ, Kashlan MB. channel antibody-associated encephalopathy: a
Acute autonomic and sensory neuropathy. potentially immunotherapy-responsive form of
Ann Neurol 1980;8(4):441–444. doi:10.1002/ limbic encephalitis. Brain 2004;127(pt 3):701–712.
ana.410080419. doi:10.1093/brain/awh077.
36 Koike H, Atsuta N, Adachi H, et al. 49 Josephs KA, Silber MH, Fealey RD, et al.
Clinicopathological features of acute Neurophysiologic studies in Morvan syndrome.
autonomic and sensory neuropathy. Brain 2010; J Clin Neurophysiol 2004;21(6):440–445.
133(10):2881–2896. doi:10.1093/brain/awq214. doi:10.1097/00004691-200411000-00008.
37 Lucchinetti CF, Camilleri M, Lennon VA. 50 Salehi N, Yuan AK, Stevens G, et al. A case of
Gastrointestinal dysmotility spectrum in patients severe anti-N-methyl D-aspartate (anti-NMDA)
seropositive for paraneoplastic type 1 anti-neuronal receptor encephalitis with refractory autonomic
nuclear autoantibodies. Clin Auton Res 1994;4:206. instability and elevated intracranial pressure.
Am J Case Rep 2018;19:1216–1221. doi:10.12659/
38 Rauer S, Andreou I. Tumor progression and serum
AJCR.911165.
anti-HuD antibody concentration in patients with
paraneoplastic neurological syndromes. 51 Boronat A, Gelfand JM, Gresa-Arribas N, et al.
Eur Neurol 2002;47(4):189–195. doi:10.1159/ Encephalitis and antibodies to dipeptidyl-
000057897. peptidase-like protein-6, a subunit of Kv4.2
potassium channels. Ann Neurol 2013;73(1):
120–128. doi:10.1002/ana.23756.
56 FEBRUARY 2020

52 Hara M, Ariño H, Petit-Pedrol M, et al. DPPX 61 Adlan AM, Lip GY, Paton JF, et al. Autonomic
antibody-associated encephalitis: main syndrome function and rheumatoid arthritis: a systematic
and antibody effects. Neurology 2017;88(14): review. Semin Arthritis Rheum 2014;44(3):
1340–1348. doi:10.1212/WNL.0000000000003796. 283–304. doi:10.1016/j.semarthrit.2014.06.003.
53 Newton JL, Frith J, Powell D, et al. Autonomic 62 Amaral TN, Peres FA, Lapa AT, et al. Neurologic
symptoms are common and are associated with involvement in scleroderma: a systematic review.
overall symptom burden and disease activity in Semin Arthritis Rheum 2013;43(3):335–347.
primary Sjogren’s syndrome. Ann Rheum Dis doi:10.1016/j.semarthrit.2013.05.002.
2012;71(12):1973–1979. doi:10.1136/annrheumdis-
63 Syngle A, Verma I, Garg N, Krishan P. Autonomic
2011-201009.
dysfunction in psoriatic arthritis. Clin Rheumatol
54 Koh JH, Kwok SK, Lee J, Park SH. Autonomic 2013;32(7):1059–1064. doi:10.1007/s10067-013-
dysfunction in primary Sjogren’s syndrome: a 2239-x.
prospective cohort analysis of 154 Korean patients.
64 Vernino S, Stiles LE. Autoimmunity in postural
Korean J Intern Med 2017;32(1):165–173. doi:10.3904/
orthostatic tachycardia syndrome: Current
kjim.2015.219.
understanding. Auton Neurosci 2018;215:78–82.
55 Mandl T, Granberg V, Apelqvist J, et al. doi:10.1016/j.autneu.2018.04.005.
Autonomic nervous symptoms in primary Sjogren’s
65 Thieben MJ, Sandroni P, Sletten DM, et al.
syndrome. Rheumatology (Oxford) 2008;47(6):
Postural orthostatic tachycardia syndrome: the
914–919. doi:10.1093/rheumatology/ken107.
Mayo clinic experience. Mayo Clin Proc 2007;
56 Ng WF, Stangroom AJ, Davidson A, et al. Primary 82(3):308–313. doi:10.4065/82.3.308.
Sjogren’s syndrome is associated with impaired
66 Shaw BH, Stiles LE, Bourne K, et al. The face of
autonomic response to orthostasis and sympathetic
postural tachycardia syndrome: a cross-
failure. QJM 2012;105(12):1191–1199. doi:10.1093/
sectional community-based survey. Heart
qjmed/hcs172.
Rhythm 2016;13:S328. doi:10.1111/joim.12895.
57 Goodman BP, Crepeau A, Dhawan PS, et al.
67 Blitshteyn S. Autoimmune markers and autoimmune
Spectrum of autonomic nervous system impairment
disorders in patients with postural tachycardia
in Sjögren syndrome. Neurologist 2017;22(4):
syndrome (POTS). Lupus 2015;24(13):1364–1369.
127–130. doi:10.1097/NRL.0000000000000134.
doi:10.1177/0961203315587566.
58 Goodman BP. Immunoresponsive autonomic
68 Li HL, Yu X, Liles C, et al. Autoimmune basis for
neuropathy in Sjögren syndrome—case series
postural tachycardia syndrome. J Am Heart
and literature review. Am J Ther 2019;26:e66–e71.
Assoc 2014;3(1):e000755. doi:10.1161/JAHA.
doi:10.1097/MJT.0000000000000583.
113.000755.
59 Matusik PS, Matusik PT, Stein PK. Heart rate
69 Yu X, Li H, Murphy TA, et al. Angiotensin II type 1
variability in patients with systemic lupus
receptor autoantibodies in postural tachycardia
erythematosus: a systematic review and
syndrome. J Am Heart Assoc 2018;7(8):e008351.
methodological considerations. Lupus 2018;
doi:10.1161/JAHA.117.008351.
27(8):1225–1239. doi:10.1177/0961203318771502.
60 Adlan AM, Paton JF, Lip GY, et al. Increased
sympathetic nerve activity and reduced cardiac
baroreflex sensitivity in rheumatoid arthritis.
J Physiol 2017;595(3):967–981. doi:10.1113/
JP272944.

REVIEW ARTICLE
Autonomic Peripheral
Neuropathy

ONLINE
By Roy Freeman, MBChB
ABSTRACT
PURPOSE OF REVIEW: This article provides a summary of the autonomic
neuropathies, including neuropathies associated with diabetes mellitus,
neuropathies due to amyloid deposition, immune-mediated autonomic
CITE AS:
C O N T I N U U M ( M I N N E AP M I N N ) neuropathies (including those associated with a paraneoplastic syndrome),
2020;26(1, AUTONOMIC DISORDERS): inherited autonomic neuropathies, and toxic autonomic neuropathies. The
58–71.
presenting features, diagnostic investigations, and natural history of these
neuropathies are discussed.
Dr Roy Freeman, Center for
Autonomic and Peripheral Nerve
Disorders, Department of
RECENT FINDINGS:Recent findings in autonomic peripheral neuropathy
Neurology, Beth Israel include data on the epidemiology and atypical presentations of diabetic
Deaconess Medical Center, autonomic neuropathy, treatment-induced neuropathy of diabetes
1 Deaconess Rd, Boston, MA
02215, rfreeman@bidmc. mellitus, the presentation of immune-mediated neuropathies, and
harvard.edu. advances in hereditary neuropathy associated with amyloidosis and other
hereditary neuropathies.
Dr Freeman has received
personal compensation and/or
SUMMARY: Knowledge and recognition of the clinical features of the
stock options for serving on
scientific advisory boards of autonomic neuropathies, combined with appropriate laboratory and
Abide Therapeutics; Applied electrophysiologic testing, will facilitate accurate diagnosis and management.
Therapeutics, Inc; Aptinyx, Inc;
Astellas Pharma; Biogen;
Biohaven Pharmaceuticals;
Chromocell; Cutaneous INTRODUCTION
Neurodiagnostics, LLC; GW
T
Pharmaceuticals, plc; Ironwood he autonomic nerve fibers, which are small and lightly myelinated
Pharmaceuticals; Lundbeck; or unmyelinated, innervate organs and structures involved in
Mundipharma; NeuroBo cardiovascular, gastrointestinal, urogenital, thermoregulatory,
Pharmaceuticals; Novartis;
Pfizer, Inc; Regenacy sudomotor, pupillary, and immune function. Autonomic symptoms
Pharmaceuticals; Spinifex may be a prominent manifestation in peripheral neuropathies that
Pharmaceuticals; Theravance
Biopharma; Toray Medical Co,
selectively or predominantly target these autonomic nerves or may be less
Ltd; and Vertex Pharmaceuticals. prominent or even subclinical in generalized peripheral neuropathies. Some
Dr Freeman has received peripheral neuropathies may have focal or segmental autonomic manifestations.1
personal compensation for
serving as editor-in-chief of
A detailed autonomic history and clinical examination is obligatory in all
Autonomic Neuroscience: Basic patients with peripheral neuropathy, but because autonomic symptoms may be
& Clinical. nonspecific, objective support is often required. Standard neurophysiologic
UNLABELED USE OF studies are unable to assess these small unmyelinated or lightly myelinated
PRODUCTS/INVESTIGATIONAL nerves as they have a high threshold to electrical stimulation and the evoked
USE DISCLOSURE:
action potentials are small. To counter these challenges, a battery of tests of the
Dr Freeman reports no
disclosure. autonomic nervous system has been developed that includes autonomic reflex
assessments, measurement of plasma catecholamines, structural studies of
cutaneous autonomic innervation, and direct measurement of sympathetic nerve
of Neurology. activity. These studies help support a diagnosis of an autonomic neuropathy,
58 FEBRUARY 2020

define the severity of autonomic dysfunction, and monitor the clinical progression.2 KEY POINT
For more information on testing for autonomic disorders, refer to the article
● A generalized autonomic
“Autonomic History, Examination, and Laboratory Evaluation” by William P. neuropathy typically occurs
Cheshire Jr, MD, FAAN,3 in this issue of Continuum. in the setting of a
generalized diabetic
DIABETIC AUTONOMIC NEUROPATHY polyneuropathy but may
occur in isolation.
The prevalence of diabetes mellitus continues to increase throughout the world.
The Centers for Disease Control and Prevention (CDC) estimates that
30.3 million individuals in the United States have diabetes mellitus (9.3% of the
population), and the prevalence of prediabetes based on fasting glucose or
hemoglobin A1c level is estimated as 84.1 million individuals (33.9% of US adults
aged 18 years or older). In adults aged 65 years or older, nearly half (48.3%) have
prediabetes.4 Worldwide figures are similar: an estimated 425 million adults
(9.0% of the population) have diabetes mellitus.5
The prevalence of peripheral neuropathy and autonomic neuropathy in
diabetes mellitus reflects those numbers. The prevalence of neuropathy is
dependent on the criteria used for diagnosis and the population being studied.
For example, in a cross-sectional community-based population study in Oxford,
England, the prevalence of autonomic neuropathy was 16.7%.6 In this study,
autonomic neuropathy was defined by the presence of one or more abnormal
heart rate variability test results. In a longitudinal, community-based study of
133 patients with newly diagnosed type 2 diabetes mellitus,7 parasympathetic
dysfunction as defined by heart rate variability test abnormalities was present in
4.9% of subjects at the start of the study and in 65% after 10 years of follow-up. In
this study, sympathetic nervous system dysfunction, defined by a systolic blood
pressure fall greater than 30 mm Hg, was present in 24.4% of patients after
10 years of follow-up. In a large study of 557 patients with newly diagnosed type 2
diabetes mellitus, the prevalence of early autonomic neuropathy was 15.3% and
the prevalence of confirmed autonomic neuropathy was 1.8%; no individuals had
severe autonomic neuropathy.7 Two of 557 patients had orthostatic hypotension.
This study defined early cardiac autonomic neuropathy as the presence of one
abnormal or two borderline heart rate tests, confirmed cardiac autonomic
neuropathy as two or more abnormal tests, and severe cardiac autonomic
neuropathy as orthostatic hypotension with two or more abnormal tests.8
Several peripheral neuropathy subtypes cause autonomic dysfunction in
diabetes mellitus, including generalized diabetic autonomic neuropathy,
autonomic neuropathy associated with the prediabetic state,9 and treatment-
induced neuropathy.10 Autonomic impairment also occurs during and after
hypoglycemia.11,12 These autonomic neuropathies are among the major contributors
to the mortality and morbidity associated with diabetes mellitus.13 This article
discusses generalized autonomic neuropathy and treatment-induced neuropathy of
diabetes mellitus. Other autonomic neuropathies associated with diabetes mellitus
include autonomic neuropathy of prediabetes and hypoglycemia-associated
autonomic failure. The interested reader is referred to a review in which all
diabetic autonomic neuropathies are discussed in greater detail.13
Generalized Diabetic Autonomic Neuropathy

Autonomic dysfunction with a generalized diabetic autonomic neuropathy
progresses gradually and may affect cardiovascular, gastrointestinal, urogenital,
sudomotor, and pupillomotor functions; it is usually gradual and progressive.

AUTONOMIC PERIPHERAL NEUROPATHY
Diabetic cardiovascular autonomic neuropathy results in much of the

morbidity and mortality of diabetes mellitus. Orthostatic hypotension14 occurs
due to impaired vasoconstriction in dependent areas in response to postural
change. Diminished cardiac output, particularly in association with exercise, may
also play a role in the presentation of this disorder.
Several gastrointestinal syndromes occur.15 The underlying pathogenesis is
multifactorial and includes abnormalities in the extrinsic innervation of the
gastrointestinal tract and the intrinsic enteric nervous system combined with
unique site-specific mechanisms. Hyperglycemia may also impair
gastrointestinal function and alter sensory perception. For example, increases in
blood glucose concentration, even within the physiologic postprandial range
(approximately 140 mg/dL), may slow gastric emptying.16 Medications,
including metformin, the α-glucosidase inhibitors (eg, acarbose), the
glucagonlike peptide-1 receptor agonists, sugar alcohols (eg, sorbitol), and the
amylin analogue pramlintide, may produce gastrointestinal symptoms that
mimic autonomic dysfunction. These should be considered in patients presenting
with symptoms referable to the gastrointestinal tract.
Esophageal symptoms are common and include reflux, regurgitation, and
dysphagia, which may result in an increase in the incidence of Barrett esophagus
in patients with diabetes mellitus.15 Diabetic gastroparesis is present in up to 50%
of individuals with diabetes mellitus. Symptoms include nausea, postprandial
vomiting, bloating, abdominal distension and pain, belching, loss of appetite, and
early satiety. The pathophysiologic mechanisms underlying these symptoms
include impaired gastric emptying, impaired gastric accommodation, visceral
hypersensitivity, and gastric dysrhythmia.17 Many patients, however, are
asymptomatic despite documented impaired gastric motility.15
Constipation is a frequently reported gastrointestinal autonomic symptom
and may be found in up to 50% of individuals with diabetes mellitus.18 Diarrhea
and other lower gastrointestinal tract symptoms also occur frequently in
individuals with diabetes mellitus.19 Fecal incontinence due to anal sphincter
incompetence or reduced rectal sensation may occur and may be exacerbated by
CASE 4-1 A 30-year-old woman with type 1 diabetes mellitus diagnosed at 15 years
of age presented with a 2-week history of orthostatic lightheadedness,
diarrhea, and severe distal pain in her arms and legs.
On examination, she had a resting tachycardia with orthostatic
hypotension and postural tachycardia. Sensory examination revealed
impaired pain and temperature sensation to her knees with hyperalgesia
and allodynia.
Her hemoglobin A1c was 6.5%. Three months previously, her hemoglobin
A1c was 18%.
COMMENT The subacute onset of a painful sensory and autonomic neuropathy in

association with a rapid decrease in hemoglobin A1c is the typical
presentation of treatment-induced neuropathy of diabetes mellitus.
60 FEBRUARY 2020

diarrhea. Small intestinal bacterial overgrowth, a consequence of slow intestinal KEY POINT
transit, may be an additional cause of diarrhea.15
● Treatment-induced
Voiding dysfunction is a common complication in diabetes mellitus and occurs neuropathy of diabetes
in more than 80% of patients.20–22 Symptoms include frequency, nocturia, mellitus should be
urinary retention, and incontinence. Urodynamic studies may show bladder considered when a patient
overactivity or hypoactivity. The underlying pathophysiologic mechanisms with diabetes mellitus
presents with the sudden
include afferent and efferent autonomic nerve dysfunction, somatosensory
onset of pain and autonomic
nerve dysfunction, bladder smooth muscle dysfunction, and abnormalities of the dysfunction. This is a
urothelium.21 Mechanism-based therapy may require urodynamic studies. reversible diabetic
Erectile failure is present in up to 75% of men with diabetes mellitus19 and may peripheral neuropathy.
be the earliest symptom of diabetic autonomic neuropathy; it is significantly
associated with an increased incidence of cardiovascular disease.19,23 Ejaculatory
failure is a concomitant manifestation of urogenital neuropathy and may be
accompanied by retrograde ejaculation due to impaired bladder neck closure
during ejaculation.24,25 Few controlled studies of sexual function and genital
autonomic neuropathy in female patients with diabetes mellitus exist. In a
controlled study of 120 patients with type 1 diabetes mellitus, impaired vaginal
lubrication was significantly different in the patients with diabetes mellitus
compared to controls.26
Sudomotor dysfunction manifestations include impaired sweating in a
stocking-glove distribution that can extend to the upper aspects of the limbs and
anterior abdomen27 and gustatory sweating that appears over the face, head,
neck, shoulders, and chest after eating spicy and other foods.28
Treatment-induced Neuropathy of Diabetes Mellitus

Treatment-induced neuropathy is associated with rapidly instituted glycemic
control, typically with a high pretreatment hemoglobin A1c. Reports have
described treatment-induced neuropathy in individuals with type 1 and type 2
diabetes mellitus treated with oral hypoglycemic agents or insulin.10 Autonomic
dysfunction and pain are the cardinal features of this neuropathy and are more
common and severe than in patients with generalized diabetic peripheral
neuropathy. Autonomic manifestations improve over time, particularly in
individuals with type 1 diabetes mellitus. Progression of nephropathy and
retinopathy may occur concomitantly with the onset of treatment-induced
neuropathy. The underlying pathophysiology of treatment-induced neuropathy
and the exacerbation of the retinopathy and nephropathy is not known
(CASE 4-1).
IMMUNE-MEDIATED AUTONOMIC NEUROPATHIES

AND GANGLIONOPATHIES
Typically, immune-mediated autonomic neuropathies are characterized by an
acute or subacute presentation. In many patients, an antecedent event is
identified. Autonomic signs and symptoms may involve both the sympathetic
and parasympathetic divisions of the autonomic nervous system and occur in
varying combinations. Autonomic features include orthostatic hypotension,
sudomotor impairment, gastrointestinal dysmotility, bladder atony, impotence,
secretomotor paralysis, and blurring of vision associated with tonic pupils.29
Sensory manifestation may be a prominent concomitant feature in some
patients.30 Other features include pain, coughing episodes, psychiatric
symptoms, sleep apnea, and aspiration. Acute autonomic and sensory

neuropathy is a rare disorder.31 This disorder differs from autoimmune

autonomic ganglionopathy by the presence of various degrees of sensory
impairment. Sensory loss may affect all modalities; may affect the face,
scalp, and trunk; and may be asymmetric and segmental. MRI of the spinal
cord may reveal high-intensity abnormalities in the posterior column on
T2-weighted gradient recalled echo (GRE) images in patients with sensory
ataxia.30
Autoimmune autonomic ganglionopathy due to ganglionic antibodies is
the paradigmatic autoimmune autonomic disorder. The majority of patients
with autoimmune autonomic ganglionopathy have autoantibodies directed
against the α3 subunit of the ganglionic nicotinic acetylcholine receptors.32
Patients typically present with a subacute autonomic neuropathy that can
progress to pandysautonomia.32 The typical clinical findings in autoimmune
autonomic neuropathy include xerostomia, xerophthalmia, orthostatic
hypotension with impaired heart rate response to orthostatic and other stresses,
impaired pupillary response to light and accommodation, gastrointestinal
dysmotility, and urinary retention.33 The presentation is heterogeneous; patients
with higher antibody titers tend to have widespread dysautonomia, whereas
those with lower antibody levels have a more focal or restricted presentation.34
Malignancies such as small cell lung carcinoma, thymoma, bladder carcinoma,
and rectal carcinoma have been associated with the antibodies and phenotypic
presentation.35 Ganglionic antibodies have been reported in patients with the
clinical phenotype of pure autonomic failure.36 Almost 50% of cases with a
subacute presentation are seronegative.32 For more information about
autoimmune autonomic ganglionopathy, refer to the article “Autoimmune
Autonomic Disorders” by Steven Vernino, MD, PhD, FAAS, FAAN,37 in this
issue of Continuum.
The anti-Hu antibody (also known as antineuronal nuclear antibody type 1
[ANNA-1]) is the most common antibody associated with paraneoplastic
syndromes; it characteristically occurs in patients with small cell lung carcinoma,
although it may be seen in patients with other malignancies too.38,39 The
autonomic manifestations may occur in the setting of a widespread
paraneoplastic syndrome. Purkinje cell antibody type 2 (PCA-2)40 and antibodies
to the neuronal cytoplasmic protein collapsin response mediator protein-5
(CRMP-5),41 P/Q voltage-gated calcium channel, voltage-gated potassium channel
complex, and N-methyl-D-aspartate (NMDA) receptor are other antibodies
associated with paraneoplastic syndromes.42,43
An acute or subacute autonomic neuropathy may occur in association with
connective tissue disease. Among these, Sjögren syndrome is the most commonly
reported associated disorder.44 Other collagen vascular disorders that may have
autonomic manifestations include rheumatoid arthritis,45 systemic lupus
erythematosus,45 and mixed connective tissue disease.
The dysautonomia associated with Lambert-Eaton myasthenic syndrome
usually includes prominent cholinergic dysfunction, such as dry mouth, erectile
failure, constipation, blurred vision, and impaired sweating.46 Autonomic test
abnormalities include poorly responsive pupils and sudomotor and secretomotor
failure consistent with cholinergic dysfunction. Adrenergic abnormalities may be
seen in some patients. Antibodies directed against presynaptic P/Q type
voltage-gated calcium channels that impair acetylcholine release may be
detectable. Autonomic dysfunction rarely accompanies myasthenia gravis. In
62 FEBRUARY 2020

42% of these patients, antibodies against neuronal ganglionic nicotinic KEY POINT
acetylcholine receptors are detectable.47
● Prominent autonomic
Autonomic manifestations occur frequently in Guillain-Barré syndrome, features do not occur in
although they are usually overshadowed by the motor features of the disorder. chronic inflammatory
Dysautonomia may be more prominent in patients with respiratory failure, demyelinating
severe motor deficits, and the axonal variant of Guillain-Barré syndrome.48–50 polyradiculoneuropathy
(CIDP), and when patients
Occasionally, autonomic features are the presenting feature of the syndrome.51
present with such features,
In contrast, autonomic manifestations of chronic inflammatory demyelinating alternative diagnoses should
polyradiculoneuropathy (CIDP) are typically subclinical and require autonomic be considered. The
testing for detection.52 The presence of prominent autonomic features, cardiac peripheral neuropathy
associated with hereditary
hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel
amyloidosis is sometimes
syndrome, renal impairment, or ocular disease in a patient with CIDP are red misdiagnosed as CIDP,
flags suggesting that alternative diagnoses should be sought, in particular particularly in nonendemic
hereditary amyloidosis, which is frequently misdiagnosed as CIDP.53–55 areas.
AMYLOID NEUROPATHY
Amyloidosis is a generic term used to describe the deposition of insoluble,
low-molecular-weight fibrillar proteins in a beta-pleated sheet configuration
within the extracellular space of various tissues and organs. Amyloid fibrils are
rigid, linear, and nonbranching. They measure approximately 7.5 nm to 10 nm
in width. The structure of the beta-pleated sheet permits Congo red stain
binding, which emits a characteristic apple-green birefringence. Both primary
immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin
amyloidosis with neuropathy (also known as familial amyloid polyneuropathy)
may result in a peripheral neuropathy.
Primary (AL) Amyloidosis

Outside the areas endemic for hereditary transthyretin amyloidosis, primary
(AL) amyloidosis is the most common form of amyloidosis in the Western world.
In the United States, 4500 new cases occur each year. In this disorder, a
monoclonal population of bone marrow plasma cells produce kappa or lambda
type immunoglobulin light chains or light chain fragments. These aggregate and
deposit as amyloid.56–58 AL amyloidosis may be preceded by an increase in serum
levels of free light chains.
The characteristic presentation is nonspecific symptoms such as weight loss
and fatigue accompanied by more specific features such as hepatomegaly,
macroglossia, cutaneous ecchymoses, nonischemic cardiomyopathy with
hypertrophy on echocardiogram, and nondiabetic nephrotic-range proteinuria.56
Autonomic involvement of the cardiovascular, gastrointestinal, and urogenital
systems is common. The most common presentation may be autonomic
dysfunction accompanied by pain and a length-dependent generalized
polyneuropathy.59 Evaluation of AL amyloidosis is by immunofixation
electrophoresis of serum and urine and serum free light chain assay. If normal,
AL amyloidosis is unlikely. If positive, the diagnosis should be confirmed
pathologically by bone marrow, fat aspirate, or lip biopsy.56
Treatment with melphalan and corticosteroids (dexamethasone or
prednisolone) was first introduced almost 50 years ago. This treatment improves
survival, particularly when associated with a reduction in serum or urine
monoclonal protein. Stem cell transplantation may improve survival further,
although this therapy is not suitable for all patients.56 Newer chemotherapy

regimens include the immunomodulating drugs thalidomide and lenalidomide;

the proteasome inhibitor bortezomib, combined with alkylating agents such
as melphalan and cyclophosphamide, may improve survival further.56,60 A
neurotoxic side effect of these drugs is a small fiber and autonomic neuropathy.61
Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis with neuropathy is a manifestation of
hereditary transthyretin amyloidosis, a progressive, debilitating, multisystem,
life-threatening disease caused by the deposition of misfolded transthyretin in
tissues throughout the body. The exact prevalence of hereditary transthyretin
amyloidosis is not known; estimates suggest a worldwide prevalence of 50,000,
with an estimated prevalence of hereditary transthyretin amyloidosis with
neuropathy of approximately 10,000.
The hereditary amyloidoses are autosomal dominant inherited diseases in
which the amyloid precursor is a mutant protein. Mutant transthyretin is a
14-kDa 127 amino acid polypeptide that serves as the transport protein for
thyroxine and retinol-binding protein; it is the most common cause of hereditary
amyloidosis. It is encoded by a single gene on chromosome 18. Hereditary
amyloidosis is associated with more than 120 mutations of the TTR gene.62,63 The
most commonly observed mutation is a substitution of methionine for valine at
position 30 (Val30Met).64,65 This is the predominant variant found in Portugal,
Brazil, and Sweden. Other TTR variants are seen in Japan, Europe, and the
Americas. Less frequently, hereditary amyloidosis is caused by mutations in the
genes encoding for apolipoprotein A-I, fibrinogen Aα, lysozyme, and gelsolin.66
Hereditary transthyretin amyloidosis typically has an insidious onset in the
third to fifth decades. Autonomic manifestations are prominent and may be the
presenting feature of the neuropathy. These include orthostatic intolerance;
upper gastrointestinal symptoms such as nausea, bloating, and early satiety; lower
gastrointestinal symptoms such as constipation, diarrhea, and fecal incontinence;
bladder disturbances; and erectile failure.59 Sensory symptoms such as numbness,
pain, paresthesia, and dysesthesia also occur early in the disease course.
Phenotypic differences exist, even among individuals carrying the same
mutation. These differences depend in part on geographic location. A spectrum
of clinical presentations exist that are only partly related to the mutation. In some
regions, for example, the clinical phenotype of patients with Val30Met
hereditary transthyretin amyloidosis may differ from those seen in Portugal. The
sporadic Japanese patients with hereditary transthyretin amyloidosis outside the
endemic foci exemplify the phenotypic diversity. These patients are older at
presentation; the initial symptom is lower extremity paresthesia, and autonomic
features are mild with prominent large fiber sensory loss. The male to female
ratio is high (>10:1), and the penetrance very low.54,67,68
A pathogenic mutation can be detected in hereditary transthyretin
amyloidosis by TTR gene sequencing. Pathologic confirmation requires
histologic confirmation of amyloid deposition. Recent reports suggest that the
skin biopsy technique may detect cutaneous amyloid deposition.69 Mass
spectrometry–based proteomics is of growing importance in the diagnosis and
typing of AL and hereditary amyloidoses. This technique shows high specificity
but limited sensitivity in the diagnosis of transthyretin amyloidosis.70
Preliminary reports suggest that magnetic resonance neurography may
contribute to the diagnosis too.71
64 FEBRUARY 2020

Orthotopic liver transplant, which removes the principal source of variant KEY POINTS
transthyretin and reduces circulating transthyretin by up to 90%, was the initial
● The peripheral
treatment for hereditary amyloidosis. Data from multiple centers show that this neuropathy associated with
intervention improves neurophysiologic measures, nerve morphology, and hereditary transthyretin
survival.72 However, pharmacotherapeutic interventions that inhibit amyloidosis has a
amyloidogenesis are available. Two RNA-targeted interventions have shown heterogeneous
presentation, even within
efficacy in clinical trials.73,74 Both bind to the 3′ untranslated region of TTR
families in endemic areas.
mRNA and thus avoid mutations in the coding region. Patisiran, a small
interfering RNA delivered as an IV infusion every 3 weeks, and inotersen, an ● When autonomic features
antisense oligonucleotide administered subcutaneously 3 times a week on occur in combination with
alternate days in the first week and then once weekly for 64 weeks, have received peripheral nerve excitability
and neuropsychiatric
regulatory approval by the US Food and Drug Administration (FDA). Other features such insomnia,
pharmacologic interventions include the mutant transthyretin stabilizers agitation, hallucinations, and
tafamidis75 and diflunisal.76 memory loss, antibodies to
the voltage-gated potassium
channel complex protein
PERIPHERAL AUTONOMIC CHANNELOPATHIES should be considered.
Autonomic manifestations may be present in patients with small fiber
neuropathies associated with ion channel mutations. Several reports have ● Among the hereditary
drawn attention to the presence of gain-of-function variants in the genes sensory and autonomic
neuropathies (HSANs),
encoding sodium channels NaV1.7 (SCN9A),77–79 NaV1.8 (SCN10A),80,81 and
autonomic manifestations
NaV1.9 (SCN11A),82 in some patients with small fiber neuropathy. These are most prominent in HSAN
voltage-gated sodium channel isoforms are preferentially expressed on III (also known as Riley-Day
sensory neurons. Proexcitatory changes in channel physiology and syndrome or familial
dysautonomia). HSAN III is
consequent hyperexcitability are seen on functional analyses of these
caused by homozygous
mutations.77 mutations in the ELP1 gene.
Autonomic features, including dry mouth and eyes, reduced urinary
sensation, hesitation, orthostatic dizziness, hyperhidrosis, palpitations, and ● Chemotherapeutic agents
alternating constipation and diarrhea, were present in some patients harboring are the most common cause
of a toxic autonomic
the SCN9A mutation.77 Similar, although less prominent, clinical manifestations neuropathy. Predisposing
have been reported in patients harboring mutations in the genes encoding factors to a chemotherapy-
Nav 1.8 (SCN10A) and Nav1.9 (SCN11A) mutations.80,81 induced peripheral
Similarly, autonomic manifestions are a frequent accompaniment to neuropathy include genetic
factors and an underlying
antibodies to the voltage-gated potassium channel complex, in particular, clinical or subclinical
contactin-associated proteinlike 2 (CASPR2) and leucine-rich glioma peripheral neuropathy.
inactivated protein 1 (LGI1).83–85 In a series of 29 patients with Morvan
syndrome, autonomic manifestations were a common accompaniment to the
neuromyotonia and neuropsychiatric features. Autonomic features included
orthostatic hypotension, tachycardia, hyperhidrosis, sialorrhea, and urinary
incontinence (CASE 4-2).
HEREDITARY AUTONOMIC NEUROPATHIES

Autonomic manifestations occur to a varying degree in the inherited autonomic
neuropathies. These inherited neuropathies include a diverse group of disorders
classified as the hereditary sensory and autonomic neuropathies (HSANs).
HSAN I is an autosomal dominant hereditary sensory radiculoneuropathy that
presents in the second decade. Causative mutations have been identified in five
genes (SPTLC1, SPTLC2, ATL1, RAB7A, and DNMT1).86 HSAN II, also known as
congenital sensory neuropathy, is an autosomal recessive or sporadic disorder
that presents in infancy or early childhood. Mutations in WNK1, RETREG1, and
KIF1A have been associated with HSAN II.86

HSAN III (also known as Riley-Day syndrome or familial dysautonomia), a

rare autosomal recessive disorder seen primarily in children of Ashkenazi Jewish
descent, has prominent autonomic manifestations. The incidence of familial
dysautonomia is 1 in 3700 live births among Ashkenazi Jews, and the carrier
frequency is 1 in 32 individuals.87
HSAN III is caused by homozygous mutations in the ELP1 gene, which
encodes elongator complex protein 1 (ELP1, also known as IκB kinase
complex–associated protein).88 HSAN III presents in infancy. Abnormal
development of primary sensory nerves underlies the disorder, resulting in
reduced pain and temperature sensation, absent deep tendon reflexes, and gait
ataxia.89 Impaired mechanosensory and chemosensory neuronal development
results in baroreflex and chemoreflex dysfunction, leading to orthostatic
hypotension, paroxysmal hypertension, and abnormal control of cardiovascular
function and ventilatory responses to hypoxia and hypercapnia.87,90 Other
clinical manifestations include absence of tears, hypoactive corneal reflexes, and
absence of lingual fungiform papillae. Poor sucking and feeding, esophageal
reflux with vomiting and aspiration, and swallowing dyscoordination may be the
first clinical manifestations.87
HSAN IV (also known as congenital insensitivity to pain with anhidrosis
[CIPA] or hereditary sensory neuropathy with anhidrosis) is the second most
common HSAN. This autosomal recessive disorder manifests in the first months
of life. Features include insensitivity to pain, anhidrosis, episodes of unexplained
fever, and intellectual and motor developmental delay. Missense, nonsense,
frameshift, and splice-site loss-of-function mutations in the NTRK1 (TRKA)
gene are associated with this disorder. In humans, this gene encodes a high-
affinity tyrosine kinase receptor for nerve growth factor (NGF).91 HSAN V is
caused by a homozygous missense or frameshift mutation in NGF, which encodes
β-NGF. The clinical presentation is characterized by loss of pain perception and
consequent acral ulceration, painless fractures, and other trophic injuries.92
CASE 4-2 A 45-year-old man presented with a 3-month history of orthostatic

hypotension, hyperhidrosis, and muscle cramps. He reported a 13.6-kg
(30-lb) weight loss, insomnia, and confusion.
On examination, he was disoriented and showed executive function
impairment. He had orthostatic hypotension with inadequate
compensatory tachycardia. Myokymia was visible in his calves. Distal
sensory loss was present, with hyperalgesia and allodynia.
Screening laboratory testing was normal. Nerve conduction studies
and EMG showed peripheral nerve hyperexcitability and myokymia. CT of
the chest and abdomen was normal. Antibodies to the voltage-gated
potassium channel–related protein contactin-associated proteinlike 2
(CASPR2) were elevated.
COMMENT This case shows the presentation of a patient with Morvan syndrome. The
combination of peripheral and central nervous system manifestations with
elevated CASPR2 antibodies is characteristic of the disorder.
66 FEBRUARY 2020

Other inherited disorders associated with autonomic dysfunction include Fabry
disease (also known as angiokeratoma corporis diffusum)93 and Allgrove syndrome.94
TOXIC NEUROPATHIES
A number of iatrogenic, industrial, and environmental toxins are implicated in
autonomic neuropathies (TABLE 4-1). Chemotherapeutic agents are the most
common iatrogenic cause. Clinically evident dysautonomia occurs with the vinca
alkaloids; platinum derivatives; taxanes; proteasome inhibitors such as bortezomib;
immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide;
the epothilones; doxorubicin; and cytosine arabinoside.61,95 Chemotherapeutic
agents are the most common cause of a toxic autonomic neuropathy. Predisposing
factors to a chemotherapy-induced peripheral neuropathy include genetic factors
and an underlying clinical or subclinical peripheral neuropathy.
In addition, industrial, environmental, and marine toxins may cause an
autonomic neuropathy. These include organic solvents, arsenic, mercury, other
heavy metals, industrial-use acrylamide, and thallium.96 Marine toxins such as
ciguatera may affect ion transport, induce channels or pores in neural and
muscular cellular membranes, alter intracellular membranes of organelles, and
release mediators of inflammation.97
Some Toxic Neuropathies TABLE 4-1
Organic Solvents (eg, n-Hexane)

Acrylamide
Heavy Metals (eg, Lead, Arsenic, Thallium, Mercury)
N-3-Pyridylmethyl-N′-p-Nitrophenyl Urea Rat Poison (of Historic Relevance)
Iatrogenic
◆ Chemotherapeutic agents
◇ Vinca alkaloids
◇ Platinum derivatives
◇ Taxanes
◇ Epothilones
◇ Bortezomib
◇ Thalidomide, lenalidomide, pomalidomide
◇ Doxorubicin
◇ Cytosine arabinoside
◆ Other medications
◇ Perhexiline maleate
◇ Amiodarone
◇ Pentamidine
◇ Gold
◇ Podophyllin
Marine Toxins (eg, Ciguatera)

CONCLUSION
Autonomic neuropathies are highly prevalent and result in diverse clinical
manifestations that affect the cardiovascular, urogenital, gastrointestinal, and
sudomotor systems. Many peripheral neuropathies also have subclinical
autonomic manifestations. Knowledge and recognition of the clinical features of
the autonomic neuropathies combined with the appropriate laboratory and
electrophysiologic testing will facilitate accurate diagnosis. The availability of
effective treatments for some of these neuropathies, for example, the
immune-mediated neuropathies and those associated with hereditary
transthyretin amyloidosis, has given added impetus to clinical recognition and
accurate diagnosis.
REFERENCES
1 Dineen J, Freeman R. Autonomic neuropathy. 11 Rao AD, Bonyhay I, Dankwa J, et al. Baroreflex
Semin Neurol 2015;35(4):458–468. doi:10.1055/ sensitivity impairment during hypoglycemia:
s-0035-1558983. implications for cardiovascular control. Diabetes
2016;65(1):209–215. doi:10.1111/j.1529-8027.
2 Freeman R, Chapleau MW. Testing the autonomic
2012.00390.x.
nervous system. Handb Clin Neurol 2013;115:
115–136. doi:10.1016/B978-0-444-52902-2.00007-2. 12 Adler GK, Bonyhay I, Failing H, et al. Antecedent
hypoglycemia impairs autonomic cardiovascular
3 Cheshire WP Jr. Autonomic history, examination,
function: implications for rigorous glycemic
and laboratory evaluation. Continuum (Minneap
control. Diabetes 2009;58(2):360–366.
Minn) 2020;26(1, Autonomic Disorders):25–43.
doi:10.2337/db08-1153.
4 Centers for Disease Control and Prevention.
13 Freeman R. Diabetic autonomic neuropathy.
National Diabetes Statistics Report, 2017. cdc.
Handb Clin Neurol 2014;126:63–79. doi:10.1016/
gov/diabetes/pdfs/data/statistics/national-
B978-0-444-53480-4.00006-0.
diabetes-statistics-report.pdf. Accessed
December 3, 2019. 14 Freeman R, Wieling W, Axelrod FB, et al. Consensus
statement on the definition of orthostatic
5 International Diabetes Federation. IDF Diabetes
hypotension, neurally mediated syncope and the
Atlas—9th Edition. diabetesatlas.org/en/.
postural tachycardia syndrome. Auton Neurosci
Accessed December 3, 2019.
2011;161(1–2):46–48. doi:10.1016/j.autneu.2011.02.004.
6 Neil HA, Thompson AV, John S, et al. Diabetic
15 Du YT, Rayner CK, Jones KL, et al. Gastrointestinal
autonomic neuropathy: the prevalence of
symptoms in diabetes: prevalence, assessment,
impaired heart rate variability in a geographically
pathogenesis, and management. Diabetes Care
defined population. Diabet Med 1989;6(1):20–24.
2018;41(3):627–637. doi:10.2337/dc17-1536.
doi:10.1111/j.1464-5491.1989.tb01133.x.
16 Schvarcz E, Palmér M, Aman J, et al. Physiological
7 Töyry JP, Niskanen LK, Mäntysaari MJ, et al.
hyperglycemia slows gastric emptying in normal
Occurrence, predictors, and clinical significance
subjects and patients with insulin-dependent
of autonomic neuropathy in NIDDM. Ten-year
diabetes mellitus. Gastroenterology 1997;113(1):
follow-up from the diagnosis. Diabetes 1996;
60–66. doi:10.1016/s0016-5085(97)70080-5.
45(3):308–315. doi:10.2337/diab.45.3.308.
17 Thazhath SS, Jones KL, Horowitz M, Rayner CK.
8 Zoppini G, Cacciatori V, Raimondo D, et al.
Diabetic gastroparesis: recent insights into
Prevalence of cardiovascular autonomic
pathophysiology and implications for
neuropathy in a cohort of patients with newly
management. Expert Rev Gastroenterol Hepatol
diagnosed type 2 diabetes: the Verona newly
2013;7(2):127–139. doi:10.1586/egh.12.82.
diagnosed type 2 diabetes study (VNDS). Diabetes
Care 2015;38(8):1487–1493. doi:10.2337/dc15-0081. 18 Maleki D, Locke GR, 3rd, Camilleri M, et al.
Gastrointestinal tract symptoms among persons
9 Smith AG. Impaired glucose tolerance and
with diabetes mellitus in the community. Arch
metabolic syndrome in idiopathic neuropathy.
Intern Med 2000;160(18):2808–2816. doi:10.1001/
J Peripher Nerv Syst 2012;17(Suppl 2):15–21.
archinte.160.18.2808.
doi:10.1111/j.1529-8027.2012.00390.x.
19 Kempler P, Amarenco G, Freeman R, et al.
10 Gibbons CH, Freeman R. Treatment-induced
Management strategies for gastrointestinal,
neuropathy of diabetes: an acute, iatrogenic
erectile, bladder, and sudomotor dysfunction in
complication of diabetes. Brain 2015;138(1):43–52.
patients with diabetes. Diabetes Metab Res Rev
doi:10.1093/brain/awu3.07.
2011;27(7):665–677. doi:10.1002/dmrr.1223.
68 FEBRUARY 2020

20 Frimodt-Moller C, Mortensen S. Treatment of 35 Nakane S, Higuchi O, Koga M, et al. Clinical
diabetic cystopathy. Ann Intern Med 1980;92(2 pt 2): features of autoimmune autonomic
327–328. doi:10.7326/0003-4819-92-2-327. ganglionopathy and the detection of
subunit-specific autoantibodies to the ganglionic
21 Yuan Z, Tang Z, He C, Tang W. Diabetic
acetylcholine receptor in Japanese patients.
cystopathy: a review. J Diabetes 2015;7(4):
PLoS One 2015;10(3):e0118312. doi:10.1371/journal.
442–447. doi:10.1111/1753-0407.12272.
pone.0118312.
22 Golbidi S, Laher I. Bladder dysfunction in
36 Goldstein DS, Holmes C, Dendi R, et al.
diabetes mellitus. Front Pharmacol 2010;1:136.
Pandysautonomia associated with impaired
doi:10.3389/fphar.2010.00136.
ganglionic neurotransmission and circulating
23 Araujo AB, Hall SA, Ganz P, et al. Does erectile antibody to the neuronal nicotinic receptor. Clin
dysfunction contribute to cardiovascular disease Auton Res 2002;12(4):281–285. doi:10.1007/
risk prediction beyond the Framingham risk s10286-002-0020-3.
score? J Am Coll Cardiol 2010;55(4):350–356.
37 Vernino S. Autoimmune autonomic disorders.
doi:10.1016/j.jacc.2009.08.058.
Continuum (Minneap Minn) 2020;26(1, Autonomic
24 DeGroat WC, Booth AM. Physiology of male Disorders):44–57.
sexual function. Ann Intern Med 1980;329(2 pt 2):
38 Lucchinetti CF, Kimmel DW, Lennon VA.
31. doi:10.7326/0003-4819-92-2-329.
Paraneoplastic and oncologic profiles of
25 Krane RJ, Siroky MB. Neurophysiology of patients seropositive for type 1 antineuronal
erection. Urol Clin North Am 1981;8(1):91–102. nuclear autoantibodies. Neurology 1998;50(3):
652–657. doi:10.1212/wnl.50.3.652.
26 Enzlin P, Mathieu C, Van den Bruel A, et al. Sexual
dysfunction in women with type 1 diabetes: 39 Camdessanché JP, Antoine JC, Honnorat J, et al.
a controlled study. Diabetes Care 2002;25(4): Paraneoplastic peripheral neuropathy associated
672–677. doi:10.2337/diacare.25.4.672. with anti-Hu antibodies. A clinical and
electrophysiological study of 20 patients. Brain
27 Fealey RD, Low PA, Thomas JE. Thermoregulatory
2002;125(pt 1):166–175. doi:10.1093/brain/awf006.
sweating abnormalities in diabetes mellitus.
Mayo Clin Proc 1989;64(6):617–628. doi:10.1016/ 40 Vernino S, Lennon VA. New Purkinje cell antibody
s0025-6196(12)65338-5. (PCA-2): marker of lung cancer-related
neurological autoimmunity. Ann Neurol 2000;
28 Blair DI, Sagel J, Taylor I. Diabetic gustatory
47(3):297–305. doi:10.1002/1531-8249(200003)47:
sweating. South Med J 2002;95(3):360–362.
3<297::AID-ANA4>3.0.CO;2-4.
29 Suarez GA, Fealey RD, Camilleri M, Low PA.
41 Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5
Idiopathic autonomic neuropathy: clinical,
neuronal autoantibody: marker of lung cancer
neurophysiologic, and follow-up studies on
and thymoma-related autoimmunity. Ann Neurol
27 patients. Neurology 1994;44(9):1675–1682.
2001;49(2):146–154. doi:10.1002/1531-8249
doi:10.1212/wnl.44.9.1675.
(20010201)49:2<146::AID-ANA34>3.0.CO;2-E.
30 Koike H, Atsuta N, Adachi H, et al.
42 Florance NR, Davis RL, Lam C, et al. Anti-N-
Clinicopathological features of acute autonomic
methyl-D-aspartate receptor (NMDAR)
and sensory neuropathy. Brain 2010;133(10):
encephalitis in children and adolescents.
2881–2896. doi:10.1093/brain/awq214.
Ann Neurol 2009;66(1):11–18. doi:10.1002/ana.21756.
31 Koike H, Watanabe H, Sobue G. The spectrum of
43 Dalmau J, Gleichman AJ, Hughes EG, et al.
immune-mediated autonomic neuropathies:
Anti-NMDA-receptor encephalitis: case series
insights from the clinicopathological features.
and analysis of the effects of antibodies. Lancet
J Neurol Neurosurg Psychiatry 2013;84(1):98–106.
Neurol 2008;7(12):1091–1098. doi:10.1002/ana.21756.
doi:10.1136/jnnp-2012-302833.
44 Chai J, Logigian EL. Neurological manifestations
32 Vernino S, Low PA, Lennon VA. Experimental
of primary Sjogren's syndrome. Curr Opin Neurol
autoimmune autonomic neuropathy.
2010;23(5):509–513. doi:10.1097/WCO.
J Neurophysiol 2003;90(3):2053–2059.
0b013e32833de6ab.
doi:10.1152/jn.00408.2003.
45 Louthrenoo W, Ruttanaumpawan P, Aramrattana
33 Sandroni P, Vernino S, Klein CM, et al. Idiopathic
A, Sukitawut W. Cardiovascular autonomic
autonomic neuropathy: comparison of cases
nervous system dysfunction in patients with
seropositive and seronegative for ganglionic
rheumatoid arthritis and systemic lupus
acetylcholine receptor antibody. Arch Neurol
erythematosus. QJM 1999;92(2):97–102.
2004;61(1):44–48. doi:10.1001/archneur.61.1.44.
doi:10.1093/qjmed/92.2.97.
34 Gibbons CH, Freeman R. Antibody titers predict
46 Waterman SA. Autonomic dysfunction in
clinical features of autoimmune autonomic
Lambert-Eaton myasthenic syndrome. Clin Auton
ganglionopathy. Auton Neurosci 2009;146(1–2):
Res 2001;11(3):145–154.
8–12. doi:10.1016/j.autneu.2008.11.013.
47 Vernino S, Cheshire WP, Lennon VA. Myasthenia
gravis with autoimmune autonomic neuropathy.
Auton Neurosci 2001;88(3):187–192. doi:10.1016/
S1566-0702(01)00239-9.

48 Feasby TE, Gilbert JJ, Brown WF, et al. An acute 63 Benson MD, Kincaid JC. The molecular biology
axonal form of Guillain-Barré polyneuropathy. and clinical features of amyloid neuropathy.
Brain 1986;109(pt 6):1115–1126. doi:10.1093/ Muscle Nerve 2007;36(4):411–423. doi:10.1002/
brain/109.6.1115. mus.20821.
49 Winer JB, Hughes RAC. Identification of patients 64 Saraiva MJM, Costa PP, Goodman DS.
at risk of arrhythmia in the Guillain-Barré Biochemical marker in familial amyloidotic
syndrome. Q J Med 1988;68(257):735–739. polyneuropathy, Portuguese type. Family studies
doi:10.1093/oxfordjournals.qjmed.a06823. of transthyretin (prealbumin)-methionine-30
variant. J Clin Invest 1985;76(6):2171–2177.
50 Ropper AH, Wijdicks EFM, Truax BT. Guillain Barré
doi:10.1172/JCI112224.
Syndrome. Philadelphia, PA: F.A. Davis, 1991.
65 Hund E, Linke RP, Willig F, Grau A. Transthyretin-
51 Cortelli P, Contin M, Lugaresi A, et al. Severe
associated neuropathic amyloidosis.
dysautonomic onset of Guillain-Barré syndrome
Pathogenesis and treatment. Neurology 2001;
with good recovery. A clinical and autonomic
56(4):431–435. doi:10.1212/wnl.56.4.431.
follow-up study. Ital J Neurol Sci 1990;11(2):
159–162. 66 Plante-Bordeneuve V, Said G. Familial amyloid
polyneuropathy. Lancet Neurol 2011;10(12):
52 Figueroa JJ, Dyck PJ, Laughlin RS, et al. Autonomic
1086–1097. doi:10.1016/S1474-4422(11)70246-0.
dysfunction in chronic inflammatory demyelinating
polyradiculoneuropathy. Neurology 2012;78(10): 67 Koike H, Tanaka F, Hashimoto R, et al. Natural
702–708. doi:10.1212/WNL.0b013e3182494d66. history of transthyretin Val30Met familial amyloid
polyneuropathy: analysis of late-onset cases
53 Mathis S, Magy L, Diallo L, et al. Amyloid
from non-endemic areas. J Neurol Neurosurg
neuropathy mimicking chronic inflammatory
Psychiatry 2012;83(2):152–158. doi:10.1136/jnnp-
demyelinating polyneuropathy. Muscle Nerve
2011-301299.
2012;45(1):26–31. doi:10.1002/mus.22229.
68 Misu K, Hattori N, Nagamatsu M, et al. Late-onset
54 Planté-Bordeneuve V, Ferreira A, Lalu T, et al.
familial amyloid polyneuropathy type I
Diagnostic pitfalls in sporadic transthyretin
(transthyretin Met30-associated familial amyloid
familial amyloid polyneuropathy (TTR-FAP).
polyneuropathy) unrelated to endemic focus in
Neurology 2007;69(7):693–698. doi:10.1212/01.
Japan. Clinicopathological and genetic features.
wnl.0000267338.45673.f4.
Brain 1999;122(pt 10):1951–1962. doi:10.1093/
55 Conceicão I, Gonzalez-Duarte A, Obici L, et al. brain/122.10.1951.
“Red-flag” symptom clusters in transthyretin
69 Ebenezer GJ, Liu Y, Judge DP, et al. Cutaneous
familial amyloid polyneuropathy. J Peripher Nerv
nerve biomarkers in transthyretin familial amyloid
Syst 2016;21(1):5–9. doi:10.1111/jns.12153.
polyneuropathy. Ann Neurol 2017;82(1):44–56.
56 Gertz MA. Immunoglobulin light chain doi:10.1002/ana.24972.
amyloidosis: 2018 update on diagnosis, prognosis,
70 Vrana JA, Theis JD, Dasari S, et al. Clinical
and treatment. Am J Hematol 2018;93(9):
diagnosis and typing of systemic amyloidosis
1169–1180. doi:10.1002/ajh.25149.
in subcutaneous fat aspirates by mass
57 Falk RH, Skinner M. The systemic amyloidoses: an spectrometry-based proteomics.
overview. Adv Intern Med 2000;45:107–137. Haematologica 2014;99(7):1239–1247. doi:10.3324/
haematol.2013.102764.
58 Cohen AD, Comenzo RL. Systemic light-chain
amyloidosis: advances in diagnosis, prognosis, 71 Kollmer J, Hund E, Hornung B, et al. In vivo
and therapy. Hematology Am Soc Hematol Educ detection of nerve injury in familial amyloid
Program 2010;2010:287–294. doi:10.1182/ polyneuropathy by magnetic resonance
asheducation-2010.1.287. neurography. Brain 2015;138(pt 3):549–562.
doi:10.1093/brain/awu344.
59 Wang AK, Fealey RD, Gehrking TL, Low PA.
Patterns of neuropathy and autonomic failure in 72 Yamamoto S, Wilczek HE, Nowak G, et al. Liver
patients with amyloidosis. Mayo Clin Proc 2008; transplantation for familial amyloidotic
83(11):1226–1230. doi:10.4065/83.11.1226. polyneuropathy (FAP): a single-center
experience over 16 years. Am J Trans 2007;7(11):
60 Kumar SK, Gertz MA, Lacy MQ, et al. Recent
2597–2604. doi:10.1111/j.1600-6143.2007.01969.x.
improvements in survival in primary systemic
amyloidosis and the importance of an early 73 Adams D, Gonzalez-Duarte A, O’Riordan WD,
mortality risk score. Mayo Clin Proc 2011;86(1): et al. Patisiran, an RNAi therapeutic, for
12–18. doi:10.4065/mcp.2010.0480. hereditary transthyretin amyloidosis. N Engl J
Med 2018;379:11–21. doi:10.1056/NEJMoa1716153.
61 Miltenburg NC, Boogerd W. Chemotherapy-
induced neuropathy: a comprehensive survey. 74 Benson MD, Waddington-Cruz M, Berk JL, et al.
Cancer Treat Rev 2014;40(7):872–882. doi:10.1016/ Inotersen treatment for patients with hereditary
j.ctrv.2014.04.004. transthyretin amyloidosis. N Engl J Med 2018;379:
22–31. doi:10.1056/NEJMoa1716793.
62 Ando Y, Nakamura M, Araki S. Transthyretin-
related familial amyloidotic polyneuropathy.
Arch Neurol 2005;62(7):1057–1062. doi:10.1001/
archneur.62.7.1057.
70 FEBRUARY 2020

75 Coelho T, Maia LF, Martins da Silva A, et al. 87 Norcliffe-Kaufmann L, Slaugenhaupt SA,
Tafamidis for transthyretin familial amyloid Kaufmann H. Familial dysautonomia: History,
polyneuropathy: a randomized, controlled trial. genotype, phenotype and translational research.
Neurology 2012;79(8):785–792. doi:10.1212/ Prog Neurobiol 2017;152:131–148. doi:10.1016/j.
WNL.0b013e3182661eb1. pneurobio.2016.06.003.
76 Berk JL, Suhr OB, Obici L, et al. Repurposing 88 Slaugenhaupt SA, Blumenfeld A, Gill SP, et al.
diflunisal for familial amyloid polyneuropathy: Tissue-specific expression of a splicing mutation
a randomized clinical trial. JAMA 2013;310(24): in the IKBKAP gene causes familial dysautonomia.
2658–2667. doi:10.1001/jama.2013.283815. Am J Hum Genet 2001;68(3):598–605.
doi:10.1086/318810.
77 Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of
function Nav 1.7 mutations in idiopathic small 89 Macefield VG, Norcliffe-Kaufmann L, Gutierrez J,
fiber neuropathy. Ann Neurol 2012;71(1):26–39. et al. Can loss of muscle spindle afferents
doi:10.1002/ana.22485. explain the ataxic gait in Riley-Day syndrome?
Brain 2011;134(pt 11):3198–3208. doi:10.1093/brain/
78 Han C, Hoeijmakers JG, Liu S, et al. Functional
awr168.
profiles of SCN9A variants in dorsal root ganglion
neurons and superior cervical ganglion neurons 90 Norcliffe-Kaufmann L, Axelrod F, Kaufmann H.
correlate with autonomic symptoms in small Afferent baroreflex failure in familial
fibre neuropathy. Brain 2012;135(pt 9):2613–2628. dysautonomia. Neurology 2010;75(21):1904–1911.
doi:10.1093/brain/aws187. doi:10.1212/WNL.0b013e3181feb283.
79 Han C, Hoeijmakers JG, Ahn HS, et al. 91 Indo Y. Nerve growth factor and the physiology
Nav1.7-related small fiber neuropathy: impaired of pain: lessons from congenital insensitivity to
slow-inactivation and DRG neuron pain with anhidrosis. Clin Genet 2012;82(4):
hyperexcitability. Neurology 2012;78(21): 341–350. doi:10.1111/j.1399-0004.2012.01943.x.
1635–1643. doi:10.1212/WNL.0b013e3182574f12.
92 Rotthier A, Baets J, Vriendt ED, et al. Genes for
80 Huang J, Yang Y, Zhao P, et al. Small-fiber hereditary sensory and autonomic neuropathies:
neuropathy Nav1.8 mutation shifts activation to a genotype-phenotype correlation. Brain 2009;
hyperpolarized potentials and increases 132(pt 10):2699–2711. doi:10.1093/brain/awp198.
excitability of dorsal root ganglion neurons.
93 Biegstraaten M, van Schaik IN, Wieling W, et al.
J Neurosci 2013;33(35):14087–14097. doi:10.1523/
Autonomic neuropathy in Fabry disease: a
JNEUROSCI.2710-13.2013.
prospective study using the Autonomic
81 Faber CG, Lauria G, Merkies IS, et al. Gain-of- Symptom Profile and cardiovascular autonomic
function Nav1.8 mutations in painful neuropathy. function tests. BMC Neurol 2010;10:38.
Proc Natl Acad Sci U S A 2012;109(47): doi:10.1186/1471-2377-10-38.
19444–19449. doi:10.1073/pnas.1216080109.
94 Kimber J, McLean BN, Prevett M, Hammans SR.
82 Huang J, Han C, Estacion M, et al. Gain-of- Allgrove or 4 “A” syndrome: an autosomal
function mutations in sodium channel Na(v)1. 9 in recessive syndrome causing multisystem
painful neuropathy. Brain 2014;137(pt 6): neurological disease. J Neurol Neurosurg
1627–1642. doi:10.1093/brain/awu079. Psychiatry 2003;74(5):654–657. doi:10.1136/
jnnp.74.5.654.
83 Klein CJ, Lennon VA, Aston PA, et al. Chronic pain
as a manifestation of potassium channel- 95 Staff NP, Grisold A, Grisold W, Windebank AJ.
complex autoimmunity. Neurology 2012;79(11): Chemotherapy-induced peripheral neuropathy:
1136–1144. doi:10.1212/WNL.0b013e3182698cab. a current review. Ann Neurol 2017;81(6):772–781.
doi:10.1002/ana.24951.
84 Irani SR, Pettingill P, Kleopa KA, et al. Morvan
syndrome: clinical and serological observations 96 Freeman R. Autonomic peripheral neuropathy.
in 29 cases. Ann Neurol 2012;72(2):241–255. Lancet 2005;365(9466):1259–1270. doi:10.1016/
doi:10.1002/ana.23577. S0140-6736(05)74815-7.
85 Gadoth A, Pittock SJ, Dubey D, et al. Expanded 97 Burnett JW, Weinrich D, Williamson JA, et al.
phenotypes and outcomes among 256 Autonomic neurotoxicity of jellyfish and marine
LGI1/CASPR2-IgG-positive patients. Ann Neurol animal venoms. Clin Auton Res 1998;8(2):125–130.
2017;82(1):79–92. doi:10.1002/ana.24979. doi:10.1007/BF02267823.
86 Rotthier A, Baets J, Timmerman V, Janssens K.
Mechanisms of disease in hereditary sensory and
autonomic neuropathies. Nat Rev Neurol 2012;
8(2):73–85. doi:10.1038/nrneurol.2011.227.

REVIEW ARTICLE

Synucleinopathies
C O N T I N UU M A UD I O By Elizabeth A. Coon, MD; Wolfgang Singer, MD
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article reviews the α-synucleinopathies pure
autonomic failure, multiple system atrophy, dementia with Lewy bodies,
and Parkinson disease with respect to autonomic failure.
RECENT FINDINGS: The pattern and severity of autonomic involvement in the

synucleinopathies is related to differences in cellular deposition and
neuronal populations affected by α-synuclein aggregation, which
influences the degree and manifestation of autonomic failure. Clinical and
laboratory autonomic features distinguish the different synucleinopathies
based on pattern and severity. These features also determine which
patients are at risk for evolution from pure autonomic failure to the
CITE AS: synucleinopathies with prominent motor involvement, such as multiple
C O N T I N U U M ( M I N N E AP M I N N )
system atrophy, dementia with Lewy bodies, or Parkinson disease.
72–92.
SUMMARY: Autonomic failure is a key feature of the synucleinopathies, with
varying type and degree of dysfunction from predominantly peripheral
Dr Wolfgang Singer, Department
of Neurology, Mayo Clinic, 200 involvement in the Lewy body disorders to central involvement in multiple
First St SW, Rochester, MN 55905, system atrophy.
singer.wolfgang@mayo.edu.
Dr Coon reports no disclosure. INTRODUCTION
T
Dr Singer serves on the editorial
board of Autonomic Neuroscience: he synucleinopathies refer to a group of disorders characterized by
Basic & Clinical, as an associate abnormally misfolded α-synuclein aggregates in the peripheral and
editor for Clinical Autonomic central nervous systems. Differences in the cellular location and
Research, as a consultant for
Biohaven Pharmaceuticals, and pattern of α-synuclein deposition lead to clinically distinct entities of
on an advisory board for synucleinopathies: pure autonomic failure, multiple system atrophy
Lundbeck. Dr Singer receives
research/grant support from
(MSA), dementia with Lewy bodies (DLB), and Parkinson disease.1,2 Autonomic
Dysautonomia International, failure in the synucleinopathies is related to dysfunction and neurodegeneration
the US Food and Drug associated with abnormal α-synuclein aggregation, with accumulating evidence
Administration (R01 FD4789),
and the National Institutes
of cell-to-cell spread of α-synuclein in a “prionlike” manner.3 Involvement of the
of Health (R01 NS092625, central autonomic network and peripheral neurons controlling autonomic function
U54 NS65736). may manifest as orthostatic hypotension, urogenital dysfunction, gastrointestinal
UNLABELED USE OF dysmotility, and thermoregulatory dysfunction.4 Another unifying feature of
PRODUCTS/INVESTIGATIONAL synucleinopathies is the occurrence of rapid eye movement (REM) sleep
USE DISCLOSURE:
behavior disorder, which may precede the autonomic or motor features.5,6
Drs Coon and Singer discuss the
unlabeled/investigational use of Pure autonomic failure is characterized by predominantly peripheral
pyridostigmine for orthostatic deposition of α-synuclein, whereas central neuronal inclusions, specifically Lewy
hypotension and clonazepam
and melatonin for dream
bodies and Lewy neurites, are the major pathologic inclusions in Parkinson
enactment behavior. disease and DLB.7 MSA is characterized by oligodendroglial cytoplasmic
inclusions in the central nervous system.8,9 While symptoms may overlap, the
© 2020 American Academy pattern and severity of autonomic dysfunction with associated clinical symptoms
of Neurology. and signs differentiate the various synucleinopathies.
72 FEBRUARY 2020

PURE AUTONOMIC FAILURE KEY POINTS
Pure autonomic failure was initially described in 1925 by Bradbury and Eggleston
● α-Synuclein aggregation
in three patients with severe orthostatic hypotension highlighted by syncope; it in central and peripheral
was previously referred to as Bradbury-Eggleston syndrome or idiopathic orthostatic autonomic structures may
hypotension.10,11 Pure autonomic failure is a sporadic, gradually progressive lead to autonomic
disorder of adult onset. Orthostatic hypotension with a tendency for syncope is manifestations of
orthostatic hypotension,
the clinical hallmark, although genitourinary dysfunction, bowel dysfunction, or
urogenital dysfunction,
heat intolerance may precede or accompany orthostatic hypotension (CASE 5-1).10 gastrointestinal dysmotility,
or thermoregulatory
Clinical Features dysfunction.
Orthostatic hypotension may be symptomatic or asymptomatic in pure
● Rapid eye movement
autonomic failure. As pure autonomic failure tends to present insidiously, a shift sleep behavior disorder is a
may occur in the cerebral autoregulatory curve, leading to patients tolerating a unifying feature of the
substantial drop in blood pressure without obvious symptoms.13 When synucleinopathies and may
symptoms are present, lightheadedness is commonly reported and may be precede autonomic or motor
features in the various
associated with dizziness, vision changes, weakness, fatigue, and cognitive diseases.
symptoms. Severe and sustained orthostatic hypotension may lead to syncope,
such as with prolonged standing.14 Postprandial hypotension and accentuation of ● Pure autonomic failure is a
orthostatic hypotension with high ambient heat and a rise in core temperature sporadic, gradually
progressive
are frequently seen in patients with pure autonomic failure.
neurodegenerative disorder
Supine hypertension accompanies orthostatic hypotension in approximately characterized by orthostatic
half of all patients with pure autonomic failure, and patients may record systolic hypotension with a
blood pressures well above 200 mm Hg.15 This seemingly paradoxical tendency for syncope.
phenomenon is incompletely understood, but residual sympathetic activity,
● Supine hypertension is
denervation hypersensitivity, and impaired baroreflex control are likely found in approximately half
involved.16 The long-term risks of supine hypertension include end organ of all patients with pure
damage, such as left ventricular hypertrophy17 and renal impairment.18 Little is autonomic failure; it may be
known about cerebrovascular effects in supine hypertension, but the limited severe and often
complicates treatment of
available information suggests that supine hypertension may be associated with orthostatic hypotension.
white matter lesion burden.19
In addition to orthostatic hypotension, approximately half of all patients with ● The diagnosis of pure
pure autonomic failure report bladder disturbances. Bladder symptoms in pure autonomic failure is based
on detection of orthostatic
autonomic failure range from urgency and frequency to urinary retention and
hypotension, usually with
incontinence and may require catheterization. Erectile dysfunction is commonly clinical history or evaluation
reported in men.20 Constipation can be an early and severe symptom of pure consistent with widespread
autonomic failure.18 Half of all patients with pure autonomic failure report autonomic failure.
abnormal sweating, which may be noted as either hypohidrosis or hyperhidrosis,
the latter likely due to anhidrosis with compensatory hyperhidrosis chiefly noted
by the patient.20 Anosmia is also frequently detected on objective testing;
however, patients rarely report this symptom.20,21
Diagnosis
The diagnosis of pure autonomic failure is based on consensus criteria by the
American Academy of Neurology and American Autonomic Society: pure
autonomic failure is an idiopathic sporadic disorder characterized by orthostatic
hypotension, usually with evidence of more widespread autonomic failure.11
Bedside testing of orthostatic blood pressure may lead to the diagnosis of
orthostatic hypotension, while autonomic function testing can be crucial in
determining whether orthostatic hypotension is due to a neurologic cause and
helping to localize the site of the lesion.

SYNUCLEINOPATHIES
Autonomic function testing typically reveals a disorder of peripheral

autonomic nerves with a reduction in sweat volumes recorded during
quantitative sudomotor axon reflex test (QSART) and impaired cardiovagal
function. Adrenergic failure is shown on beat-to-beat blood pressure response to
Valsalva maneuver, whereas head-up tilt is able to determine the presence of
supine hypertension and the degree of orthostatic hypotension. The severity
of autonomic failure can be graded using a composite autonomic severity
score, with higher scores indicating more severe autonomic failure.22 The
thermoregulatory sweat test can be used with QSART to assess for peripheral
or central sudomotor failure and determine the degree of anhidrosis. An area
of hypohidrosis or anhidrosis on the thermoregulatory sweat test with a
CASE 5-1 A 76-year-old woman presented with lightheadedness. Her symptoms

began around the age of 72, with progressive orthostatic lightheadedness
occurring immediately after standing or walking up steps. She could
tolerate standing for up to 3 minutes before needing to sit. She had a
history of urinary urgency with no incontinence and constipation treated
with dietary measures. She had not noticed changes in sweating but
reported worsening orthostasis in warm environments.
Her neurologic examination was normal. Autonomic testing revealed
cardiovagal failure reflected by severely reduced heart rate responses to
Valsalva and deep breathing. Severe adrenergic failure was evident
based on beat-to-beat blood pressure responses to the Valsalva
maneuver revealing absent late phase II and phase IV with prolonged
blood pressure recovery time. Her supine blood pressure was 154/78 mm Hg
with pulse of 78 beats/min, which dropped to 72/58 mm Hg with pulse of
86 beats/min after 10 minutes of 70-degree head-up tilt, associated with
symptoms of lightheadedness and coat-hanger distribution pain. The
quantitative sudomotor axon reflex test (QSART) and thermoregulatory
sweat test revealed reduced sweating in the lower limbs (FIGURE 5-112).
Laboratory causes of autonomic neuropathy or ganglionopathy, including
antibodies to the ganglionic (α3) nicotinic acetylcholine receptor
were negative.
COMMENT The clinical history in this case is suggestive of pure autonomic failure; the
patient demonstrates autonomic failure in the absence of motor findings.
Autonomic testing revealed severe cardiovagal and adrenergic failure with
orthostatic hypotension. The combination of QSART and thermoregulatory
sweat test results in this patient is consistent with a peripheral pattern of
sudomotor failure.
74 FEBRUARY 2020

normal QSART is indicative of a preganglionic or central lesion, whereas
reduced or absent QSART volumes corresponding to an area of hypohidrosis or
anhidrosis on the thermoregulatory sweat test is indicative of a postganglionic
or peripheral etiology.
Imaging studies in pure autonomic failure may include brain MRI to rule out
evidence of central nervous system pathology.17 Cardiac functional imaging with
123
I-metaiodobenzylguanidine (123I-MIBG) myocardial single-photon emission
CT (SPECT) and 6-[18F]fluorodopamine positron emission tomography (PET)
characteristically demonstrate decreased cardiac sympathetic innervation
similar to patients with Parkinson disease and in contrast to patients with MSA,
who typically show normal cardiac innervation.23–25
FIGURE 5-1
Pure autonomic failure. Autonomic testing demonstrates reduced heart rate responses
(red) to deep breathing and Valsalva maneuver, indicative of severe cardiovagal failure.
Beat-to-beat blood pressure responses to Valsalva maneuver show adrenergic failure with
absent late phase II and phase IV with prolonged blood pressure time, whereas tilt shows
immediate and sustained orthostatic hypotension. The thermoregulatory sweat test
demonstrates anhidrosis over the abdomen and lower extremities, and the quantitative
sudomotor axon reflex test (QSART) shows reduction in sweat volumes over the lower
extremity sites, indicative of postganglionic sudomotor failure.
Reprinted with permission from Benarroch EE, Singer W.12 © 2014 Oxford University Press.

SYNUCLEINOPATHIES
Low supine norepinephrine levels, with minimal to no increase upon standing,

are often seen on laboratory testing in pure autonomic failure. Once a peripheral
etiology of neurogenic orthostatic hypotension is confirmed, causes of peripheral
neuropathy known to be associated with substantial autonomic involvement,
such as amyloidosis, diabetes mellitus, connective tissue disorders, and
autoimmune diseases, should be considered and ruled out as appropriate before a
diagnosis of pure autonomic failure is made.
Treatment
No disease-modifying therapy has yet been identified for pure autonomic
failure; however, individual autonomic symptoms can usually be well managed
with a multispecialty team. Patients often respond to treatments aimed at
controlling orthostatic hypotension and supine hypertension, using both
nonpharmacologic and pharmacologic approaches. For more information on the
treatment of orthostatic hypotension, refer to the article “Management of
Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD, and Horacio
Kaufmann, MD, FAAN,26 in this issue of Continuum. Treatment of neurogenic
bladder dysfunction should be based on urologic testing. If urinary frequency or
urgency predominates and patients have no urinary retention, they may benefit
from anticholinergic medications or a β3-adrenergic agonist. If urinary hesitancy
and retention predominate, selective α1A-adrenergic receptor antagonists can
theoretically be helpful; however, the associated worsening of orthostatic
hypotension often precludes their use. Patients with severe urinary retention may
require catheterization. REM sleep behavior disorder can be treated with
melatonin or clonazepam, or both, if the condition is frequent or severe enough to
cause concern for potential injury.27
TABLE 5-1 Factors Associated With Evolution From Pure Autonomic Failure to Other
Synucleinopathiesa
Conversion to Multiple System Atrophy

◆ Subtle motor signs
◆ Rapid eye movement (REM) sleep behavior disorder
◆ Preserved olfaction
◆ Preserved norepinephrine levels
◆ Preganglionic pattern of anhidrosis
◆ Severe bladder dysfunction
Conversion to Dementia With Lewy Bodies or Parkinson Disease
◆ Subtle motor signs
◆ REM sleep behavior disorder
◆ Impaired olfaction
◆ Longer duration of illness
a
Data from Singer W, et al, Neurology,34 and Kaufmann, et al, Ann Neurol.20
76 FEBRUARY 2020

Pathophysiology KEY POINTS
The classic phenotype of pure autonomic failure is of postganglionic efferent
● Evaluation in pure
autonomic failure, with dysfunction or degeneration of peripheral sympathetic autonomic failure reveals
nerves leading to impaired catecholamine production and release.28,29 Evidence peripheral involvement with
of low plasma concentrations of norepinephrine with no or marginal increase decreased uptake on
upon standing is seen. Loss of noradrenergic and cholinergic autonomic nerves cardiac functional imaging
and low levels of supine
leads to impaired vasoconstriction and contributes to venous pooling and
norepinephrine that have
orthostatic hypotension as well as anhidrosis. Prominent cardiac sympathetic minimal to no increase upon
denervation is seen, similar to other Lewy body disorders.21,30,31 The prominent standing.
peripheral denervation in pure autonomic failure leads to receptor
hypersensitivity, and agents with direct peripheral action on sympathetic ● A subset of patients with
pure autonomic failure
receptors produce exaggerated responses.32 phenoconvert to a
synucleinopathy with motor
Phenoconversion to Other Synucleinopathies or cognitive impairment, or
Subtle signs of neurologic motor dysfunction may be present in patients with both. Greater severity and
earlier autonomic symptoms
pure autonomic failure and were even described in one of the original cases with central autonomic
by Bradbury and Eggleston.10,33 Patients with pure autonomic failure may failure on autonomic testing
demonstrate hyperreflexia, bradykinesia, tremulousness, or abnormal gait, predicts conversion to
which do not meet clinical diagnostic criteria for MSA, Parkinson disease, or multiple system atrophy
(MSA).
DLB.20,34 While not absolute, the presence of subtle motor signs and probable
REM sleep behavior disorder may indicate later development of MSA, Parkinson ● MSA is characterized by
disease, or DLB.20,34 autonomic failure with
The majority of patients with pure autonomic failure have a slowly motor symptoms of
predominant parkinsonism
progressive course of autonomic dysfunction over many years. However, a 2017
(MSA-P) or predominant
retrospective cohort study describes a subset of patients with pure autonomic cerebellar ataxia (MSA-C),
failure evolving into another synucleinopathy with motor and cognitive although parkinsonism and
impairment.35 A prospective study found that approximately one-third of ataxia often overlap later in
patients met clinical criteria for a synucleinopathy, including Parkinson disease.
disease, DLB, or MSA, within 4 years of follow-up.20 Patients who did not
phenoconvert tended to be slightly younger at onset and had very low plasma
norepinephrine levels.20 Clinical features predictive of eventual evolution to
a motor synucleinopathy are summarized in TABLE 5-1 and differ between
MSA and the Lewy body disorders of Parkinson disease and DLB. Patients
who are eventually diagnosed with MSA have evidence of predominantly
central dysfunction on autonomic testing and may have subtle motor signs
on examination and early evidence of severe bladder dysfunction.34,35
Characteristics of patients with pure autonomic failure who are eventually
diagnosed with Parkinson disease or DLB include less severe autonomic failure on
autonomic function testing, subtle signs of parkinsonism on early examination,
and anosmia.20,34 Patients with pure autonomic failure who phenoconvert to MSA
tend to do so earlier than those who later manifest Parkinson disease or DLB,
typically within 3 years from the original pure autonomic failure diagnosis,
whereas evidence of Parkinson disease or DLB was eventually found up to 8 years
after pure autonomic failure diagnosis.20,34,36
MULTIPLE SYSTEM ATROPHY

MSA is a progressive neurodegenerative disorder characterized by autonomic
failure with motor signs of predominant parkinsonism (MSA-P) (CASE 5-2) or
predominant cerebellar ataxia (MSA-C). The term multiple system atrophy has
been used since it was introduced in 1969 by Graham and Oppenheimer37 and

SYNUCLEINOPATHIES
encompasses disorders previously referred to as striatonigral degeneration,

olivopontocerebellar degeneration, and Shy-Drager syndrome.37
MSA affects an estimated 0.6 per 100,000 people per year, which increases to
3 per 100,000 people per year in those older than 50 years of age,39 with onset
typically occurring in the sixth decade.40 While generally considered a sporadic
disease, a loss-of-function mutation in COQ2, a gene involved in coenzyme Q10
synthesis, has been reported in familial cases and rare sporadic cases from Japan
but not in North American or European populations.41 Survival in MSA is poor,
with a progressive course culminating in death with median survival from onset
to death ranging from 6 to 10 years.42–44
CASE 5-2 A 55-year-old man presented for evaluation of lightheadedness. His

symptoms were characterized by transient lightheadedness upon
standing associated with darkening of vision after climbing stairs or when
arising from squatting. Six months before presentation, he noticed a fine
tremor in his upper extremities.
His past medical history included polysomnogram-confirmed rapid
eye movement (REM) sleep behavior disorder since age 48. Erectile
dysfunction also began at age 48, with worsening bladder function.
Following a transurethral resection procedure, he became incontinent
and initiated clean intermittent catheterization.
Neurologic examination revealed hypomimia and a mild hypokinetic
dysarthria with antecollis. Tone was increased axially and in all
extremities. Brief jerkiness was noted with his arms held in posture,
consistent with myoclonus. His gait was characterized by shuffling steps
with reduced arm swing bilaterally.
Autonomic testing revealed normal quantitative sudomotor axon reflex
test (QSART) volumes. Heart rate responses to Valsalva and deep
breathing were decreased. Beat-to-beat blood pressure responses to the
Valsalva maneuver revealed absent late phase II and phase IV overshoot
and prolonged blood pressure recovery time. Supine blood pressure was
138/86 mm Hg with pulse of 86 beats/min with an immediate and
progressive drop to 72/48 mm Hg with pulse of 95 beats/min after
5 minutes of 70-degree head-up tilt, in the absence of symptoms.
Thermoregulatory sweat test showed global anhidrosis with light acral
sweating (FIGURE 5-238).
COMMENT The clinical history is suggestive of multiple system atrophy with

predominant parkinsonism; the patient demonstrates autonomic failure
and REM sleep behavior disorder with motor findings of parkinsonism,
dystonia, and myoclonus. Autonomic testing revealed severe adrenergic
failure with orthostatic hypotension and cardiovagal impairment. The
sudomotor findings are consistent with a central pattern of sudomotor
failure, with intact QSART responses over areas of anhidrosis on the
thermoregulatory sweat test.
78 FEBRUARY 2020

Clinical Features
MSA begins with motor symptoms in the majority of patients. These may manifest
as parkinsonism with bradykinesia, rigidity, and a jerky postural tremor,
whereas an asymmetric “pill-rolling” resting tremor as classically seen in
Parkinson disease is rare in MSA-P. When initially presenting with
predominantly cerebellar features such as ataxic limb movements, wide-based
gait, and nystagmus, the phenotype is referred to as MSA-C.45 With progression
of disease, however, parkinsonism and ataxic signs and symptoms tend to
overlap.43 The irregular postural and action tremor is frequently seen in patients
with MSA with evidence of minipolymyoclonus on neurophysiologic
FIGURE 5-2
Multiple system atrophy with predominant parkinsonism. Autonomic testing demonstrates
severe cardiovagal failure with reduced heart rate responses (red) to deep breathing and
Valsalva maneuver. Severe adrenergic failure is shown on beat-to-beat blood pressure
responses to Valsalva maneuver, with absent late phase II and phase IV with prolonged
blood pressure time. Orthostatic hypotension is immediate and progressive on tilt.
Thermoregulatory sweat test demonstrates global anhidrosis with acral hypohidrosis. In
conjunction with the quantitative sudomotor axon reflex test (QSART) showing intact
postganglionic sudomotor function, this pattern is indicative of a central autonomic disorder.
Reprinted with permission from Benarroch EE, Singer W.38 © 2014 Oxford University Press.

SYNUCLEINOPATHIES
examination.46 Pyramidal tract dysfunction may manifest as hyperreflexia,

spasticity, and extensor plantar responses. Dystonia may be prominent, with
disproportionate antecollis, camptocormia, or dystonia affecting hand or foot.47
Motor impairment frequently leads to falls, and approximately half of all patients
require gait aids within 3 years from the onset of motor symptoms.48 Speech is
often affected and may demonstrate hypokinetic, ataxic, spastic, or mixed
characteristics. As the disease advances, dysarthria may progress to anarthria and
dysphagia may also become prominent.
Autonomic dysfunction in MSA tends to be severe and widespread early in
disease. Orthostatic hypotension may be associated or manifest first with
supine hypertension. Some patients may not exhibit symptoms even with severe
drops in blood pressure, whereas others may experience recurrent syncope.
Genitourinary failure may also be early and severe. Sexual dysfunction frequently
manifests as erectile dysfunction in males and genital hyposensitivity in females.
Neurogenic bladder may initially manifest as frequency and urgency and
progress to incontinence and incomplete bladder emptying. Thermoregulatory
disturbances may be clinically silent, or patients may have symptoms of heat
intolerance due to anhidrosis or excessive sweating due to compensatory
hyperhidrosis.49
Respiratory and sleep disturbances are common in MSA. Approximately
half of all patients develop diurnal or nocturnal inspiratory laryngeal stridor;
nocturnal stridor may occur in association with sleep apneas.50 Periodic limb
movements and excessive daytime sleepiness may be noted.
Awareness of cognitive impairment in MSA is increasing, which most
commonly presents as frontal-executive impairment followed by memory and
visuospatial dysfunction. However, early and prominent multidomain cognitive
deficits or visual hallucinations make the diagnosis of MSA unlikely.51,52
Diagnosis
The current diagnostic criteria for MSA include the categories of definite,
probable, and possible. Definite MSA requires confirmed neuropathologic
findings on postmortem examination.45 Criteria for probable and possible MSA
are shown in TABLE 5-2. Core criteria include evidence of autonomic failure in
addition to characteristic motor involvement.
Autonomic function testing in MSA generally reveals evidence of central
autonomic dysfunction. On autonomic function testing, adrenergic failure is
frequently the most pronounced finding, whereas head-up tilt is used to detect
supine hypertension and the degree of orthostatic hypotension. The
thermoregulatory sweat test typically shows a high degree of anhidrosis that is in
a predominantly central pattern but, with time, may demonstrate peripheral
involvement.53 Urologic testing in MSA classically shows large postvoid residuals
(>100 mL), and urodynamic studies may reveal an atonic bladder with low
urethral pressure and detrusor-sphincter dyssynergia.
Polysomnography is recommended for the diagnosis of REM sleep behavior
disorder, and screening for nocturnal stridor is also recommended. The presence
of stridor should lead to direct laryngoscopy, which may reveal vocal cord
motion abnormalities or paralysis.54
Characteristic MRI findings in MSA may vary based on the clinical subtype
(FIGURE 5-3). Patients with MSA-P frequently show putaminal atrophy with
the putaminal rim sign, a hyperintense T2 border of the lateral putamen, often
80 FEBRUARY 2020

with T2 hypointensity of the body of the putamen with diffusion-weighted KEY POINTS
abnormalities. The hot cross bun sign is the classic sign in patients with MSA-C
● Autonomic dysfunction in
and refers to cruciform T2 hyperintensities of the pons.55,56 MSA tends to occur early
Cardiac functional imaging with 123I-MIBG and 6-[18F]fluorodopamine PET and be severe, with
typically show normal cardiac innervation, but this is not invariably the case.23–25,57 orthostatic hypotension that
may have concomitant
supine hypertension and
Treatment
genitourinary failure
While no disease-modifying therapy for MSA is currently available, individual characterized by sexual
symptoms may be managed with a subspecialty team. Supine hypertension dysfunction and urinary
and orthostatic hypotension may be managed with nonpharmacologic and retention leading to
incontinence.
pharmacologic approaches. For more information on the treatment of supine
hypertension and orthostatic hypotension, refer to the article “Management ● Autonomic function
of Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD, and Horacio testing in MSA generally
Kaufmann, MD, FAAN,26 in this issue of Continuum. Often, patients with shows orthostatic
severe urinary retention eventually require catheterization. Patients should be hypotension with central
autonomic dysfunction
treated for REM sleep behavior disorder with involvement of sleep medicine characterized by a large
specialists guiding polysomnography for screening of stridor and apneas. When degree of anhidrosis on
present, sleep apnea or stridor should be treated with continuous positive airway thermoregulatory sweat test
pressure (CPAP) or, potentially, bilevel positive airway pressure (BiPAP). When with relatively preserved
quantitative sudomotor
stridor is severe with evidence of vocal cord paralysis, tracheostomy may axon reflex test volumes.
be indicated.58,59
Levodopa should be trialed for treatment of parkinsonism but should be used ● Characteristic brain MRI
cautiously to avoid worsening of orthostatic hypotension and dyskinesia, which findings in MSA include the
putaminal rim sign, which is
can be severe in patients with MSA. No treatments have proven effective for
more commonly seen in
cerebellar features of MSA, although clonazepam may improve myoclonus or MSA-P, and the hot cross
action tremor.49 A comprehensive neurorehabilitation team, including physical, bun sign, which is more
occupational, and speech therapy, is recommended. Neuropalliative specialists commonly seen in MSA-C.
also have a role in caring for patients with MSA.60
● Treatment for MSA
involves a multidisciplinary
Pathophysiology team managing autonomic
The neuropathologic hallmark of MSA is oligodendroglial cytoplasmic inclusions, failure, motor features,
with the principal autonomic manifestations relating to degeneration of sleep, and respiratory
dysfunction.
preganglionic autonomic brainstem and spinal cord neurons (FIGURE 5-4).8,61,62
Neurons in the rostral ventrolateral medulla are severely affected, leading to ● The neuropathologic
orthostatic hypotension, whereas bladder involvement is likely linked to hallmark of MSA is
involvement of the pontine micturition center and the sacral Onuf nucleus.63–66 oligodendroglial
cytoplasmic inclusions,
Glial cytoplasmic inclusions in the basal ganglia, substantia nigra, cerebellum,
which are frequently found
and brainstem likely underlie the motor involvement in MSA. in the substantia nigra, basal
ganglia, brainstem,
Trends cerebellum, and spinal cord.
Progression in synucleinopathies is increasingly considered to be due to
cell-to-cell transmission of α-synuclein. In Parkinson disease and DLB, misfolded
α-synuclein aggregates spread through stereotypic patterns related to staging of
disease.67–69 In MSA, aggregated α-synuclein deposits are predominantly found
within glial cells, and etiologic and pathogenic factors and mechanisms remain
incompletely understood.70 Beginning in 2013, Prusiner and colleagues3,71–73
published a series of articles suggesting that α-synuclein aggregates in
experimental models of MSA act as prions, leading to debate as to whether MSA
may be a prion disorder. However, the lack of known infectivity of α-synuclein
aggregates in humans argues against the use of this exact terminology.74

SYNUCLEINOPATHIES
Regardless, our understanding of seeding and propagation mechanisms of

α-synuclein has significantly increased over the past decade, with implications
for understanding the onset and progression of the synucleinopathies.75
LEWY BODY DISORDERS

The Lewy body disorders of dementia with Lewy bodies (DLB) and Parkinson
disease are characterized by neuronal α-synuclein inclusions in the form of Lewy
bodies (FIGURE 5-5).
TABLE 5-2 Diagnostic Criteria for Multiple System Atrophya

Probable Multiple System Atrophy (MSA)
◆ Sporadic, progressive, adult-onset disease characterized by
◇ Autonomic failure involving urinary incontinence with erectile dysfunction in males or
an orthostatic decrease of blood pressure within 3 minutes of standing by at least
30 mm Hg systolic or 15 mm Hg diastolic, AND
◇ Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural
instability), OR
◇ A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar
oculomotor dysfunction)
Possible MSA
◆ Sporadic, progressive, adult-onset disease characterized by
◇ Parkinsonism, OR
◇ A cerebellar syndrome, AND
◇ At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary
urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or
significant orthostatic blood pressure decline that does not meet the level required in
probable MSA), AND
◇ At least one of the additional features
Additional Features
◆ Possible MSA-P or MSA-C
◇ Babinski sign with hyperreflexia
◇ Stridor
◆ Possible MSA-P
◇ Rapidly progressive parkinsonism
◇ Poor response to levodopa
◇ Postural instability within 3 years of motor onset
◇ Gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
◇ Dysphagia within 5 years of motor onset
◇ Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum
CONTINUED ON PAGE 83
82 FEBRUARY 2020

Dementia With Lewy Bodies
Lewy bodies were named after Friedrich Lewy, who described cytoplasmic
inclusions in a 1923 publication on a series of patients with parkinsonism, half
of whom had manifestations of dementia.76 The syndrome of dementia that
precedes parkinsonism or occurs within 1 year of the onset of Parkinson
disease was termed dementia with Lewy bodies in 1996.77 DLB is the second
most common form of dementia, with an incidence of 3.5 cases per 100,000
person-years.78
CONTINUED FROM PAGE 82
◆ Possible MSA-C
◇ Parkinsonism (bradykinesia, rigidity)
◇ Atrophy on MRI of putamen, middle cerebellar peduncle, or pons
◇ Hypometabolism on fludeoxyglucose positron emission tomography (FDG-PET) in
putamen
◇ Presynaptic nigrostriatal dopaminergic denervation on single-photon emission CT
(SPECT) or PET
Supporting Features
◆ Orofacial dystonia
◆ Disproportionate antecollis
◆ Camptocormia (severe anterior flexion of the spine) and/or Pisa syndrome (severe lateral
flexion of the spine)
◆ Contractures of hands or feet
◆ Inspiratory sighs
◆ Severe dysphonia
◆ Severe dysarthria
◆ New or increased snoring
◆ Cold hands and feet
◆ Pathologic laughter or crying
◆ Jerky, myoclonic postural/action tremor
Nonsupporting Features
◆ Classic pill-rolling resting tremor
◆ Clinically significant neuropathy
◆ Hallucinations not induced by drugs
◆ Onset after 75 years of age
◆ Family history of ataxia or parkinsonism
◆ Dementia
◆ White matter lesions suggesting multiple sclerosis
CT = computed tomography; MRI = magnetic resonance imaging; MSA-C = multiple system atrophy
with predominant cerebellar ataxia; MSA-P = multiple system atrophy with predominant parkinsonism.
a
Modified with permission from Gilman S, et al, Neurology.45 © 2008 American Academy of Neurology.

SYNUCLEINOPATHIES
CLINICAL FEATURES. Progressive

and severe cognitive decline,
with disproportionate attentional
and executive dysfunction with
visual processing deficits, is
required for the diagnosis of
DLB.79 Core clinical features
include fluctuating cognition,
recurrent visual hallucinations,
and REM sleep behavior disorder
with at least one cardinal feature
of parkinsonism (bradykinesia,
resting tremor, or rigidity).
Along with autonomic
dysfunction, neuroleptic
sensitivity, postural instability
with repeated falls, and
FIGURE 5-3 neuropsychiatric manifestations
MRI findings in multiple system atrophy. Axial are supportive clinical features.79
MRIs show characteristic changes in multiple Autonomic dysfunction is
system atrophy with predominant parkinsonism of
abnormal T2 hyperintensity adjacent to the
commonly found in DLB;
putamen with putaminal atrophy (A, arrow) and however, the degree is typically
low signal on gradient recalled echo (GRE) less severe than in MSA but more
sequence (B, arrow). Patients with multiple system prominent than in Parkinson
atrophy with prominent cerebellar ataxia may
disease. Symptoms of orthostatic
demonstrate abnormal T2 hyperintensity in a
cruciform pattern in the central pons (the hot intolerance are frequently
cross bun sign) as shown on axial T2-weighted encountered in DLB, whereas
imaging (C, circle), as well as marked cerebellar the degree of blood pressure
and pontine atrophy as shown on a sagittal
drop is considered moderate.80
T1-weighted image (D, arrows).
While the time from onset of
disease to orthostatic hypotension
is typically later than in other parkinsonian syndromes, some patients may have
initial manifestations of orthostatic hypotension.81,82 Constipation is also common
in DLB, as are genitourinary symptoms, which occur in approximately one-third
of patients.80,83
DIAGNOSIS. Current diagnostic criteria for

DLB include autonomic dysfunction as a
supportive clinical feature. Autonomic
function testing tends to show
postganglionic sudomotor failure with
moderate cardiovagal and adrenergic
failure.80,81 The degree of sweat loss on the
thermoregulatory sweat test tends to
follow a distal pattern as in Parkinson
disease with a greater degree of anhidrosis
than in Parkinson disease but less than in FIGURE 5-4
Neuropathologic features of multiple
MSA. Postganglionic sympathetic cardiac system atrophy. Immunostaining for
denervation is classically seen on 123I- α-synuclein reveals a characteristic
MIBG, similar to Parkinson disease.84 glial cytoplasmic inclusion (arrow).
84 FEBRUARY 2020

Characteristic head imaging findings KEY POINTS
include relative preservation of medial
● The diagnosis of dementia
temporal lobe structures with generalized with Lewy bodies (DLB) is
low uptake with reduced occipital activity based on the presence of
on SPECT/PET perfusion/metabolism dementia, often with early
scan. The cingulate island sign may be prominent deficits in
attention, executive
demonstrated on fludeoxyglucose (FDG)-
function, and
PET corresponding to preserved posterior visuoperceptual ability
cingulate cortex metabolism.85 along with core clinical
features that include
FIGURE 5-5 fluctuating cognition, visual
TREATMENT. Management of DLB is
Neuropathologic features of dementia hallucinations, rapid eye
with Lewy bodies and Parkinson multifaceted. While orthostatic movement sleep behavior
disease. Immunostaining for intolerance is common in DLB, most disorder, and parkinsonism.
α-synuclein reveals a characteristic patients may respond to Syncope and severe
Lewy body (arrow). autonomic dysfunction are
nonpharmacologic treatments such as
supportive clinical features.
volume expansion. It is also suggested that
patients with DLB may respond to treatment of orthostatic hypotension better ● The degree of autonomic
than patients with MSA, supporting the lesser degree of autonomic impairment failure in DLB is less severe
in DLB.80 than MSA but more
prominent than typically
Cognitive and neuropsychiatric symptoms in DLB may respond to the seen in Parkinson disease.
cholinesterase inhibitors rivastigmine and donepezil.86,87 Parkinsonism may
respond to dopaminergic treatments; however, patients with DLB often have a ● Constipation, neurogenic
less robust response than those with Parkinson disease, and treatment may bladder, and orthostasis
are common nonmotor
worsen orthostatic intolerance.
symptoms in Parkinson
disease reflecting
Parkinson Disease autonomic dysfunction.
The syndrome first described by James Parkinson in 1817 is characterized by
bradykinesia, resting tremor, rigidity, and postural and gait impairment. In his
original work, An Essay on the Shaking Palsy, Parkinson described autonomic
dysfunction referring to constipation and urination disorders in addition to the
movement disorder.88 The incidence of Parkinson disease is the highest of the
synucleinopathies at 14 per 100,000 person-years, which increases with age.89
CLINICAL FEATURES. In addition to the motor features of parkinsonism,

approximately 90% of patients with Parkinson disease will develop at least one
nonmotor symptom.90,91 Autonomic symptoms are common nonmotor
symptoms (CASE 5-3) and may even be the presenting symptom of disease.82,92
Constipation is frequently noted by patients with Parkinson disease, as are
symptoms of neurogenic bladder with urinary urgency and incontinence
and orthostasis.
Constipation may precede the onset of motor symptoms in Parkinson disease
by over 2 decades.92 In patients with Parkinson disease, colonic motility is
reduced, resulting in reduced frequency of defecation; pelvic floor dyssynergia
may also play a role.93 Involvement of the upper gastrointestinal tract may lead to
gastric retention of food, leading to symptoms of nausea, early satiety, and
abdominal distention. Additionally, delayed gastric emptying may slow the
delivery of levodopa to the duodenum where it is absorbed and offers one
explanation for fluctuations that develop later in disease.94 Swallowing may also
be affected in Parkinson disease and typically involves disruption of all three
swallowing phases (oral phase, pharyngeal phase, and esophageal stage).

SYNUCLEINOPATHIES
Sialorrhea is frequently a distressing problem to patients with later-stage

Parkinson disease and is related to a reduction in swallowing frequency leading to
saliva accumulation rather than excessive salivation.
Orthostatic hypotension is found in up to 50% of all patients with Parkinson
disease (CASE 5-3).95,96 Orthostatic hypotension may be detected early in the
disease and may be caused by autonomic failure, although non-neurogenic
causes such as hypovolemia, deconditioning, and medication effects often
contribute.97 Dopaminergic agents, including levodopa and dopamine agonists,
may contribute to orthostatic hypotension. Levodopa, when metabolized in the
periphery, has a diuretic action and induces vasodilation. In the setting of
patients with autonomic failure from Parkinson disease, this can contribute to a
reduction in blood pressure and orthostatic intolerance.
Urinary symptoms affect up to 85% of patients with Parkinson disease.98
Classic urinary symptoms include neurogenic detrusor overactivity. Patients
may report irritative bladder symptoms, including urgency, frequency, and
CASE 5-3 A 71-year-old woman with a 6-year history of Parkinson disease

presented with postural lightheadedness and three episodes of syncope
over the past year. Her parkinsonism symptoms responded well to
carbidopa/levodopa on a regimen of two tablets of 25 mg/100 mg
immediate release every 4 hours, starting at 7 AM.
An autonomic reflex screen identified orthostatic hypotension, with
supine blood pressure of 118/72 mm Hg dropping to 84/66 mm Hg after
10 minutes of tilt with a blunted heart rate response. Cardiovagal function
was normal. Quantitative sudomotor axon reflex test (QSART) values
were reduced at the distal leg and foot sites and normal elsewhere. Blood
pressure monitoring for 24 hours showed a maximum supine systolic
blood pressure of 125 mm Hg. After her dose of carbidopa/levodopa,
systolic blood pressures were frequently recorded in the 80s mm Hg and
associated with orthostatic symptoms.
Examined off carbidopa/levodopa, the patient had parkinsonism with
hypomimia, hypophonic dysarthria, asymmetric bradykinesia with upper
limb rigidity, and resting tremor. Her gait was characterized by stooped
posture and reduced arm swing. Reflexes and sensory examination were
normal. On the Montreal Cognitive Assessment (MoCA), the patient’s
score was 30/30; Laboratory evaluations for reversible causes of
autonomic neuropathy were negative.
COMMENT This patient has Parkinson disease responding to dopaminergic therapy

with no red flags for multiple system atrophy and no cognitive or behavioral
involvement. However, low standing blood pressures with a history of
syncope are a concern. In this setting, initiating midodrine with morning and
early afternoon carbidopa/levodopa doses is indicated. The patient was
counseled not to lie supine for 4 hours after taking midodrine because of
the risk of supine hypertension. Additionally, the patient was counseled on
nonpharmacologic measures to combat orthostatic hypotension.
86 FEBRUARY 2020

nocturia, whereas retention is less commonly noted. The degree of urinary KEY POINTS
dysfunction tends to remain mild or moderate in comparison to the severe and
● Orthostatic hypotension
early dysfunction in MSA. Erectile dysfunction is reported in up to 79% of males is found in 30% to 50% of all
with Parkinson disease. Women report sexual dysfunction including vaginal patients with Parkinson
dryness, decreased libido, and difficulty reaching orgasm. While sexual disease, and treatment with
dysfunction can be a premotor symptom of disease, the severity typically dopaminergic medications
may contribute to blood
increases with longer disease duration.99
pressure drop.
Clinically, patients with Parkinson disease may manifest thermoregulatory
dysfunction. The spectrum of thermoregulatory symptoms includes heat or cold ● Thermoregulatory
intolerance, intermittent hyperhidrosis episodes such as night sweats, and dysfunction in Parkinson
hyperhidrosis or hypohidrosis. The underlying neurodegenerative disorder and disease may manifest as
heat or cold intolerance,
medication effect may contribute to thermoregulatory symptoms. For example, intermittent hyperhidrosis
hyperhidrosis episodes are more frequently reported by patients with Parkinson episodes, and hypohidrosis.
disease during off periods or times of motor fluctuations.100
DIAGNOSIS. The diagnosis of Parkinson disease remains clinical, with evidence

of parkinsonism defined as bradykinesia in combination with resting tremor
and/or rigidity.101 Various levels of certainty are established using the current
Movement Disorder Society’s Clinical Diagnostic Criteria for Parkinson’s
Disease, including clinically established and clinically probable.101 Evaluation of
autonomic function in patients with Parkinson disease may include evaluation
for orthostatic hypotension, which can be done at the bedside or with autonomic
function testing or prolonged blood pressure monitoring. The use of prolonged
blood pressure monitoring can be useful when suspicion exists that medication
effect, such as from levodopa, is contributing to orthostatic hypotension;
prolonged blood pressure monitoring may also screen for supine hypertension.
The degree of orthostatic hypotension in Parkinson disease tends to be less severe
than that found in DLB or MSA.80
Urodynamic studies in patients with Parkinson disease frequently reveal a
high prevalence of detrusor overactivity.98 The thermoregulatory sweat test
typically shows distal postganglionic sudomotor impairment, which is usually of
mild severity.80
Brain MRI may be useful in patients with Parkinson disease with significant
autonomic features to assess for atypical parkinsonism such as MSA. Most
patients with Parkinson disease, and especially patients with Parkinson disease
with neurogenic orthostatic hypotension, demonstrate loss of sympathetic
innervation of the heart on MIBG testing.36,102
TREATMENT. While Parkinson disease has no known cure, dopaminergic agents

are the mainstay of treatment. Additionally, aerobic exercise may slow progression
of the disease.103,104 This makes treatment of orthostatic intolerance imperative
in improving quality of life in patients with Parkinson disease and providing the
best potential to modify the disease course. Use of nonpharmacologic and
pharmacologic measures to improve orthostatic hypotension may be done
concomitantly with the use of dopaminergic agents for motor symptoms.
Bladder symptoms of neurogenic detrusor overactivity may be managed with
antimuscarinic agents, with caution to avoid worsening of other autonomic
symptoms, as well as the β3-adrenergic agonist mirabegron. Treatment of
constipation in patients with Parkinson disease involves both nonpharmacologic
measures, including dietary measures such as fiber supplements and increasing

SYNUCLEINOPATHIES
KEY POINT water intake, and pharmacologic measures. Pyridostigmine, when prescribed for
orthostatic hypotension, may help constipation; other pharmacologic measures
● The Lewy body disorders
typically have early and
include stimulants, osmotic laxatives, stool softeners, and the use of enemas and
more extensive peripheral suppositories. Sexual dysfunction symptoms in males may be treated with
α-synuclein involvement, phosphodiesterase-5 inhibitors, with caution to reduce the chance of orthostatic
although central hypotension due to systemic vasodilation. For more information on the
involvement of autonomic
management of bladder and gastrointestinal symptoms, refer to the article
structures likely contributes
to orthostatic hypotension “Lower Urinary Tract and Bowel Dysfunction in Neurologic Disease” by Jalesh
in DLB. N. Panicker, MD, DM, FRCP, and Ryuji Sakakibara, MD, PhD, FAAN,105 in this
issue of Continuum.
PATHOPHYSIOLOGY. In the Lewy body disorders of DLB and Parkinson disease,
α-synuclein tends to have earlier and more extensive involvement of peripheral
autonomic structures, although a degree of central autonomic involvement is
present. Involvement of the enteric nervous system contributes to constipation,
which may be the earliest manifestation of disease.106 Degeneration of peripheral
postganglionic noradrenergic fibers causes reductions in plasma norepinephrine
concentrations and likely accounts for the orthostatic hypotension seen in these
patients.107,108 In DLB, orthostatic hypotension may be more severe and is likely
also related to central involvement of the rostral ventrolateral medulla and
medullary raphe controlling sympathetic outflow.109
CONCLUSION
Autonomic failure is a key feature of the synucleinopathies of pure autonomic
failure, MSA, DLB, and Parkinson disease. Involvement of the autonomic
nervous system varies from predominantly peripheral involvement in the Lewy
body disorders to predominantly central involvement in MSA. The severity of
autonomic dysfunction also varies, with the most severe involvement in MSA,
moderate involvement in DLB, and less severe impairment classically seen in
Parkinson disease. Patients with pure autonomic failure typically manifest a
severe degree of autonomic failure, and certain clinical and laboratory features
may predict evolution into other synucleinopathies.
REFERENCES
1 Spillantini MG, Goedert M. The alpha- 4 Cersosimo MG, Benarroch EE. Central control
synucleinopathies: Parkinson’s disease, of autonomic function and involvement in
dementia with Lewy bodies, and multiple system neurodegenerative disorders. Handb Clin Neurol
atrophy. Ann N Y Acad Sci 2000;920:16–27. 2013;117:45–57. doi:10.1016/B978-0-444-53491-
0.00005-5.
2 Campbell BC, McLean CA, Culvenor JG, et al. The
solubility of alpha-synuclein in multiple system 5 Schenck CH, Callies AL, Mahowald MW.
atrophy differs from that of dementia with Lewy Increased percentage of slow-wave sleep in
bodies and Parkinson’s disease. J Neurochem REM sleep behavior disorder (RBD): a reanalysis
2001;76(1):87–96. doi:10.1046/j.1471-4159.2001.00021.x. of previously published data from a controlled
study of RBD reported in SLEEP. Sleep 2003;
3 Prusiner SB, Woerman AL, Mordes DA, et al.
26(8):1066; author reply 1067.
Evidence for α-synuclein prions causing multiple
system atrophy in humans with parkinsonism. 6 Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy
Proc Natl Acad Sci U S A 2015;112(38):E5308–E5317. pathology and REM sleep behavior disorder
doi:10.1073/pnas.1514475112. plus dementia or parkinsonism. Neurology
2003;61(1):40–45. doi:10.1212/01.WNL.
0000073619.94467.B0.
88 FEBRUARY 2020

7 Spillantini MG, Schmidt ML, Lee VM, et al. Alpha- 21 Goldstein DS, Sewell L. Olfactory dysfunction in
synuclein in Lewy bodies. Nature 1997;388(6645): pure autonomic failure: Implications for the
839–840. doi:10.1038/42166. pathogenesis of Lewy body diseases.
Parkinsonism Relat Disord 2009;15(7):516–520.
8 Papp MI, Lantos PL. The distribution of
doi:10.1016/j.parkreldis.2008.12.009.
oligodendroglial inclusions in multiple system
atrophy and its relevance to clinical symptomatology. 22 Low PA. Composite autonomic scoring scale
Brain 1994;117(pt 2):235–243. doi:10.1093/ for laboratory quantification of generalized
brain/117.2.235. autonomic failure. Mayo Clin Proc 1993;68(8):
748–752. doi:10.1016/S0025-6196(12)60631-4.
9 Inoue M, Yagishita S, Ryo M, et al. The distribution
and dynamic density of oligodendroglial 23 Golstein DS. Imaging studies in chronic
cytoplasmic inclusions (GCIs) in multiple system autonomic disorders. In: Low PA Benarroch EE,
atrophy: a correlation between the density editors. Clinical autonomic disorders. 3rd ed.
of GCIs and the degree of involvement of Baltimore, MD: Lippincott Williams and Wilkins,
striatonigral and olivopontocerebellar systems. 2008:336–344.
Acta Neuropathol 1997;93(6):585–591.
24 Yoshida M, Fukumoto Y, Kuroda Y, Ohkoshi N.
doi:10.1007/s004010050655.
Sympathetic denervation of myocardium
10 Bradbury S, Eggleston C. Postural hypotension: a demonstrated by 123I-MIBG scintigraphy in pure
report of three cases. Am Heart J 1925;1(1):73–86. progressive autonomic failure. Eur Neurol 1997;
doi:10.1016/S0002-8703(25)90007-5. 38(4):291–296. doi:10.1159/000113396.
11 Consensus statement on the definition of 25 Tipre DN, Goldstein DS. Cardiac and extracardiac
orthostatic hypotension, pure autonomic failure, sympathetic denervation in Parkinson's disease
and multiple system atrophy. Neurology 1996; with orthostatic hypotension and in pure autonomic
46(5):1470. doi:10.1212/WNL.46.5.1470. failure. J Nucl Med 2005;46(11):1775–1781.
12 Benarroch EE, Singer W. Neurogenic orthostatic 26 Palma JA, Kaufmann H. Management of orthostatic
hypotension. In: Benarroch EE, ed. Autonomic hypotension. Continuum (Minneap Minn) 2020;
neurology. New York, NY: Oxford University 25(1, Autonomic Disorders):154–177.
Press, 2014:73–88.
27 Biaggioni I, Robertson D, Krantz S, et al. The anemia
13 Freeman R. Pure autonomic failure. In: Robertson of primary autonomic failure and its reversal with
D, Biaggiona I, eds. Disorders of the autonomic recombinant erythropoietin. Ann Intern Med 1994;
nervous system. New York, NY: Taylor & Francis 121(3):181–186. doi:10.7326/0003-4819-121-3-
Group, LLC, 1995:83–105. 199408010-00004.
14 Bleasdale-Barr KM, Mathias CJ. Neck and other 28 Isonaka R, Holmes C, Cook GA, et al. Pure
muscle pains in autonomic failure: their association autonomic failure without synucleinopathy. Clin
with orthostatic hypotension. J R Soc Med 1998; Auton Res 2017;27(2):97–101. doi:10.1007/s10286-
91(7):355–359. doi:10.1177/014107689809100704. 017-0404-z.
15 Fujimura J, Camilleri M, Low PA, et al. Effect of 29 Goldstein DS, Eisenhofer G, Kopin IJ. Sources and
perturbations and a meal on superior mesenteric significance of plasma levels of catechols and
artery flow in patients with orthostatic hypotension. their metabolites in humans. J Pharmacol Exp
J Auton Nerv Syst 1997;67(1–2):15–23. doi:10.1016/ Ther 2003;305(3):800–811. doi:10.1124/jpet.103.
S0165-1838(97)00087-8. 049270.
16 Shannon JR, Jordan J, Diedrich A, et al. Sympathetically 30 Goldstein DS, Holmes C, Cannon RO 3rd, et al.
mediated hypertension in autonomic failure. Sympathetic cardioneuropathy in
Circulation 2000;101(23):2710–2715. dysautonomias. N Engl J Med 1997;336(10):
696–702. doi:10.1056/NEJM199703063361004.
17 Vagaonescu TD, Saadia D, Tuhrim S, et al.
Hypertensive cardiovascular damage in patients 31 Goldstein DS, Holmes CS, Dendi R, et al. Orthostatic
with primary autonomic failure. Lancet 2000; hypotension from sympathetic denervation in
355(9205):725–726. doi:10.1016/S0140-6736(99) Parkinson’s disease. Neurology 2002;58(8):
05320-9. 1247–1255. doi:10.1212/WNL.58.8.1247.
18 Garland EM, Gamboa A, Okamoto L, et al. Renal 32 Bannister R, Davies B, Holly E, et al. Defective
impairment of pure autonomic failure. cardiovascular reflexes and supersensitivity to
Hypertension 2009;54(5):1057–1061. doi:10.1161/ sympathomimetic drugs in autonomic failure.
HYPERTENSIONAHA.109.136853. Brain 1979;102(1):163–176. doi:10.1093/brain/102.1.163.
19 Struhal W, Lahrmann H, Mathias CJ. Incidence of 33 Thomas JE, Schirger A. Neurologic manifestations
cerebrovascular lesions in pure autonomic in idiopathic orthostatic hypotension. Arch
failure. Auton Neurosci 2013;179(1–2):159–162. Neurol 1963;8:204–208. doi:10.1001/archneur.
doi:10.1016/j.autneu.2013.04.006. 1963.00460020104008.
20 Kaufmann H, Norcliffe-Kaufmann L, Palma JA, 34 Singer W, Berini SE, Sandroni P, et al. Pure autonomic
et al. Natural history of pure autonomic failure: a failure: predictors of conversion to clinical CNS
United States prospective cohort. Ann Neurol involvement. Neurology 2017;88(12):1129–1136.
2017;81(2):287–297. doi:10.1002/ana.24877. doi:10.1212/WNL.0000000000003737.

SYNUCLEINOPATHIES
35 Kaufmann H, Jordan J. The Clinical Autonomic 49 Fanciulli A, Wenning GK. Multiple-system

Research journal 2017 and onward. Clin Auton Res atrophy. N Engl J Med 2015;372(3):1375–1376.
2017;27(1):1–2. doi:10.1007/s10286-016-0394-2. doi:10.1056/NEJMc1501657.
36 Goldstein DS, Holmes C, Li ST, et al. Cardiac 50 Köllensperger M, Geser F, Seppi K, et al. Red
sympathetic denervation in Parkinson disease. flags for multiple system atrophy. Mov Disord
Ann Intern Med 2000;133(5):338–347. 2008;23(8):1093–1099. doi:10.1002/mds.21992.
doi:10.7326/0003-4819-133-5-200009050-00009.
51 Koga S, Parks A, Uitti RJ, et al. Profile of cognitive
37 Graham JG, Oppenheimer DR. Orthostatic impairment and underlying pathology in multiple
hypotension and nicotine sensitivity in a case of system atrophy. Mov Disord 2017;32(3):405–413.
multiple system atrophy. J Neurol Neurosurg doi:10.1002/mds.26874.
Psychiatry 1969;32(5):28–34.
52 Stankovic I, Krismer F, Jesic A, et al. Cognitive
38 Benarroch EE, Singer W. Neurodegenerative impairment in multiple system atrophy: a position
autonomic disorders. In: Benarroch EE, ed. statement by the Neuropsychology Task Force of
Autonomic neurology. New York, NY: Oxford the MDS Multiple System Atrophy (MODIMSA)
University Press, 2014:187–204. study group. Mov Disord 2014;29(7):857–867.
doi:10.1002/mds.25880.
39 Bower JH, Maraganore DM, McDonnell SK, Rocca
WA. Incidence of progressive supranuclear palsy 53 Coon EA, Fealey RD, Sletten DM, et al. Anhidrosis
and multiple system atrophy in Olmsted County, in multiple system atrophy involves pre- and
Minnesota, 1976 to 1990. Neurology 1997;49(5): postganglionic sudomotor dysfunction. Mov Disord
1284–1288. doi:10.1212/WNL.49.5.1284. 2017;32(3):397–404. doi:10.1002/mds.26864.
40 Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. 54 Lalich IJ, Ekbom DC, Starkman SJ, et al. Vocal fold
Survival of patients with pathologically proven motion impairment in multiple system atrophy.
multiple system atrophy: a meta-analysis. Laryngoscope 2014;124(3):730–735. doi:10.1002/
Neurology 1997;48(2):384–393. doi:10.1212/ lary.24402.
WNL.48.2.384.
55 Schrag A, Kingsley D, Phatouros C, et al. Clinical
41 Multiple-System Atrophy Research Collaboration. usefulness of magnetic resonance imaging in
Mutations in COQ2 in familial and sporadic multiple system atrophy. J Neurol Neurosurg
multiple-system atrophy. N Engl J Med 2013; Psychiatry 1998;65(1):65–71. doi:10.1136/jnnp.65.1.65.
369(3):233–244. doi:10.1056/NEJMoa1212115.
56 Palma JA, Norcliffe-Kaufmann L, Kaufmann H.
42 Wenning GK, Geser F, Krismer F, et al. The natural Diagnosis of multiple system atrophy. Auton
history of multiple system atrophy: a prospective Neurosci 2018;211:15–25. doi:10.1016/j.autneu.
European cohort study. Lancet Neurol 2013;12(3): 2017.10.007.
264–274. doi:10.1016/S1474-4422(12)70327-7.
57 Kimpinski K, Iodice V, Burton DD, et al. The role of
43 Coon EA, Sletten DM, Suarez MD, et al. Clinical autonomic testing in the differentiation of Parkinson's
features and autonomic testing predict survival disease from multiple system atrophy. J Neurol Sci
in multiple system atrophy. Brain 2015;138(pt 12): 2012;317(1–2):92–96. doi:10.1016/j.jns.2012.02.023.
3623–3631. doi:10.1093/brain/awv274.
58 Silber MH, Levine S. Stridor and death in multiple
44 Low PA, Reich SG, Jankovic J, et al. Natural history of system atrophy. Mov Disord 2000;15(4):699–704.
multiple system atrophy in the USA: a prospective doi:10.1002/1531-8257(200007)15:4<699::AID-
cohort study. Lancet Neurol 2015;14(7):710–719. MDS1015>3.0.CO;2-L.
doi:10.1016/S1474-4422(15)00058-7.
59 Iranzo A. Management of sleep-disordered
45 Gilman S, Wenning GK, Low PA, et al. Second breathing in multiple system atrophy. Sleep Med
consensus statement on the diagnosis of 2005;6(4):297–300. doi:10.1016/j.sleep.2005.01.006.
multiple system atrophy. Neurology 2008;71(9):
60 Wiblin L, Lee M, Burn D. Palliative care and its
670–676. doi:10.1212/01.wnl.0000324625.
emerging role in multiple system atrophy and
00404.15.
progressive supranuclear palsy. Parkinsonism
46 Köllensperger M, Geser F, Ndayisaba JP, et al. Relat Disord 2017;34:7–14. doi:10.1016/j.
Presentation, diagnosis, and management of parkreldis.2016.10.013.
multiple system atrophy in Europe: final analysis
61 Ozawa T. Morphological substrate of autonomic
of the European multiple system atrophy
failure and neurohormonal dysfunction in multiple
registry. Mov Disord 2010;25(15):2604–2612.
system atrophy: impact on determining phenotype
doi:10.1002/mds.23192.
spectrum. Acta Neuropathol 2007;114(3):201–211.
47 Quinn N. Disproportionate antecollis in multiple doi:10.1007/s00401-007-0254-1.
system atrophy. Lancet 1989;1(8642):844. 62 Benarroch EE. New findings on the neuropathology
doi:10.1016/S0140-6736(89)92300-3. of multiple system atrophy. Auton Neurosci 2002;
48 Watanabe H, Saito Y, Terao S, et al. Progression 96(1):59–62. doi:10.1016/S1566-0702(01)00374-5.
and prognosis in multiple system atrophy: an 63 Benarroch EE, Smithson IL, Low PA, Parisi JE.
analysis of 230 Japanese patients. Brain 2002; Depletion of catecholaminergic neurons of the
125(pt 5):1070–1083. doi:10.1093/brain/awf117. rostral ventrolateral medulla in multiple systems
atrophy with autonomic failure. Ann Neurol 1998;
43(2):156–163. doi:10.1002/ana.410430205.
90 FEBRUARY 2020

64 Benarroch EE, Schmeichel AM, Low PA, Parisi JE. 78 Savica R, Grossardt BR, Bower JH, et al. Incidence
Depletion of ventromedullary NK-1 receptor- of dementia with Lewy bodies and Parkinson
immunoreactive neurons in multiple system disease dementia. JAMA Neurol 2013;70(11):
atrophy. Brain 2003;126(pt 1):2183–2190. 1396–1402. doi:10.1001/jamaneurol.2013.3579.
doi:10.1093/brain/awg220.
79 McKeith IG, Boeve BF, Dickson DW, et al.
65 Benarroch EE, Schmeichel AM. Depletion of Diagnosis and management of dementia with
corticotrophin-releasing factor neurons in the Lewy bodies: fourth consensus report of the DLB
pontine micturition area in multiple system Consortium. Neurology 2017;89(1):88–100.
atrophy. Ann Neurol 2001;50(5):640–645. doi:10.1212/WNL.0000000000004058.
doi:10.1002/ana.1258.
80 Thaisetthawatkul P, Boeve BF, Benarroch EE,
66 Winge K, Fowler CJ. Bladder dysfunction in et al. Autonomic dysfunction in dementia with
Parkinsonism: mechanisms, prevalence, symptoms, Lewy bodies. Neurology 2004;62(10):1804–1809.
and management. Mov Disord 2006;21(6):737–745. doi:10.1212/01.WNL.0000125192.69777.6D.
doi:10.1002/mds.20867.
81 Wenning GK, Scherfler C, Granata R, et al. Time
67 Marui W, Iseki E, Nakai T, et al. Progression and course of symptomatic orthostatic hypotension
staging of Lewy pathology in brains from patients and urinary incontinence in patients with
with dementia with Lewy bodies. J Neurol Sci postmortem confirmed parkinsonian syndromes:
2002;195(2):153–159. doi:10.1016/S0022-510X(02) a clinicopathological study. J Neurol Neurosurg
00006-0. Psychiatry 1999;67(5):620–623. doi:10.1136/
jnnp.67.5.620.
68 Braak H, Del Tredici K, Bratzke H, et al. Staging
of the intracerebral inclusion body pathology 82 Kaufmann H, Nahm K, Purohit D, Wolfe D.
associated with idiopathic Parkinson's disease Autonomic failure as the initial presentation of
(preclinical and clinical stages). J Neurol 2002; Parkinson disease and dementia with Lewy
249(suppl 3):III/1–5. doi:10.1007/s00415-002-1301-4. bodies. Neurology 2004;63(6):1093–1095.
doi:10.1212/01.WNL.0000138500.73671.DC.
69 Braak H, Del Tredici K, Rüb U, et al. Staging of
brain pathology related to sporadic Parkinson's 83 Horimoto Y, Matsumoto M, Akatsu H, et al.
disease. Neurobiol Aging 2003;24(2):197–211. Autonomic dysfunctions in dementia with Lewy
doi:10.1016/S0197-4580(02)00065-9. bodies. J Neurol 2003;250(5):530–533.
doi:10.1007/s00415-003-1029-9.
70 Goedert M, Jakes R, Spillantini MG. The
synucleinopathies: twenty years on. J Parkinsons 84 Yoshita M, Arai H, Arai H, et al. Diagnostic accuracy
Dis 2017;7(s1):S51–S69. doi:10.3233/JPD-179005. of 123I-meta-iodobenzylguanidine myocardial
scintigraphy in dementia with Lewy bodies: a
71 Watts JC, Giles K, Oehler A, et al. Transmission of
multicenter study. PLoS One 2015;10(3):e0120540.
multiple system atrophy prions to transgenic
doi:10.1371/journal.pone.0120540.
mice. Proc Natl Acad Sci U S A 2013;110(48):
19555–19560. doi:10.1073/pnas.1318268110. 85 Mak E, Su L, Williams GB, O'Brien JT. Neuroimaging
characteristics of dementia with Lewy bodies.
72 Woerman AL, Stöhr J, Aoyagi A, et al. Propagation
Alzheimers Res Ther 2014;6(2):18. doi:10.1186/
of prions causing synucleinopathies in cultured
alzrt248.
cells. Proc Natl Acad Sci U S A 2015;112(35):
E4949–E4958. doi:10.1073/pnas.1513426112. 86 Wang HF, Yu JT, Tang SW, et al. Efficacy and
safety of cholinesterase inhibitors and
73 Woerman AL, Kazmi SA, Patel S, et al. MSA prions
memantine in cognitive impairment in Parkinson's
exhibit remarkable stability and resistance to
disease, Parkinson's disease dementia, and
inactivation. Acta Neuropathol 2018;135(1):49–63.
dementia with Lewy bodies: systematic review
doi:10.1007/s00401-017-1762-2.
with meta-analysis and trial sequential analysis.
74 Wenning G, Trojanowski JQ, Kaufmann H, et al. Is J Neurol Neurosurg Psychiatry 2015;86(2):135–143.
multiple system atrophy an infectious disease? doi:10.1136/jnnp-2014-307659.
Ann Neurol 2018;83(1):10–12. doi:10.1002/ana.25132.
87 Stinton C, McKeith I, Taylor JP, et al. Pharmacological
75 Karpowicz RJ Jr, Trojanowski JQ, Lee VM. Transmission management of Lewy body dementia: a systematic
of α-synuclein seeds in neurodegenerative disease: review and meta-analysis. Am J Psychiatry 2015;
recent developments. Lab Invest 2019;99(7): 172(8):731–742. doi:10.1176/appi.ajp.2015.14121582.
971–981. doi:10.1038/s41374-019-0195-z.
88 Parkinson J. An essay on the shaking palsy.
76 Lewy FH. Die Lehre vom Tonus und der Bewegung London, United Kingdom: Sherwood, Neeley,
Zugleich Systematische Untersuchungen zur Klinik, and Jones, 1817.
Physiologie, Pathologie und Pathogenese der
89 Savica R, Grossardt BR, Bower JH, et al. Time
Paralysis agitans. Berlin, Germany: Julius
trends in the incidence of Parkinson disease.
Springer, 1923.
JAMA Neurol 2016;73(8):981–989. doi:10.1001/
77 McKeith IG, Galasko D, Kosaka K, et al. Consensus jamaneurol.2016.0947.
guidelines for the clinical and pathologic diagnosis
90 Shulman LM, Taback RL, Bean J, Weiner WJ.
of dementia with Lewy bodies (DLB): report of
Comorbidity of the nonmotor symptoms of
the consortium on DLB international workshop.
Parkinson's disease. Mov Disord 2001;16(3):
Neurology 1996;47(5):1113–1124. doi:10.1212/
507–510. doi:10.1002/mds.1099.
WNL.47.5.1113.

SYNUCLEINOPATHIES
91 Park A, Stacy M. Non-motor symptoms in 100 Pursiainen V, Haapaniemi TH, Korpelainen JT,
Parkinson's disease. J Neurol 2009;256(suppl 3): et al. Sweating in Parkinsonian patients with
293–298. doi:10.1007/s00415-009-5240-1. wearing-off. Mov Disord 2007;22(6):828–832.
doi:10.1002/mds.21422.
92 Savica R, Carlin JM, Grossardt BR, et al. Medical
records documentation of constipation preceding 101 Postuma RB, Berg D, Stern M, et al. MDS clinical
Parkinson disease: a case-control study. Neurology diagnostic criteria for Parkinson’s disease.
2009;73(21):1752–1758. doi:10.1212/WNL. Mov Disord 2015;30(12):1591–1601. doi:10.1002/
0b013e3181c34af5. mds.26424.
93 Mathers SE, Kempster PA, Law PJ, et al. Anal 102 Braune S, Reinhardt M, Bathmann J, et al.
sphincter dysfunction in Parkinson's disease. Impaired cardiac uptake of meta-[123I]
Arch Neurol 1989;46(10):1061–1064. doi:10.1001/ iodobenzylguanidine in Parkinsons disease with
archneur.1989.00520460037010. autonomic failure. Acta Neurol Scand 1998;97(5):
307–314. doi:10.1111/j.1600-0404.1998.tb05958.x.
94 Kurlan R. Acute parkinsonism induced by the
combination of a serotonin reuptake inhibitor 103 Goodwin VA, Richards SH, Taylor RS, et al. The
and a neuroleptic in adults with Tourette's effectiveness of exercise interventions for
syndrome. Mov Disord 1998;13(1):178–179. people with Parkinson’s disease: a systematic
doi:10.1002/mds.870130136. review and meta-analysis. Mov Disord 2008;23(5):
631–640. doi:10.1002/mds.21922.
95 Goldstein DS. Orthostatic hypotension as an
early finding in Parkinson's disease. Clin Auton 104 Xu Q, Park Y, Huang X, et al. Physical activities
Res 2006;16(1):46–54. doi:10.1007/s10286-006- and future risk of Parkinson disease. Neurology
0317-8. 2010;75(4):341–348. doi:10.1212/
WNL.0b013e3181ea1597.
96 Velseboer DC, de Haan RJ, Wieling W, et al.
Prevalence of orthostatic hypotension in 105 Panicker JN, Sakakibara R. Lower urinary tract
Parkinson's disease: a systematic review and and bowel dysfunction in neurologic disease.
meta-analysis. Parkinsonism Relat Disord 2011; Continuum (Minneap Minn) 2020;26(1, Autonomic
17(10):724–729. doi:10.1016/j.parkreldis.2011.04.016. Disorders):178–199.
97 Senard JM, Pathak A. Neurogenic orthostatic 106 Iranzo A, Gelpi E, Tolosa E, et al. Neuropathology
hypotension of Parkinson’s disease: what of prodromal Lewy body disease. Mov Disord
exploration for what treatment? Rev Neurol 2014;29(3):410–415. doi:10.1002/mds.25825.
(Paris) 2010;166(10):779–784. doi:10.1016/j.
107 Kaufmann H, Biaggioni I. Autonomic failure in
neurol.2010.07.007.
neurodegenerative disorders. Semin Neurol
98 McDonald C, Winge K, Burn DJ. Lower urinary 2003;23(4):351–363. doi:10.1055/s-2004-817719.
tract symptoms in Parkinson’s disease: prevalence,
108 Orimo S, Uchihara T, Nakamura A, et al. Axonal
aetiology and management. Parkinsonism Relat
alpha-synuclein aggregates herald centripetal
Disord 2017;35:8–16. doi:10.1016/j.parkreldis.
degeneration of cardiac sympathetic nerve in
2016.10.024.
Parkinson’s disease. Brain 2008;131(pt 3):
99 Özcan T, Benli E, Özer F, et al. The association 642–650. doi:10.1093/brain/awm302.
between symptoms of sexual dysfunction and
109 Benarroch EE, Schmeichel AM, Low PA, et al.
age at onset in Parkinson’s disease. Clin Auton
Involvement of medullary regions controlling
Res 2016;26(3):205–209. doi:10.1007/s10286-016-
sympathetic output in Lewy body disease. Brain
0356-8.
2005;128(pt 2):338–344. doi:10.1093/brain/
awh376.
92 FEBRUARY 2020

Postural Tachycardia REVIEW ARTICLE

Syndrome and Neurally 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
Mediated Syncope
By Jeremy K. Cutsforth-Gregory, MD
ABSTRACT
PURPOSE OF REVIEW: This article reviews the diagnosis and management of the
most common disorders of orthostatic intolerance: postural tachycardia
syndrome (POTS) and neurally mediated syncope.
RECENT FINDINGS: POTS is a heterogeneous syndrome caused by several

pathophysiologic mechanisms that may coexist (limited autonomic
neuropathy, hyperadrenergic state, hypovolemia, venous pooling, joint
hypermobility, deconditioning). Neurally mediated syncope occurs
despite intact autonomic reflexes. Management of orthostatic intolerance
aims to increase functional capacity, including standing time, performance
of daily activities, and exercise tolerance. Nonpharmacologic strategies
(fluid and salt loading, physical countermaneuvers, compression garments,
exercise training) are fundamental for patients with POTS, occasionally
CITE AS:
complemented by medications to raise blood pressure or slow heart rate. C O N T I N U U M ( M I N N E AP M I NN )
Neurally mediated syncope is best managed by recognition and avoidance 2020;26(1, AUTONOMIC DISORDERS):
of triggers. 93–115.
SUMMARY: Significant negative effects on quality of life occur in patients Dr Jeremy K. Cutsforth-Gregory,
with POTS and in patients with recurrent neurally mediated syncope, which Department of Neurology,
Mayo Clinic, 200 First St SW,
can be mitigated through targeted evaluation and thoughtful management.
Rochester, MN 55905,
JeremyCG@mayo.edu.
INTRODUCTION Dr Cutsforth-Gregory receives
U
pright posture in the setting of the earth’s gravity involves publishing royalties from Mayo
Clinic Scientific Press and
considerable physiologic stress on the cardiovascular system to Oxford University Press.
maintain adequate cerebral blood flow. The normal response to
standing, via activation of the baroreflex, is a small fall in systolic UNLABELED USE OF
blood pressure (5 mm Hg to 10 mm Hg), a rise in diastolic blood USE DISCLOSURE:
pressure (5 mm Hg to 10 mm Hg), and a rise in heart rate (10 beats/min to Dr Cutsforth-Gregory discusses
20 beats/min).1 When this complex series of physiologic reactions fails, the result the unlabeled/investigational
use of droxidopa, fludrocortisone,
is orthostatic intolerance. Orthostatic intolerance, then, is the inability to tolerate ivabradine, midodrine,
upright posture because of symptoms of cerebral hypoperfusion or sympathetic propranolol, and pyridostigmine
for postural tachycardia
activation, or both, which are relieved with recumbency. The spectrum of syndrome and neurally
orthostatic intolerance includes orthostatic hypotension, postural tachycardia mediated syncope.
syndrome (POTS), and syncope. This article focuses on POTS and syncope,
discussing their definitions, demographics, clinical features, pathophysiology, © 2020 American Academy
evaluation, management, and prognosis, with particular attention to details of Neurology.

POSTURAL TACHYCARDIA SYNDROME AND NEURALLY MEDIATED SYNCOPE
relevant to the practicing clinician. Orthostatic hypotension is very briefly

defined here at the start, to contrast the findings with those of POTS and neurally
mediated syncope.
ORTHOSTATIC HYPOTENSION
Orthostatic hypotension is a sustained drop in blood pressure of at least 20 mm
Hg systolic and/or 10 mm Hg diastolic that occurs within 3 minutes of active
standing or head-up tilt. Some centers, including the Autonomic Laboratory at
Mayo Clinic, use stricter criteria for orthostatic hypotension of a blood pressure
drop of at least 30 mm Hg systolic or 15 mm Hg diastolic during tilt-table testing
because this passive maneuver does not activate the lower limb “muscle pump”
and is therefore expected to cause somewhat more blood pooling in the lower
body. Neurogenic orthostatic hypotension refers to orthostatic hypotension
caused by failure of the carotid baroreflex or of the cardiovascular adrenergic
limb of the autonomic nervous system. The pathophysiology, testing, and
management of orthostatic hypotension are discussed in the article
“Management of Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD,
and Horacio Kaufmann, MD, FAAN,2 in this issue of Continuum.
POSTURAL TACHYCARDIA SYNDROME

POTS is a disorder in which patients frequently experience symptoms of
orthostatic intolerance in response to postural stressors despite autonomic
reflexes that are generally preserved; it is the most prevalent form of orthostatic
TABLE 6-1 Symptoms of Orthostatic Intolerance
Cerebral Hypoperfusion
◆ Lightheadedness or dizziness
◆ Presyncope
◆ Tiredness
◆ Weakness
◆ Difficulty concentrating
◆ Blurred, dimmed, or tunnel vision
◆ Muffled hearing
◆ Tinnitus
Sympathetic Activation
◆ Palpitations, chest pain, or dyspnea
◆ Tremulousness
◆ Sweating
◆ Pallor
◆ Anxiety
◆ Nausea
◆ Fecal urgency
◆ Headache
94 FEBRUARY 2020

intolerance. Identical syndromes have been recognized, although referred to by a KEY POINTS
variety of names, for over a century. The hallmark of the disorder is an excessive
● The normal response to
rise in heart rate in response to standing; however, unlike in classic autonomic standing, via activation of
failure, blood pressure does not fall. The current definition of POTS focuses on the baroreflex, is a small fall
symptoms and heart rate increment induced by postural changes, which is in systolic blood pressure, a
appropriate because an excessive rise in heart rate is the earliest and most small rise in diastolic blood
pressure, and a small rise in
consistent of the readily measured indices of orthostatic intolerance.3
heart rate.
POTS is defined as a symptomatic and sustained heart rate increment of
30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of ● Orthostatic intolerance is
orthostatic hypotension; the standing heart rate is often 120 beats/min or higher.4 the inability to tolerate
For individuals 12 to 19 years of age, the required increment is at least 40 beats/min.5 upright posture because of
symptoms of cerebral
Diagnostic criteria have not been established for younger children. hypoperfusion or
sympathetic activation, or
Demographics both, which are relieved
Most patients with POTS present between 15 and 50 years of age. Women are with recumbency.
more often affected than men at a ratio of approximately 5:1.6 Multiple relatives ● Postural tachycardia
occasionally report orthostatic intolerance, with or without formal POTS diagnoses, syndrome (POTS) is the most
but a genetic mutation convincingly pathogenic for POTS (loss-of-function prevalent form of
mutation in the norepinephrine transporter) has been identified only in a orthostatic intolerance.
single family.7
● POTS is defined as a
symptomatic and sustained
Clinical Features heart rate increment of
Symptoms of cerebral hypoperfusion that may occur with any of the disorders 30 beats/min or more within
of orthostatic intolerance include lightheadedness, dizziness, presyncope, 10 minutes of standing or
head-up tilt in the absence
vision and hearing changes, lower limb or generalized weakness, and cognitive of orthostatic hypotension;
difficulties (often vaguely termed brain fog). Symptoms of sympathoexcitation, the standing heart rate is
which distinguish POTS from orthostatic hypotension, include palpitations, often 120 beats/min or
chest pain, dyspnea, tremulousness, sweating, pallor, nausea, diarrhea, and higher. For individuals 12 to
19 years of age, the required
coldness of the extremities (TABLE 6-1). Many patients with POTS also experience increment is at least
posturally triggered syncope. Symptoms tend to be exacerbated by heat, physical 40 beats/min.
exertion, large meals, prolonged recumbency, menses, and certain medications
(eg, diuretics, vasodilators, sympathomimetics).8 For some women with POTS,
symptoms are markedly worse during certain phases of the menstrual cycle.
These women usually report significant fluid shifts and weight fluctuations of
2.27 kg (5 lb) or more.9
Despite its definition by orthostatic features, POTS is often also associated
with nonorthostatic symptoms. Chronic fatigue, sleep disturbances, migraine
headaches, fibromyalgia, and functional gastrointestinal and bladder disorders
are common. Exercise intolerance is a nearly universal symptom and contributes
to physical deconditioning and exacerbation of symptoms with basic activities of
daily living.
The neurologic examination in patients with POTS is almost always normal.
Many patients will have some degree of joint hypermobility.10 Palpating the
radial pulse may become more difficult with continued standing or with the
performance of a Valsalva maneuver. Prolonged standing may also cause acral
coldness, blueness, or swelling.3
Pathophysiology
POTS is not one disorder but rather a heterogeneous syndrome resulting from
several distinct pathophysiologic mechanisms that are not mutually exclusive.

The main POTS mechanisms are impaired sympathetically mediated

vasoconstriction in the lower limbs (neuropathic POTS), excessive cardiac
sympathoexcitatory responses (hyperadrenergic POTS), volume dysregulation,
joint hypermobility, and physical deconditioning. POTS may also develop in the
setting of and be dominated by fibromyalgia or chronic fatigue syndrome.
NEUROPATHIC POSTURAL TACHYCARDIA SYNDROME. A length-dependent

autonomic neuropathy may cause impaired vasomotor and venomotor tone in
the lower limbs and result in venous pooling in the face of orthostatic stress.
Evidence of such a neuropathy is common and includes loss of sweating in the feet
(sudomotor impairment) and reduced increment of norepinephrine release in
the lower limbs but not the upper limbs upon standing (adrenergic
impairment).11,12 The cause of the restricted autonomic neuropathy is often not
identified, but the report of an antecedent illness of presumed viral etiology by
approximately one-half of patients suggests a postinfectious autoimmune
process in some.6 Furthermore, organ-specific autoantibodies can be found in up
to one-third of patients (against thyroid antigens more often than the α3 subunit
of the ganglionic nicotinic acetylcholine receptor or other targets).13
HYPERADRENERGIC POSTURAL TACHYCARDIA SYNDROME. The presence of

tachycardia, palpitations, sweating, tremulousness, and anxiety implies
excessive sympathetic activity (ie, a hyperadrenergic state). In these patients,
episodes of tachycardia, sweating, and hypertension can be triggered by upright
posture, physical activity, and emotional stimuli, and episodes may even occur
during sleep (CASE 6-1).14
Hyperadrenergic POTS may be further subdivided into primary (central) and
secondary forms. Patients with primary hyperadrenergic POTS have very high
plasma norepinephrine concentrations of 1000 pg/mL to 2000 pg/mL and comprise
only 5% to 10% of cases.14 Secondary hyperadrenergic POTS is heterogeneous,
but usually the elevated norepinephrine levels reflect pharmacologic norepinephrine
transporter blockade by tricyclic antidepressants, selective norepinephrine
transporter inhibitors (eg, atomoxetine), or methylphenidate and other
amphetaminelike drugs.14,15
VOLUME DYSREGULATION. Most patients with POTS have some degree of

hypovolemia, with low plasma and total blood volumes resulting in reduced
cardiac preload upon standing. Many of these patients have low levels of
plasma renin activity and aldosterone compared with controls.16 Other
patients have reduced angiotensin-converting enzyme 2 activity, leading to
inappropriately high plasma angiotensin II levels.17 In patients with functional
gastrointestinal disorders associated with poor oral intake or excess fluid loss,
POTS should be considered secondary. The gastrointestinal diagnosis is the
preferred diagnosis, since treating it will usually improve volume status and
orthostatic intolerance.14
Excessive venous pooling also occurs in many patients with POTS. Poor
venomotor tone causes blood to pool in the veins of the lower limbs and abdomen
(splanchnic-mesenteric bed).18 Capillary leakage on standing, compounded by
venous pooling, leads to a net loss of plasma volume. Pooling also reduces cardiac
preload, unloads the baroreceptors in the upright position, and results in increased
sympathetic outflow.
96 FEBRUARY 2020

JOINT HYPERMOBILITY. A sizable minority of patients with POTS have KEY POINTS
hypermobile joints consistent with an underlying disorder of the connective
● The main POTS
tissue matrix, most commonly Ehlers-Danlos syndrome hypermobility type.19 A mechanisms are impaired
study of 24 patients with Ehlers-Danlos syndrome (20 with hypermobility type) sympathetically mediated
found reduced intraepidermal nerve fiber density consistent with small fiber vasoconstriction in the
peripheral neuropathy in all patients, most of whom reported diffuse lower limbs (neuropathic
POTS), excessive cardiac
neuropathic pain, sensitive skin, and restless legs.20 None of these patients
sympathoexcitatory
reported postural tachycardia, but tilt-table testing was not performed. responses (hyperadrenergic
POTS), volume
DECONDITIONING. The overwhelming majority of patients with POTS have poor dysregulation, joint
hypermobility, and physical
exercise tolerance. Physical deconditioning is evidenced by reduced stroke
deconditioning.
volume and left ventricular mass as well as greater and more persistent
tachycardia and reduced peak oxygen uptake when upright and with ● A postinfectious
exercise.21–23 Physical deconditioning will compound essentially any other autoimmune process is likely
pathophysiology contributing to POTS. in many patients with POTS,
as evidenced by an
antecedent illness of
OTHER MECHANISMS OF POSTURAL TACHYCARDIA SYNDROME. Psychological presumed viral etiology in
mechanisms such as anxiety, panic, and somatic hypervigilance have significant approximately one-half
but poorly understood roles in POTS. Symptoms of sympathoexcitation are and organ-specific
autoantibodies in up to
common to both panic disorders and POTS, and the sympathetic noradrenergic one-third.
system is involved in both disorders. Somatic hypervigilance and behavioral
amplification, previously demonstrated in patients with visceral pain,24 ● Hyperadrenergic POTS is
fibromyalgia,25 chronic dizziness,26 and migraine,27 could contribute to the characterized by episodes
of tachycardia, sweating,
persistence of symptoms and the coexistence of many nonorthostatic symptoms
and hypertension that can
in patients with POTS, despite adequate control of heart rate. be triggered by upright
posture, physical activity,
Comorbidities and emotional stimuli, and
Many patients with POTS have additional chronic conditions, including episodes may even occur
during sleep.
inappropriate sinus tachycardia, migraine and other headaches, visceral
hypersensitivity, gastrointestinal dysmotility, chronic fatigue, insomnia, and ● Most patients with POTS
fibromyalgia. have some degree of
hypovolemia, with low
plasma and total blood
INAPPROPRIATE SINUS TACHYCARDIA. The syndrome of inappropriate sinus volumes resulting in reduced
tachycardia is defined as a sinus heart rate higher than 100 beats/min at rest, with a cardiac preload upon
mean 24-hour heart rate higher than 90 beats/min, accompanied by bothersome standing.
palpitations.4 Occasional patients with inappropriate sinus tachycardia will have
● A sizable minority of
additional acceleration of heart rate and symptoms of orthostatic intolerance with
patients with POTS have
standing, indicating comorbid inappropriate sinus tachycardia and POTS. hypermobile joints
consistent with an
HEADACHE. Chronic headache, often with migrainous features and occasionally with underlying disorder of the
a postural pattern, is a common comorbidity in patients with POTS.28 Volume connective tissue matrix,
most commonly
expansion for treatment of orthostatic tachycardia is rarely effective for the headaches Ehlers-Danlos syndrome
in these patients.29 Orthostatic headache is the most common symptom of spinal hypermobility type.
CSF leak, and underlying disorders of the connective tissue matrix predispose to
both POTS and spontaneous CSF leaks, yet radiographic or other diagnostic
evidence of CSF volume depletion is uncommon in patients presenting with POTS.
VISCERAL PAIN AND DYSMOTILITY. Nausea, bloating, diarrhea, constipation,

abdominal pain, and bladder symptoms are common in POTS. Similar symptoms
are reported in patients with functional motility disorders such as functional

CASE 6-1 A 16-year-old girl was seen in clinic for 6 months of postural
lightheadedness and sweating. She could no longer stand through choir
rehearsal without dim or tunnel vision, palpitations, shaking limbs, and
feeling as if she would faint, so she sat between songs. She also reported
spells of palpitations, tremulousness, and sweating that occurred with
mild exertion and, occasionally, even during sleep. She could not recall
any illness or trauma before the onset of the orthostatic symptoms.
Neurologic and cardiac examinations were normal. General
examination revealed cool, clammy hands and hyperextensibility of both
little fingers and the right elbow. Autonomic testing showed excessive
and symptomatic heart rate rise during head-up tilt and other evidence of
a hyperadrenergic state (FIGURE 6-1).
COMMENT This patient had postural tachycardia syndrome (POTS), with typical
features of the hyperadrenergic subtype and underlying joint
hypermobility. Note that excessive heart rate acceleration with standing or
head-up tilt in the adolescent age group is 40 beats/min or more.
Hyperadrenergic POTS is characterized by prominent palpitations,
tremulousness, and sweating, even from sleep. This patient’s cool, clammy
hands reflected adrenaline-related peripheral vasoconstriction; plasma
levels of norepinephrine are also typically elevated (>600 pg/mL) in these
patients.
The patient improved with low-dose propranolol (10 mg 3 times a day),
but only after increasing dietary sodium and switching from knee-high
socks to compression garments covering the abdomen and thighs.
Beta-blockers are most helpful for patients with hyperadrenergic POTS.
Appropriate compression garments are requisite to symptomatic
improvement in patients with orthostatic intolerance and joint hypermobility.
98 FEBRUARY 2020

FIGURE 6-1
Autonomic laboratory testing of the patient in CASE 6-1 with hyperadrenergic postural
tachycardia syndrome. A, Head-up tilt (shaded region) triggered an excessive heart rate
increase from 57 beats/min to 124 beats/min (red line) and symptoms despite stable blood
pressure (black line). B, Beat-to-beat blood pressure responses during the Valsalva maneuver
(shaded region) showed an exaggerated phase IV overshoot, indicating excessive sympathetic
activation. The phases of the Valsalva maneuver are labeled below the blood pressure
tracing. II_E indicates early phase II; II_L indicates late phase II.

dyspepsia, abnormal gastric emptying, irritable bowel syndrome, and interstitial

cystitis.30,31 By scintigraphic transit study, gastric emptying may be rapid (48%),
normal (34%), or delayed (18%).32 The overrepresentation of these symptoms
in patients with POTS does not necessarily suggest a widespread autonomic
neuropathy because these are disorders of visceral sensitivity mediated by
visceral afferents and central processing circuits and not of the enteric nervous
system per se or of the efferent sympathetic or parasympathetic outflow via the
vagus, pelvic, or splanchnic nerves.
MAST CELL ACTIVATION DISORDER. Secondary hyperadrenergic POTS has been

associated with mast cell activation disorder, which may be suspected clinically
by episodes of flushing, diarrhea, nausea, and vomiting.33 The diagnosis is
supported by the finding of elevated serum tryptase and urinary leukotriene E4,
N-methylhistamine, and prostaglandin F2α.
MEDIAN ARCUATE LIGAMENT SYNDROME. The celiac artery and associated

nervous structures can be compressed by the median arcuate ligament as they
traverse the diaphragm. Patients with median arcuate ligament syndrome have
prominent weight loss, nausea, vomiting, and abdominal pain worsened by
eating.34 Diagnosis is by duplex ultrasonography, CT angiography, or magnetic
resonance angiography (MRA). Treatment is controversial and, if pursued,
should be directed toward the abdominal symptoms, not toward POTS.
CHRONIC FATIGUE, INSOMNIA, AND FIBROMYALGIA. Chronic fatigue, sleep

disturbances, and fibromyalgia are frequent in patients with POTS and can be
TABLE 6-2 Laboratory Evaluation for Patients With Orthostatic Intolerancea
Investigations Rationale
ECG, echocardiogram, Holter monitoring Exclude primary cardiac cause of tachycardia
Head-up tilt (at 60- to 70-degree angle for 10 min) Distinguish types of orthostatic intolerance
Exercise testing with VO2 max Quantify physical deconditioning
24-hour urinary sodium excretion Assess for hypovolemia
Sudomotor and cardiovagal function tests; fasting Detect neuropathic subtype of POTS, and, if found, its cause
glucose, hemoglobin A1c; serum and urine protein
electrophoresis; ganglionic nicotinic acetylcholine
receptor autoantibodies
Supine and standing plasma catecholamines; AM and Detect hyperadrenergic subtype of POTS and, if found, its cause
PM cortisol; thyroid function tests; plasma and urine
metanephrines; serum tryptase, urinary methylhistamine
Scintigraphic motility studies, urologic evaluation Investigate suspected functional visceral dysmotility syndromes
MRI of the head with gadolinium Exclude CSF leak in patients with orthostatic headache
CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = magnetic resonance imaging; POTS = postural tachycardia syndrome; VO2
max = maximal oxygen uptake.
a
Modified with permission from Benarroch EE, Mayo Clin Proc.14 © 2012 Mayo Foundation for Medical Education and Research.
100 FEBRUARY 2020

differentiated from chronic fatigue syndrome by the predominance of KEY POINTS
orthostatic symptoms, despite considerable overlap.
● Many patients with POTS
have additional chronic
Evaluation conditions, including
The evaluation of a patient with suspected POTS should begin with a complete inappropriate sinus
history and physical examination. The key components of the history are the tachycardia, migraine and
other headaches, visceral
timing of onset and progression of orthostatic symptoms, the presence of
hypersensitivity,
nonorthostatic symptoms, precipitating and aggravating factors, amounts of gastrointestinal dysmotility,
fluid and caffeine intake, level of physical activity and standing time, response to chronic fatigue, insomnia,
previously attempted treatments, and current drug therapy. The excessive heart and fibromyalgia.
rate rise of 30 beats/min (40 beats/min in adolescents) that defines POTS when
● The syndrome of
accompanied by symptoms of orthostatic intolerance can be demonstrated by inappropriate sinus
measuring supine and standing blood pressure and heart rate or by tilt-table testing. tachycardia is defined as a
Expert consensus guidelines state that patients with suspected POTS should sinus heart rate higher than
undergo comprehensive cardiac and neurologic examinations, supine and 100 beats/min at rest, with a
mean 24-hour heart rate
standing heart rate and blood pressure measurement, and a 12-lead ECG.4 higher than 90 beats/min,
Laboratory evaluation aims to exclude primary cardiac causes of tachycardia, accompanied by
determine the most likely pathophysiologic basis of orthostatic intolerance, bothersome palpitations.
assess the degree of cardiovascular conditioning, investigate the mechanisms
● Patients with suspected
of gastrointestinal and other associated symptoms, and address possible
POTS should undergo
psychiatric comorbidities (TABLE 6-2). Sudomotor impairment can be detected comprehensive cardiac and
in one-half to two-thirds of patients with POTS by quantitative sudomotor axon neurologic examinations,
reflex test (QSART) or thermoregulatory sweat test. The pattern is typically supine and standing heart
rate and blood pressure
length dependent, with anhidrotic feet and variable involvement of the
measurement, and a
remainder of the legs.12 In patients with neuropathic POTS, treatable causes of 12-lead ECG.
autonomic neuropathy should be pursued. In patients with hyperadrenergic
POTS, primary endocrine or other systemic causes of a hyperadrenergic state ● The primary objective of
should be checked. POTS management is to
improve patients’ functional
capacity (ie, increase the
CARDIAC TESTING. Prolonged Holter monitor and ambulatory event loop time that they can stand,
recordings most often show only sinus rhythm and sinus tachycardia; hence, perform daily activities, and
12-lead ECG will usually suffice.4 Echocardiogram is usually normal, with mitral exercise).
valve prolapse occasionally found. Invasive electrophysiologic studies should be
reserved for patients with documented arrhythmias. Exercise testing with
measurement of peak oxygen uptake reveals a degree of physical deconditioning
in most patients with POTS and supports retraining as a major
treatment strategy.35
Management
The primary objective of POTS management is to improve patients’ functional
capacity, that is, to increase the time that they can stand, perform daily activities,
and exercise. Management involves nonpharmacologic approaches (TABLE 6-3),
with occasional add-on pharmacologic therapies. Patient education is critical and
should include review of potential aggravating or precipitating factors of
orthostatic and exercise intolerance and emphasize improving function and not
necessarily symptoms or heart rate per se. Few treatments have been subjected to
the rigor of randomized clinical trials.
FLUID AND SODIUM INTAKE. Fluid intake should be about 2 L (64 oz) of water and
other noncaffeinated beverages per day. Some of this can be in the form of water

bolus therapy, which refers to rapidly drinking approximately 500 mL (12 oz to

16 oz) of cold plain water immediately before anticipated upright activity, up to
3 times per day. Excessive caffeine intake should be avoided because it promotes
diuresis and hypovolemia.8 In the absence of heart failure or kidney disease,
dietary sodium intake should be aggressive: at least 2 g (5 g of table salt, which is
40% sodium) and often as much as 8 g (20 g of table salt). Over-the-counter
sodium chloride tablets may be used but often produce stomach upset; buffered
tablets may be better tolerated. The total urine volume and sodium excretion
over 24 hours can be used to gauge fluid and sodium intake; targets are at least
170 mmol sodium in 1.5 L to 2.5 L of urine.36
PHYSICAL COUNTERMANEUVERS. When performed immediately at the onset of

orthostatic symptoms, physical counterpressure maneuvers produce small
increases in mean arterial pressure to augment cerebral blood flow and prevent
syncope.37 These maneuvers include crossing the legs, bending forward at the
waist, rising on toes, slow marching in place, and squatting, all of which aim to
counteract venous pooling.
COMPRESSION GARMENTS. Compression garments should cover the abdomen

38
and thighs. Thigh-high or waist-high compression stockings (30 mm Hg to
40 mm Hg strength) are effective but not always tolerated. Compression shorts
are a reasonable, although less effective, alternative and should fit snugly. For the
abdomen, a compression shirt or an abdominal binder, or both, should be worn
when upright and taken off at night.
EXERCISE TRAINING. Patients should engage in a graduated exercise program

that includes both endurance and resistance training.39 Endurance training
should be performed vigorously for at least 30 minutes on the majority of days
per week. Recumbent biking, swimming, and rowing (ie, nonupright exercises)
are generally better tolerated initially. Resistance training should be performed 2
or 3 days per week and target the proximal lower limbs and core with more
repetitions at lower weight.
PHARMACOLOGIC TREATMENT. Medications should be considered for treatment

of POTS only after nonpharmacologic strategies have been implemented. The
only medications shown in randomized trials to be beneficial are propranolol and
TABLE 6-3 Nonpharmacologic Management of Orthostatic Intolerance
Treatment Rationale
Increase water and sodium intake Avoid hypovolemia
Physical counterpressure maneuvers Reduce venous pooling
Compression garments Reduce venous pooling
Exercise training, including graded endurance and lower limb Improve physical
resistance training deconditioning and
reduce venous pooling
102 FEBRUARY 2020

pyridostigmine, and these trials were only short term. Considerable clinical KEY POINTS
experience, however, supports additional agents. Medications that might worsen
● Physical counterpressure
POTS, such as stimulants and norepinephrine transporter inhibitors, should maneuvers for patients with
be withdrawn.15 POTS aim to counteract
Propranolol at low dose (10 mg by mouth 1 to 3 times per day) lowers standing venous pooling and include
heart rate and improves orthostatic symptoms in patients with POTS; higher crossing the legs, bending
forward at the waist, rising
doses are less well tolerated.40 Quality-of-life measures did not improve in a
on toes, slow marching in
study of long-acting propranolol for POTS.41 Bisoprolol and metoprolol may also place, and squatting.
improve symptoms.42 Beta-blockers are probably most beneficial for patients
with hyperadrenergic POTS. ● Compression garments
Midodrine elicits peripheral vasoconstriction (veins and arteries) to reduce for patients with POTS
should cover the abdomen
venous pooling and orthostatic hypotension. This strategy of exogenous and thighs.
peripheral α1 agonism may be most beneficial for patients with neuropathic
POTS. Midodrine may cause bothersome scalp paresthesia, urinary retention, ● Patients with POTS should
and bladder spasms. Patients should be advised not to lie flat for at least 4 hours engage in a graduated
exercise program that
after any dose of midodrine to avoid supine hypertension. includes both endurance
Pyridostigmine reduces orthostatic tachycardia and improves chronic symptoms and resistance training.
without aggravating supine hypertension.43,44 Use may be limited by diarrhea,
abdominal cramps and pain, nausea, and urinary frequency and urgency. ● Medications should be
considered for treatment of
Fludrocortisone expands plasma volume via sodium retention. The effects
POTS only after
may last only 1 to 2 days,45 and long-term use should be avoided for risk of renal nonpharmacologic
and cardiac fibrosis. Other side effects include weight gain, edema, headache, strategies have been
vertigo, hypokalemia, and supine hypertension. implemented.
The use of droxidopa for POTS is expanding, although published data remain
● Beta-blockers are
limited. One retrospective series reported improvement in symptoms of probably most beneficial
dizziness, syncope, and fatigue despite no statistically significant difference in for patients with
standing or sitting blood pressure.46 Only 27% of patients reported improved hyperadrenergic POTS.
quality of life, and 40% of patients stopped droxidopa because of side effects
● Pyridostigmine reduces
or ineffectiveness.
orthostatic tachycardia and
Ivabradine slows the heart rate without affecting blood pressure. It blocks the improves chronic symptoms
inward-directed hyperpolarization-activated cyclic nucleotide–gated (HCN) of POTS without aggravating
channels (also called funny channels) in sinoatrial node cells that normally supine hypertension.
facilitate repolarization and help set the rate of pacemaker cells.47 An open-label
trial in eight patients with POTS showed that a single dose can slow both
resting and upright heart rate without significant adverse effects.48 Ivabradine
improved symptoms in 60% of patients with POTS in a retrospective series49 and
in 91% of patients with inappropriate sinus tachycardia in a randomized
placebo-controlled trial.50
IV fluid administration generally relieves symptoms promptly, but the effect
is not long-lasting.51 A 2017 prospective series of patients with POTS refractory to
an average of 3.6 medications suggested a possible role for IV fluids as bridge
therapy. Patients who received 1 L to 2 L of normal saline from once a month up
to twice a week reported reduced symptoms and improved quality of life, and 50
of 57 patients were able to wean off saline completely within 6 months.51
Prognosis
Data are limited on the long-term prognosis of POTS. In one large study with at
least 18 months of prospective follow-up for all patients, who were treated with a
variety of nonpharmacologic and pharmacologic measures, 60% had returned to
normal function, 80% were improved, and 90% were able to return to work.52

Another prospective study showed that 70% of patients had improvement of

symptoms at 1 year, although the group average heart rate increment was not
significantly reduced.53 More recent work has shown impaired quality-of-life
measures and increased thoughts of suicide in patients with POTS, highlighting
the need for better understanding and treatment of this disorder.54
SYNCOPE
Syncope is a transient loss of consciousness and postural muscle tone due to
global cerebral hypoperfusion, with relatively abrupt onset and spontaneous,
complete, and relatively prompt recovery. The lay term is fainting, and this
common event should be viewed as a heterogeneous brain-heart syndrome
rather than a specific disease. The lifetime prevalence of syncope is 30% to 50%.
The most common type is neurally mediated syncope, which involves reflex
dysfunction between the central nervous system and the cardiovascular system.
The terms neurocardiogenic syncope, vasovagal syncope, and vasodepressor syncope
emphasize different physiologic aspects of related syncope types that originate in
the nervous system and together constitute neurally mediated syncope. Upright
posture is perhaps the most common of several potential triggers of neurally
mediated syncope, positioning it definitively among the disorders of orthostatic
intolerance. Syncope is also the final common pathway of autonomic failure with
progressive orthostatic hypotension.
While syncope is usually evaluated by cardiologists to rule out potentially
life-threatening cardiac arrhythmias or structural heart disease, neurologists may
be involved to discriminate between various other causes of transient loss of
consciousness. Neurologists are often involved in distinguishing syncope from
seizures, transient ischemic attack, panic, cataplexy, psychogenic pseudosyncope,
and acute metabolic derangements such as hypoglycemia.
Demographics
Syncope can occur at any age, with the first peak occurring in the teen or
young adult years and a second peak near 80 years of age.55 Syncope at a younger
age is usually the neurally mediated type. With advancing age, cardiac causes,
orthostatic hypotension, and medication effects become more common.56,57 The
prevalence of all syncope types in the general population up to 60 years of age is
20% to 40%.55,58 The incidence is 1.5 times higher in women than men, and
familial clustering is common. A heritable component is estimated in at least 20%
of cases of syncope, but the genetic influence is almost certainly multifactorial
with additional psychological and environmental factors.59,60
Clinical Features
Syncope is, by definition, transient, so the clinician is likely to encounter an
individual who appears well and has a normal neurologic examination. A careful
history is therefore of utmost importance. Valuable details include the
circumstances leading up to the loss of consciousness, the patient’s subjective
symptoms, and objective accounts from any witnesses. Common provoking
factors for neurally mediated syncope include prolonged upright posture, a
warm environment, pain, fear, emotional distress, venipuncture, and the sight of
blood, so it is worth probing these factors explicitly. The typical episode of
neurally mediated syncope can be divided into prodrome and unresponsive
phases (CASE 6-2).
104 FEBRUARY 2020

PRODROME. The prodrome can be of variable duration, generally less than KEY POINTS
1 minute, and is recognized or later recalled by only two-thirds of patients.61 The
● Syncope is a transient
symptoms and signs that occur during the prodrome (presyncope) result from loss of consciousness and
cerebral hypoperfusion or autonomic activation, or both. Facial pallor often postural muscle tone due
happens early in the progression of neurally mediated syncope. Other common to global cerebral
symptoms of impending syncope include those listed in TABLE 6-1. When hypoperfusion, with
relatively abrupt onset and
syncope occurs abruptly without any prodrome, the clinician should be
spontaneous, complete, and
suspicious for ventricular arrhythmia. relatively prompt recovery.
UNRESPONSIVENESS. Loss of consciousness occurs when perfusion of the ● Syncope can occur at any
reticular activating system in the brainstem and diencephalon becomes age, with the first peak
usually occurring in the teen
inadequate. The duration of unconsciousness is brief (average of 12 seconds in or young adult years and a
healthy volunteers with syncope provoked by the sequence of hyperventilation, second peak near 80 years
orthostasis, and Valsalva maneuver).62 Just as an absent prodrome should prompt of age. Syncope at younger
consideration of alternative diagnoses, prolonged unresponsiveness raises age is usually the neurally
mediated type.
concern for epilepsy, vertebrobasilar insufficiency, subarachnoid hemorrhage,
traumatic brain injury, hypoglycemia, drug or medication intoxication, or ● The typical episode of
psychogenic pseudosyncope. Note that unconsciousness will be prolonged in neurally mediated syncope
otherwise typical syncope if the patient is prevented from achieving the can be divided into
prodrome and unresponsive
recumbent position in which cerebral circulation is restored. Propping the patient
phases. The prodrome can
in the seated position only keeps the adverse effect of gravity in play longer, be of variable duration,
and potential for watershed ischemic infarction even exists in this situation. generally less than 1 minute,
and is recognized or later
recalled by only two-thirds
OTHER FEATURES OF SYNCOPE. Myoclonic jerks during the unresponsive phase of
of patients.
syncope are frequently mistaken by witnesses to the event as epileptic seizures,
but these ictal-appearing phenomena have distinguishing features (TABLE 6-463). ● When syncope occurs
Syncope-related myoclonic jerks are usually multifocal and arrhythmic, involve abruptly without any
proximal and distal muscles, begin after the patient has fallen, and last less than prodrome, the clinician
should be suspicious for
15 seconds.64 A video study of 65 syncope cases and 50 seizures separated ventricular arrhythmia.
convulsive syncope from epilepsy based on the number of myoclonic jerks: fewer
than 10 in syncope, more than 20 in epileptic seizures.65 ● Prolonged
Transient focal neurologic deficits are seen in up to 5% of patients with syncope, unresponsiveness in alleged
syncope should raise
especially if frequent or with onset in childhood, with delayed diastolic blood
concern for epilepsy,
pressure recovery during active standing, or associated with carotid or vertebrobasilar
vertebrobasilar stenosis.66 Headache immediately after neurally mediated syncope insufficiency, subarachnoid
may result from cerebral reperfusion or hyperperfusion.67 hemorrhage, traumatic brain
injury, hypoglycemia, drug
or medication intoxication,
SITUATIONAL SYNCOPE. Just as neurally mediated syncope is often triggered by or psychogenic
phlebotomy and other medical instrumentation, several other forms of syncope pseudosyncope.
are triggered by very specific circumstances. These types of situational syncope
are generally benign, although occasionally they reflect underlying neurologic or ● Convulsive syncope can
be distinguished from an
systemic disease. Key features of several types of situational syncope are listed in epileptic seizure by the
TABLE 6-5. number of myoclonic jerks:
fewer than 10 in syncope,
Pathophysiology more than 20 in seizures.
Neurally mediated syncope is associated with one or both of two hemodynamic
patterns: the vasodepressor pattern is an abrupt fall in blood pressure that occurs
beyond the time cutoff (3 minutes) for orthostatic hypotension, and the
cardioinhibitory pattern is a pronounced bradycardia of fewer than 40 beats/min
or asystole of more than 3 seconds.68 The most common subtype of neurally

CASE 6-2 A 21-year-old woman experienced her first episode of transient loss of
consciousness at 16 years of age while standing in her kitchen before
breakfast. In the ensuing 5 years, she had recurrence of essentially the
same event an average of once per month. Spells were generally
preceded by 2 to 3 seconds of tingling in her face that spread down her
body to her toes, then her vision darkened and she passed out and fell.
Her girlfriend witnessed several of the spells and said she was never
unconscious for more than 30 seconds and usually less than 10 seconds.
Her legs or arms occasionally twitched 5 or 6 times after she fell, and
once she lost bladder continence, but she never bit her tongue. Every
spell began while she was standing, except one event that occurred after
she had lacerated her finger. Neither fludrocortisone nor metoprolol had
reduced the frequency of spells.
Physical examination was normal. She experienced a typical spell
during head-up tilt (FIGURE 6-2).
COMMENT This patient had recurrent vasovagal syncope (the most common form of
neurally mediated syncope) with triggers of upright posture and pain.
Vasodepressor syncope is also commonly triggered by upright posture but
is usually associated with palpitations and a longer prodrome. Vasovagal
syncope is distinguished by the presence of a cardioinhibitory
(bradycardic) response, whereas vasodepressor syncope is distinguished
by the absence of that response; the vasodepressor profile is seen in both
forms (FIGURE 6-3). A history of limb twitching and urinary incontinence
raises the possibility of epileptic seizures, but these features are also
common during syncope. As exemplified in this patient, medications are
less effective for neurally mediated syncope than is avoidance of
recognized triggers. This patient had fewer syncopal events after learning
to avoid common orthostatic stressors, such as alcohol, dehydration, large
meals, and high ambient temperatures.
106 FEBRUARY 2020

FIGURE 6-2
Tilt-table testing in the patient in CASE 6-2 with vasovagal syncope. Head-up tilt (shaded region)
triggered a precipitous and concomitant fall in heart rate (red line) and blood pressure
(black line), consistent with the vasovagal type of neurally mediated syncope.
FIGURE 6-3
Tilt-table testing in a 33-year-old man with vasodepressor syncope. After several minutes of
head-up tilt (shaded region), blood pressure (black line) fell quickly while heart rate (red line)
remained steady, consistent with the vasodepressor type of neurally mediated syncope.

mediated syncope, vasovagal syncope, is characterized by simultaneous

vasodepressor and cardioinhibitory (vagal) hemodynamics. Vasodepressor
syncope, in contrast, consists of an abrupt fall in blood pressure without an
associated slowing of heart rate (vasodepressor without cardioinhibitory
response).
Syncope does not occur as long as cerebral blood flow is maintained. In the
face of orthostatic stressors such as standing, syncope is generally prevented by
an intact baroreflex and cardiovascular system. Neurally mediated syncope
occurs despite intact autonomic reflexes, however, through mechanisms that are
not fully understood. A recently proposed heart defense theory may better
TABLE 6-4 Distinguishing Features of Convulsive Syncope and Epileptic Seizuresa
Feature Convulsive Syncope Epileptic Seizure
Onset of myoclonus After loss of consciousness Immediate
Tempo Arrhythmic jerks Rhythmic jerks
Jerks per event <10 >20
Duration 1–15 sec 30 sec–2 min
Eye deviation Upward Lateral
Tongue bite Occasional, tip of tongue Frequent, side of tongue
Postictal period Fatigue Confusion
a
Modified with permission from Cheshire WP, Continuum (Minneap Minn).63 © 2017 American Academy of
Neurology.
TABLE 6-5 Situational Syncope
Syncope Type Typical Features

Cough (tussive) Middle-aged man with obstructive airway disease, child with asthma, patient with Chiari
malformation or space-occupying intracranial lesion
Micturition Middle-aged man using vasodilators or after drinking alcohol; absent prodrome
Defecation Elderly woman; prodromal abdominal cramping, nausea, and fecal urge
Postexertion Young athlete who abruptly stops vigorous exercise in a hot environment
Laughter (gelastic) Rare; no stereotypical demographic
Swallow (deglutition) Patient with underlying esophageal spasm, esophageal stricture, or achalasia; prodromal facial
flushing and palpitations
Glossopharyngeal neuralgia Defined by paroxysmal stabbing throat or ear pain triggered by swallowing
Carotid sinus Older patient; triggered by mechanical compression or stretching of carotid sinus, as by tight
collar, massage, or head turning
108 FEBRUARY 2020

explain vasovagal syncope as a cardioprotective reflex against excessive KEY POINTS
sympathetic activity than does the classic model (Bezold-Jarisch reflex), which
● Neurally mediated
does not fully coincide with all available data. syncope is associated with
Neurally mediated syncope has classically been explained by the Bezold- one or both of two
Jarisch reflex. This reflex is triggered by excessive venous pooling, which reduces hemodynamic patterns. The
cardiac preload and ventricular filling. Ventricular contractility increases to vasodepressor pattern is an
abrupt fall in blood pressure
maintain cardiac output, and this hypercontractile state activates stretch-
that occurs beyond the time
sensitive mechanoreceptors in the left ventricle. These receptors mediate a cutoff (3 minutes) for
sympathetic vasodepressor response and a parasympathetic cardioinhibitory orthostatic hypotension; the
response through the nucleus tractus solitarius. In short, this paradoxical reflex cardioinhibitory pattern is a
pronounced bradycardia of
translates reduced ventricular filling into peripheral vasodilation, bradycardia,
fewer than 40 beats/min or
hypotension, and syncope. asystole of more than
Not accounted for solely by the Bezold-Jarisch reflex theory of neurally 3 seconds.
mediated syncope are the findings of persistent muscle sympathetic nerve
activity during syncope69 and a period of sympathetic excitation preceding ● Vasovagal syncope may
be a protective reflex
sympathetic withdrawal.70 Tilt-induced syncope and spontaneous neurally response to excessive
mediated syncope are preceded by a progressive imbalance between plasma sympathetic activity, to
epinephrine from the adrenal glands (markedly elevated) and norepinephrine which the heart is
from postganglionic sympathetic nerves (less elevated), and this particularly prone.
sympathoadrenal imbalance results in skeletal muscle vasodilation, hypotension,
● Prodromal symptoms
and syncope.71 The heart defense theory posits that the vasovagal reflex, in typically occur when mean
response to rising sympathetic activity, transiently inhibits the sympathetic blood pressure falls
nervous system to reduce myocardial oxygen consumption and improve diastolic below 60 mm Hg.
Unresponsiveness occurs
filling and coronary perfusion.72 In this way, vasovagal syncope may be a
below 50 mm Hg at heart
protective reflex response to excessive sympathetic activity, to which the heart is level, corresponding to
particularly prone. 30 mm Hg cerebral arterial
Ultimately, individual susceptibilities to neurally mediated syncope that pressure.
reflect differences in orthostatic tolerance, cerebrovascular and peripheral
● In contrast to
vascular responses to hyperventilation, emotional state, baroreflex physiology, postexertional syncope,
and catecholamine availability probably exist.4 By whatever mechanism, which is a benign reflex
prodromal symptoms typically occur when mean blood pressure falls below syncope, syncope during
60 mm Hg. Unresponsiveness occurs below 50 mm Hg at heart level, exertion points toward
ventricular arrhythmias,
corresponding to 30 mm Hg cerebral arterial pressure.64 atrioventricular block,
hypertrophic obstructive
Evaluation cardiomyopathy, aortic
Since the clinician is unlikely to encounter a patient during the syncopal event, stenosis, or subclavian
steal syndrome.
which is, by definition, transient, establishing the diagnosis relies heavily on
gathering a thorough history from the patient and any witnesses. Distinguishing
neurally mediated syncope from other causes of transient loss of consciousness
(or apparent loss of consciousness) principally involves comparing the patient’s
story to that of syncope and the various alternative diagnoses.
CARDIAC ARRHYTHMIA. Chief among the potentially life-threatening mimics of

neurally mediated syncope is cardiac arrhythmia, which may be suggested by
sudden loss of consciousness without any prodrome, especially if occurring at
rest. In contrast to postexertional syncope, which is a benign reflex syncope,
syncope during exertion points toward ventricular arrhythmias, atrioventricular
block, hypertrophic obstructive cardiomyopathy, aortic stenosis, or subclavian
steal syndrome.73 Cardiac syncope is associated with a high risk of cardiac
morbidity and mortality.74

EPILEPSY. Seizures and syncope have several clinical features in common, which
can sometimes make the diagnosis difficult. As described above, myoclonic jerks
are a common feature of syncope. Epileptic seizures are suggested by aura,
jacksonian march, oral or manual automatisms, and postictal confusion. A bite to
the lateral aspect of the tongue, as opposed to the tip, is highly specific to a
generalized seizure.75 Urinary incontinence does not distinguish seizure from
syncope.76 Ictal arrhythmias—including ictal tachycardia (occurring in 80% to
90% of seizures), ictal bradycardia, and asystole (rare)—can occur with seizure
onset in the temporal, insular, or frontal regions.
Other diagnoses to consider when evaluating a patient with transient
loss of consciousness include transient ischemic attack, pulmonary embolism,
cataplexy, hypoglycemia, hypothermia, hypoxia, and intoxication. Psychogenic
pseudosyncope should be considered when the features of the spell do not conform
to recognized organic causes of syncope and is best diagnosed by certain
positive features. Whereas the eyes remain open during neurally mediated
syncope, the eyes are almost always forcibly closed during psychogenic
pseudosyncope.77 Also in contrast to neurally mediated syncope, patients with
psychogenic pseudosyncope often deny any prodrome, report longer periods of
apparent loss of consciousness (up to several minutes), and may be suggestible (ie,
faint and revive on command). A definite diagnosis of psychogenic pseudosyncope
is made by recording normal blood pressure, heart rate, and EEG during
an episode.
TESTING. The diagnosis of neurally mediated syncope resides largely in the

history. Diagnostic testing in suspected syncope, therefore, seeks to identify
orthostatic hypotension, POTS, baroreflex failure, and non-neurologic causes
such as cardiac arrhythmia. The best assessment of cardiovascular adrenergic
function is made with continuous monitoring of beat-to-beat blood pressure and
heart rate during Valsalva maneuver and head-up tilt. Bedside orthostatic vital
signs can provide less comprehensive but still useful diagnostic information;
appropriate testing of orthostatic vital signs is described in the article
“Management of Orthostatic Hypotension” by Jose-Alberto Palma, MD, PhD,
and Horacio Kaufmann, MD, FAAN,2 in this issue of Continuum.
The head-up tilt test, or tilt-table test, is a widely available and well-
established means by which to reproduce the orthostatic stress that provokes
many cases of neurally mediated syncope. Published guidelines from the
European Society of Cardiology provide a class IIa recommendation for tilt-table
testing in all patients with suspected reflex syncope, psychogenic pseudosyncope,
POTS, or orthostatic hypotension.68 More conservatively, the American College
of Cardiology guidelines recommend tilt-table testing for suspected neurally
mediated syncope when a confident diagnosis cannot be made after the initial
assessment, when pseudosyncope is suspected, and when convulsive syncope
and epilepsy cannot otherwise be distinguished.78
A tilt-table test is positive when it produces pronounced hypotension with or
without bradycardia, presyncope, or, as some prefer but which does not alter
specificity, full loss of consciousness. Pharmacologic provocation during tilt-
table testing, typically with IV isoproterenol or sublingual nitroglycerin,
improves sensitivity at the expense of specificity.79 Tilt-table test results must be
interpreted with caution, as both false negatives and false positives are common.
In one study, tilt-table testing provoked syncope in 8% to 40% of subjects who
110 FEBRUARY 2020

had no prior history of syncope, with greater frequencies with pharmacologic KEY POINTS
provocation and higher angles of tilt.80
● Patients with
psychogenic
Management pseudosyncope often deny
Neurally mediated syncope, especially vasovagal and the various situational any prodrome, report longer
syncopes, is most effectively managed by recognition and avoidance of triggers. periods of apparent loss of
consciousness (up to several
Other proven strategies to reduce the frequency of syncope are physical
minutes), and may be
counterpressure maneuvers and intravascular volume expansion.81 By suggestible. A definite
teaching patients about orthostatic stressors and the premonitory diagnosis of psychogenic
(prodromal) symptoms that signal falling blood pressure, syncope can often pseudosyncope is made by
recording normal blood
be avoided by timely sitting or lying down. The nonpharmacologic strategies
pressure, heart rate, and
of liberal intake of fluid and salt, compression garments on the abdomen and EEG during an episode.
thighs, and physical counterpressure maneuvers were discussed earlier in this
article and are listed in TABLE 6-3. ● Tilt-table test results
Medications are generally less helpful but not completely without potential must be interpreted with
caution, as both false
benefit for preventing neurally mediated syncope. In an open-label trial of negatives and false positives
25 patients with recurrent syncope preceded by sinus tachycardia, ivabradine are common.
reduced or abolished symptoms in 18 (72%).82 Fludrocortisone showed a trend
toward significance in a randomized controlled trial with 210 patients ● Neurally mediated
syncope, especially
followed for 1 year, with syncope recurrence in 60.5% of the placebo arm and
vasovagal and the various
44.0% of the fludrocortisone arm (P=.069).83 Midodrine was associated with a situational syncopes, is most
37% risk reduction in a systematic review of five randomized controlled effectively managed by
trials.84 In a subgroup analysis of an observational cohort study, beta-blockers recognition and avoidance
of triggers.
reduced syncope recurrence by 48% in patients 42 years of age or older but not
in younger patients.85 Guidelines from the European Society of Cardiology
give class IIb recommendations for fludrocortisone and midodrine and a
class III recommendation against beta-blockers for syncope recurrence.68
The American College of Cardiology guidelines support midodrine,
fludrocortisone, selective serotonin reuptake inhibitors (SSRIs), and
beta-blockers (only for patients 42 years of age or older) with class IIa or
IIb recommendations.78
Cardiac pacemaker implantation for treating neurally mediated syncope is
controversial. It is not first-line therapy but, according to American College of
Cardiology and European Society of Cardiology guidelines, may be considered
for those patients with documented profound bradycardia or asystole.68,78
Prognosis
Neurally mediated syncope is typically not a harbinger of sinister pathology,
but it often recurs and may negatively impact quality of life. Syncope recurrence
is predicted by the number of syncopal events in the preceding year.86 The
mortality risk of patients with first-time syncope and no preexisting comorbidity
is low and not significantly different from controls.87 In contrast, and not
surprisingly, first-time syncope in the setting of cardiovascular comorbidities is
associated with increased mortality (1.2 to 2.2 times that of age-matched
subjects).87
CONCLUSION
POTS and neurally mediated syncope are the predominant forms of orthostatic
intolerance at younger ages, with orthostatic hypotension occurring more often

later in life. All forms of orthostatic intolerance have overlapping symptoms of

cerebral hypoperfusion, with sympathoexcitation only in POTS and the
prodromal phase of syncope. Quality of life is negatively impacted by orthostatic
intolerance, but patients’ functional capacity can be improved with trigger
avoidance, rigorous implementation of several nonpharmacologic strategies,
and, in select cases, medications.
USEFUL WEBSITES
AMERICAN AUTONOMIC SOCIETY NATIONAL DYSAUTONOMIA RESEARCH FOUNDATION
The American Autonomic Society website provides The National Dysautonomia Research Foundation
information on clinical autonomic research; offers information on what dysautonomia is,
conferences for clinicians; and centers, research opportunities, a network of medical
foundations, and societies for autonomic disorders. specialists, and a discussion forum for patients with
americanautonomicsociety.org dysautonomia.
ndrf.org
DYSAUTONOMIA INTERNATIONAL
The Dysautonomia International website offers SYNCOPEDIA
information on research on dysautonomia and Syncopedia.org is a website that contains free
resources for physicians, patients, families of educational information on syncope for medical
patients, and caregivers. professionals.
dysautonomiainternational.org syncopedia.org
REFERENCES
1 Smit AA, Halliwill JR, Low PA, Wieling W. 9 Fu Q, VanGundy TB, Shibata S, et al. Menstrual
Pathophysiological basis of orthostatic hypotension cycle affects renal-adrenal and hemodynamic
in autonomic failure. J Physiol 1999;519(pt 1):1–10. responses during prolonged standing in the
doi:10.1111/j.1469-7793.1999.0001o.x. postural orthostatic tachycardia syndrome.
Hypertension 2010;56(1):82–90. doi:10.1161/
2 Palma JA, Kaufmann H. Management of orthostatic
HYPERTENSIONAHA.110.151787.
hypotension. Continuum (Minneap Minn) 2020;
26(1, Autonomic Disorders):154–177. 10 Roma M, Marden CL, De Wandele I, et al. Postural
tachycardia syndrome and other forms of
3 Streeten DHP. Orthostatic disorders of the circulation:
orthostatic intolerance in Ehlers–Danlos
mechanisms, manifestations, and treatment. 1st
syndrome. Auton Neurosci 2018;215:89–96.
ed. New York, NY: Plenum Press; 1987:286 pp.
doi:10.1016/j.autneu.2018.02.006.
4 Sheldon RS, Grubb BP 2nd, Olshansky B, et al.
11 Jacob G, Costa F, Shannon JR, et al. The
2015 Heart Rhythm Society expert consensus
neuropathic postural tachycardia syndrome.
statement on the diagnosis and treatment of
N Engl J Med 2000;343(14):1008–1014. doi:10.1056/
postural tachycardia syndrome, inappropriate
NEJM200010053431404.
sinus tachycardia, and vasovagal syncope. Heart
Rhythm 2015;12(6):e41–e63. doi:10.1016/j. 12 Low PA, Sandroni P, Joyner M, Shen WK. Postural
hrthm.2015.03.029. tachycardia syndrome (POTS). J Cardiovasc
Electrophysiol 2009;20(3):352–358. doi:10.1111/
5 Singer W, Sletten DM, Opfer-Gehrking TL, et al.
j.1540-8167.2008.01407.x.
Postural tachycardia in children and adolescents:
what is abnormal? J Pediatr 2012;160(2):222–226. 13 Dahan S, Tomljenovic L, Shoenfeld Y. Postural
doi:10.1016/j.jpeds.2011.08.054. orthostatic tachycardia syndrome (POTS)—a novel
member of the autoimmune family. Lupus 2016;
6 Thieben MJ, Sandroni P, Sletten DM, et al.
25(4):339–342. doi:10.1177/0961203316629558.
Postural orthostatic tachycardia syndrome: the
Mayo clinic experience. Mayo Clin Proc 2007; 14 Benarroch EE. Postural tachycardia syndrome: a
82(3):308–313. doi:10.4065/82.3.308. heterogeneous and multifactorial disorder. Mayo
Clin Proc 2012;87(12):1214–1225. doi:10.1016/j.
7 Shannon JR, Flattem NL, Jordan J, et al.
mayocp.2012.08.013.
Orthostatic intolerance and tachycardia associated
with norepinephrine-transporter deficiency. 15 Cheshire WP. Stimulant medication and postural
N Engl J Med 2000;342(8):541–549. doi:10.1056/ orthostatic tachycardia syndrome: a tale of two
NEJM200002243420803. cases. Clin Auton Res 2016;26(3):229–233.
doi:10.1007/s10286-016-0347-9.
8 Mathias CJ, Low DA, Iodice V, et al. Postural
tachycardia syndrome—current experience and
concepts. Nat Rev Neurol 2011;8(1):22–34.
doi:10.1038/nrneurol.2011.187.
112 FEBRUARY 2020

16 Raj SR, Biaggioni I, Yamhure PC, et al. Renin- 29 Mokri B, Low PA. Orthostatic headaches without
aldosterone paradox and perturbed blood volume CSF leak in postural tachycardia syndrome.
regulation underlying postural tachycardia Neurology 2003;61(7):980–982. doi:10.1212/01.
syndrome. Circulation 2005;111(13):1574–1582. WNL.0000085868.37963.7D.
doi:10.1161/01.CIR.0000160356.97313.5D.
30 Adibi P, Behzad E, Shafieeyan M, Toghiani A.
17 Stewart JM, Ocon AJ, Clarke D, et al. Defects in Upper functional gastrointestinal disorders in
cutaneous angiotensin-converting enzyme 2 young adults. Med Arh 2012;66(2):89–91.
and angiotensin-(1–7) production in postural doi:10.5455/medarh.2012.66.89-91.
tachycardia syndrome. Hypertension 2009;53(5):
31 Fukudo S, Kuwano H, Miwa H. Management and
767–774. doi:10.1161/HYPERTENSIONAHA.
pathophysiology of functional gastrointestinal
108.127357.
disorders. Digestion 2012;85(2):85–89.
18 Tani H, Singer W, McPhee BR, et al. Splanchnic- doi:10.1159/000334652.
mesenteric capacitance bed in the postural
32 Loavenbruck A, Iturrino J, Singer W, et al.
tachycardia syndrome (POTS). Auton Neurosci
Disturbances of gastrointestinal transit and
2000;86(1–2):107–113. doi:10.1016/S1566-0702(00)
autonomic functions in postural orthostatic
00205-8.
tachycardia syndrome. Neurogastroenterol Motil
19 Wallman D, Weinberg J, Hohler AD. Ehlers–Danlos 2015;27(1):92–98. doi:10.1111/nmo.12480.
syndrome and postural tachycardia syndrome: a
33 Shibao C, Arzubiaga C, Roberts LJ 2nd, et al.
relationship study. J Neurol Sci 2014;340(1–2):
Hyperadrenergic postural tachycardia syndrome
99–102. doi:10.1016/j.jns.2014.03.002.
in mast cell activation disorders. Hypertension
20 Cazzato D, Castori M, Lombardi R, et al. Small 2005;45(3):385–390. doi:10.1161/01.
fiber neuropathy is a common feature of Ehlers– HYP.0000158259.68614.40.
Danlos syndromes. Neurology 2016;87(2):155–159.
34 Kim EN, Lamb K, Relles D, et al. Median arcuate
doi:10.1212/WNL.0000000000002847.
ligament syndrome—review of this rare disease.
21 Masuki S, Eisenach JH, Johnson CP, et al. Excessive JAMA Surg 2016;151(5):471–477. doi:10.1001/
heart rate response to orthostatic stress in postural jamasurg.2016.0002.
tachycardia syndrome is not caused by anxiety.
35 Parsaik A, Allison TG, Singer W, et al. Deconditioning
J Appl Physiol (1985) 2007;102(3):896–903.
in patients with orthostatic intolerance. Neurology
doi:10.1152/japplphysiol.00927.2006.
2012;79(14):1435–1439. doi:10.1212/WNL.
22 Masuki S, Eisenach JH, Schrage WG, et al. 0b013e31826d5f95.
Reduced stroke volume during exercise in
36 El-Sayed H, Hainsworth R. Salt supplement
postural tachycardia syndrome. J Appl Physiol
increases plasma volume and orthostatic
(1985) 2007;103(4):1128–1135. doi:10.1152/
tolerance in patients with unexplained syncope.
japplphysiol.00175.2007.
Heart 1996;75(2):134–140. doi:10.1136/hrt.75.2.134.
23 Fu Q, VanGundy TB, Galbreath MM, et al. Cardiac
37 Krediet CT, de Bruin IG, Ganzeboom KS, et al. Leg
origins of the postural orthostatic tachycardia
crossing, muscle tensing, squatting, and the
syndrome. J Am Coll Cardiol 2010;55(25):2858–2868.
crash position are effective against vasovagal
doi:10.1016/j.jacc.2010.02.043.
reactions solely through increases in cardiac
24 Koloski NA, Jones M, Kalantar J, et al. The brain–gut output. J Appl Physiol (1985) 2005;99(5):1697–1703.
pathway in functional gastrointestinal disorders is doi:10.1152/japplphysiol.01250.2004.
bidirectional: a 12-year prospective population-
38 Figueroa RA, Arnold AC, Nwazue VC, et al. Acute
based study. Gut 2012;61(9):1284–1290. doi:10.1136/
volume loading and exercise capacity in postural
gutjnl-2011-300474.
tachycardia syndrome. J Appl Physiol (1985) 2014;
25 Clauw DJ, Arnold LM, McCarberg BH, 117(6):663–668. doi:10.1152/japplphysiol.
FibroCollaborative. The science of fibromyalgia. 00367.2014.
Mayo Clin Proc 2011;86(9):907–911. doi:10.4065/
39 George SA, Bivens TB, Howden EJ, et al. The
mcp.2011.0206.
international POTS registry: evaluating the
26 Dieterich M, Staab JP. Functional dizziness: from efficacy of an exercise training intervention in a
phobic postural vertigo and chronic subjective community setting. Heart Rhythm 2016;13(4):
dizziness to persistent postural-perceptual 943–950. doi:10.1016/j.hrthm.2015.12.012.
dizziness. Curr Opin Neurol 2017;30(1):107–113.
40 Raj SR, Black BK, Biaggioni I, et al. Propranolol
doi:10.1097/WCO.0000000000000417.
decreases tachycardia and improves symptoms
27 Yavuz BG, Aydinlar EI, Dikmen PY, Incesu C. in the postural tachycardia syndrome: less is
Association between somatic amplification, more. Circulation 2009;120(9):725–734.
anxiety, depression, stress and migraine. doi:10.1161/CIRCULATIONAHA.108.846501.
J Headache Pain 2013;14:53. doi:10.1186/1129-
41 Fu Q, VanGundy TB, Shibata S, et al. Exercise
2377-14-53.
training versus propranolol in the treatment of
28 Mack KJ, Johnson JN, Rowe PC. Orthostatic the postural orthostatic tachycardia syndrome.
intolerance and the headache patient. Semin Hypertension 2011;58(2):167–175. doi:10.1161/
Pediatr Neurol 2010;17(2):109–116. doi:10.1016/j. HYPERTENSIONAHA.111.172262.
spen.2010.04.006.

42 Chen L, Du JB, Zhang QY, et al. A multicenter 55 Ganzeboom KS, Mairuhu G, Reitsma JB, et al.
study on treatment of autonomous nerve- Lifetime cumulative incidence of syncope in the
mediated syncope in children with beta-receptor general population: a study of 549 Dutch subjects
blocker [in Chinese]. Zhonghua Er Ke Za Zhi 2007; aged 35–60 years. J Cardiovasc Electrophysiol
45(12):885–888. 2006;17(11):1172–1176. doi:10.1111/j.1540-8167.2006.
00595.x.
43 Singer W, Opfer-Gehrking TL, Nickander KK, et al.
Acetylcholinesterase inhibition in patients with 56 Colman N, Nahm K, Ganzeboom KS, et al.
orthostatic intolerance. J Clin Neurophysiol 2006; Epidemiology of reflex syncope. Clin Auton Res
23(5):476–481. doi:10.1097/01.wnp.0000229946. 2004;14(suppl 1):9–17. doi:10.1007/s10286-004-1003-3.
01494.4c.
57 Matthews IG, Tresham IA, Parry SW. Syncope in
44 Kanjwal K, Karabin B, Sheikh M, et al. the older person. Cardiol Clin 2015;33(3):411–421.
Pyridostigmine in the treatment of postural doi:10.1016/j.ccl.2015.04.009.
orthostatic tachycardia: a single-center experience.
58 Chen LY, Shen WK, Mahoney DW, et al. Prevalence
Pacing Clin Electrophysiol 2011;34(6):750–755.
of syncope in a population aged more than
doi:10.1111/j.1540-8159.2011.03047.x.
45 years. Am J Med 2006;119(12):1088.e1–e7.
45 Rowe PC, Calkins H, DeBusk K, et al. doi:10.1016/j.amjmed.2006.01.029.
Fludrocortisone acetate to treat neurally mediated
59 Serletis A, Rose S, Sheldon AG, Sheldon RS.
hypotension in chronic fatigue syndrome: a
Vasovagal syncope in medical students and their
randomized controlled trial. JAMA 2001;285(1):
first-degree relatives. Eur Heart J 2006;27(16):
52–59. doi:10.1001/jama.285.1.52.
1965–1970. doi:10.1093/eurheartj/ehl147.
46 Ruzieh M, Dasa O, Pacenta A, et al. Droxidopa in
60 Márquez MF, Urias KI, Hermosillo AG, et al.
the treatment of postural orthostatic tachycardia
Familial vasovagal syncope. Europace 2005;7(5):
syndrome. Am J Ther 2017;24(2):e157–e161.
472–474. doi:10.1016/j.eupc.2005.05.004.
doi:10.1097/MJT.0000000000000468.
61 Grubb BP. Clinical practice. Neurocardiogenic
47 Palma JA, Benarroch EE. Neural control of the
syncope. N Engl J Med 2005;352(10):1004–1010.
heart: recent concepts and clinical correlations.
doi:10.1056/NEJMcp042601.
Neurology 2014;83(3):261–271. doi:10.1212/
WNL.0000000000000605. 62 Lempert T, Bauer M, Schmidt D. Syncope: a
videometric analysis of 56 episodes of transient
48 Barzilai M, Jacob G. The effect of ivabradine on
cerebral hypoxia. Ann Neurol 1994;36(2):233–237.
the heart rate and sympathovagal balance in
doi:10.1002/ana.410360217.
postural tachycardia syndrome patients.
Rambam Maimonides Med J 2015;6(3):e0028. 63 Cheshire WP Jr. Syncope. Continuum (Minneap Minn)
doi:10.5041/RMMJ.10213. 2017;23(2, Selected Topics in Outpatient Neurology):
335–358. doi:10.1212/CON.0000000000000444.
49 McDonald C, Frith J, Newton JL. Single centre
experience of ivabradine in postural orthostatic 64 Wieling W, Thijs RD, van Dijk N, et al. Symptoms
tachycardia syndrome. Europace 2011;13(3): and signs of syncope: a review of the link between
427–430. doi:10.1093/europace/euq390. physiology and clinical clues. Brain 2009;132(pt 10):
2630–2642. doi:10.1093/brain/awp179.
50 Cappato R, Castelvecchio S, Ricci C, et al. Clinical
efficacy of ivabradine in patients with inappropriate 65 Shmuely S, Bauer PR, van Zwet EW, et al.
sinus tachycardia: a prospective, randomized, Differentiating motor phenomena in tilt-induced
placebo-controlled, double-blind, crossover syncope and convulsive seizures. Neurology
evaluation. J Am Coll Cardiol 2012;60(15): 2018;90(15):e1339–e1346. doi:10.1212/
1323–1329. doi:10.1016/j.jacc.2012.06.031. WNL.0000000000005301.
51 Ruzieh M, Baugh A, Dasa O, et al. Effects of 66 Ryan DJ, Harbison JA, Meaney JF, et al. Syncope
intermittent intravenous saline infusions in patients causes transient focal neurological symptoms.
with medication-refractory postural tachycardia QJM 2015;108(9):711–718. doi:10.1093/qjmed/hcv005.
syndrome. J Interv Card Electrophysiol 2017;48(3):
67 Khurana RK, Van Meerbeke S. Headache of neurally
255–260. doi:10.1007/s10840-017-0225-y.
mediated syncope. Cephalalgia 2016;36(14):
52 Sandroni P, Opfer-Gehrking TL, McPhee BR, Low 1350–1355. doi:10.1177/0333102416631967.
PA. Postural tachycardia syndrome: clinical features
68 Brignole M, Moya A, de Lange FJ, et al. 2018 ESC
and follow-up study. Mayo Clin Proc 1999;74(11):
Guidelines for the diagnosis and management of
1106–1110. doi:10.4065/74.11.1106.
syncope [in Polish]. Eur Heart J 2018;39(21):
53 Kimpinski K, Figueroa JJ, Singer W, et al. A 1883–1948. doi:10.5603/KP.2018.0161.
prospective, 1-year follow-up study of postural
69 Iwase S, Nishimura N, Mano T. Role of sympathetic
tachycardia syndrome. Mayo Clin Proc 2012;
nerve activity in the process of fainting. Front
87(8):746–752. doi:10.1016/j.mayocp.2012.02.020.
Physiol 2014;5:343. doi:10.3389/fphys.2014.00343.
54 Pederson CL, Brook JB. Health-related quality of
70 Fu Q, Verheyden B, Wieling W, Levine BD. Cardiac
life and suicide risk in postural tachycardia
output and sympathetic vasoconstrictor responses
syndrome. Clin Auton Res 2017;27(2):75–81.
during upright tilt to presyncope in healthy humans.
doi:10.1007/s10286-017-0399-5.
J Physiol 2012;590(8):1839–1848. doi:10.1113/
jphysiol.2011.224998.
114 FEBRUARY 2020

71 Goldstein DS, Holmes C, Frank SM, et al. 80 Natale A, Akhtar M, Jazayeri M, et al. Provocation
Sympathoadrenal imbalance before neurocardiogenic of hypotension during head-up tilt testing in
syncope. Am J Cardiol 2003;91(1):53–58. subjects with no history of syncope or
doi:10.1016/S0002-9149(02)02997-1. presyncope. Circulation 1995;92(1):54–58.
doi:10.1161/01.CIR.92.1.54.
72 Alboni P, Alboni M. Typical vasovagal syncope as
a “defense mechanism” for the heart by 81 Guzman JC, Armaganijan LV, Morillo CA.
contrasting sympathetic overactivity. Clin Auton Treatment of neurally mediated reflex syncope.
Res 2017;27(4):253–261. doi:10.1007/s10286-017- Cardiol Clin 2013;31(1):123–129. doi:10.1016/j.
0446-2. ccl.2012.10.007.
73 Vettor G, Zorzi A, Basso C, et al. Syncope as a 82 Sutton R, Salukhe TV, Franzen-McManus AC,
warning symptom of sudden cardiac death in et al. Ivabradine in treatment of sinus tachycardia
athletes. Cardiol Clin 2015;33(3):423–432. mediated vasovagal syncope. Europace 2014;
doi:10.1016/j.ccl.2015.04.010. 16(2):284–288. doi:10.1093/europace/eut226.
74 Soteriades ES, Evans JC, Larson MG, et al. 83 Sheldon R, Raj SR, Rose MS, et al. Fludrocortisone
Incidence and prognosis of syncope. N Engl J for the prevention of vasovagal syncope: a
Med 2002;347(12):878–885. doi:10.1056/ randomized, placebo-controlled trial. J Am Coll
NEJMoa012407. Cardiol 2016;68(1):1–9. doi:10.1016/j.jacc.2016.
04.030.
75 Brigo F, Bongiovanni LG, Nardone R. Lateral
tongue biting versus biting at the tip of the 84 Izcovich A, González Malla C, Manzotti M, et al.
tongue in differentiating between epileptic Midodrine for orthostatic hypotension and
seizures and syncope. Seizure 2013;22(9):801. recurrent reflex syncope: a systematic review.
doi:10.1016/j.seizure.2013.05.009. Neurology 2014;83(13):1170–1177. doi:10.1212/
WNL.0000000000000815.
76 Brigo F, Nardone R, Ausserer H, et al. The diagnostic
value of urinary incontinence in the differential 85 Sheldon RS, Morillo CA, Klingenheben T, et al.
diagnosis of seizures. Seizure 2013;22(2):85–90. Age-dependent effect of β-blockers in
doi:10.1016/j.seizure.2012.10.011. preventing vasovagal syncope. Circ Arrhythm
Electrophysiol 2012;5(5):920–926. doi:10.1161/
77 Tannemaat MR, van Niekerk J, Reijntjes RH, et al.
CIRCEP.112.974386.
The semiology of tilt-induced psychogenic
pseudosyncope. Neurology 2013;81(8):752–758. 86 Sheldon R. Syncope diagnostic scores. Prog
doi:10.1212/WNL.0b013e3182a1aa88. Cardiovasc Dis 2013;55(4):390–395. doi:10.1161/
CIRCEP.112.974386.
78 Writing Committee Members, Shen WK, Sheldon
RS, et al. 2017 ACC/AHA/HRS guideline for the 87 Ruwald MH, Hansen ML, Lamberts M, et al.
evaluation and management of patients with Prognosis among healthy individuals discharged
syncope: a report of the American College of with a primary diagnosis of syncope. J Am Coll
Cardiology/American Heart Association Task Cardiol 2013;61(3):325–332. doi:10.1016/j.
Force on Clinical Practice Guidelines and the jacc.2012.08.1024.
Heart Rhythm Society. Heart Rhythm 2017;14(8):
e155–e217. doi:10.1016/j.hrthm.2017.03.004.
79 Saal DP, Thijs RD, van Dijk JG. Tilt table testing in
neurology and clinical neurophysiology. Clin
Neurophysiol 2016;127(2):1022–1030. doi:10.1016/j.
clinph.2015.07.037.

REVIEW ARTICLE

Sweating Disorders
C O N T I N UU M A UD I O By Elizabeth A. Coon, MD; William P. Cheshire Jr, MD, FAAN
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article reviews disorders of sweating, including
hyperhidrosis and anhidrosis due to central or peripheral autonomic
nervous system causes.
RECENT FINDINGS:Disorders of thermoregulation and sweating may manifest

with hyperhidrosis or hypohidrosis/anhidrosis. Primary disorders of
hyperhidrosis may significantly impact quality of life yet tend to be benign.
Many sweating disorders present with compensatory hyperhidrosis due to
areas of anhidrosis. Anhidrosis may occur due to either central or
peripheral damage to the autonomic nervous system. The
thermoregulatory control of sweating involves central pathways from the
hypothalamus to the brainstem and then spinal cord as well as projections
CITE AS:
to peripheral structures, including the sympathetic chain ganglia,
2020;26(1, AUTONOMIC DISORDERS): peripheral nerves, and eccrine sweat glands. Disruption at any point of this
116–137.
pathway may lead to impaired sweating. Characterization of sweating
dysfunction helps localize different autonomic disorders to guide
Dr William P. Cheshire, diagnosis and may allow for evaluation of treatment effect.
Department of Neurology,
Mayo Clinic, 4500 Mellish Dr,
SUMMARY: Sweating dysfunction manifests in myriad ways, including
Jacksonville, FL 32224,
cheshire@mayo.edu. essential hyperhidrosis, complete anhidrosis with heat intolerance, and
compensatory hyperhidrosis due to anhidrosis, and often indicates
Dr Coon reports no disclosure. involvement of underlying central or peripheral autonomic dysfunction.
Dr Cheshire serves as an
associate editor for Clinical
Autonomic Research and on the
editorial boards of Autonomic INTRODUCTION
T
Neuroscience: Basic & Clinical he autonomic nervous system maintains internal body temperature
and Parkinsonism & Related
Disorders. Dr Cheshire has
with a strict margin around 37°C (98.6°F). Eccrine sweating is the
received personal compensation chief mechanism of evaporative heat loss to maintain thermoregulation
for travel from Biohaven and for in humans. Elevation in the core temperature triggers warm-sensitive
speaking engagements for Trinity
Graduate School.
neurons in the hypothalamus to activate sweating pathways that
descend to the thoracic spinal cord to synapse on preganglionic sympathetic
UNLABELED USE OF neurons in the intermediolateral cell column to exit in segmental pathways.
USE DISCLOSURE: Postganglionic unmyelinated C fibers pass through the gray ramus, combine
Drs Coon and Cheshire discuss with peripheral nerves, and travel to the skin, where they innervate predominantly
the unlabeled/investigational
cholinergic sweat glands. Any lesion along this pathway, central to peripheral,
use of amitriptyline, clonidine,
endoscopic transthoracic may manifest as abnormal sweating.
sympathotomy, gabapentin, Disorders of sweating are categorized into hyperhidrosis and hypohidrosis/
glycopyrrolate, morphine, and
steroids for the treatment of
anhidrosis. Hyperhidrosis may interfere with quality of life, whereas compensatory
sweating disorders. hyperhidrosis may occur in areas adjacent to hypohidrosis or anhidrosis. Disorders
causing anhidrosis are often manifestations of autonomic failure or neuropathy and
© 2020 American Academy can lead to hyperthermia with heat intolerance or, in circumstances of heat stress,
of Neurology. can lead to heatstroke, which can be fatal.1–3
116 FEBRUARY 2020

ANATOMIC CONSIDERATIONS KEY POINTS
Sweating from eccrine glands is the principal mechanism of evaporative heat loss
● Warm-sensitive neurons
in humans to maintain thermoregulation. To maintain a narrow core body in the preoptic nucleus of
temperature margin around 37°C (98.6°F), the autonomic nervous system the hypothalamus respond
balances heat loss and heat production. Core and skin thermoreceptors sense to subtle changes in core
both temperature and nonthermal factors. Cutaneous, visceral, and spinal cord temperature to invoke a
sympathetic nervous system
thermoreceptors ascend in the spinothalamic tract with multisynaptic fibers
response of generalized
reaching the reticular formation of the brainstem, thalamus, and hypothalamus. sweating, vasodilation, and
The medial preoptic area of the hypothalamus is the primary thermosensitive hyperpnea triggering radiant
area of the central nervous system (CNS) (FIGURE 7-14). Warm-sensing neurons and evaporative heat loss.
in the medial preoptic area respond to subtle changes in core temperature.5 With
● Innervation of sweat
elevation in core temperature, the sympathetic nervous system response involves glands is predominantly by
generalized sweating, vasodilation, and hyperpnea to trigger radiant and unmyelinated C fibers to
evaporative heat loss and restore thermal homeostasis.6 From the preoptic area, cholinergic M3-type
warm-sensing neurons trigger evaporative sweat loss through inputs to neurons receptors.
in the rostral ventromedial medulla, which project ipsilaterally through the
medial portion of the lateral funiculus to synapse on preganglionic neurons in the
intermediolateral column of the spinal cord.7 Spinal innervation of sweating is
segmental: T1 through T4 segments innervate the face, T2 through T8 segments
innervate the upper limbs, T4
through T12 segments innervate
the trunk, and T10 through L2
segments innervate the lower
limbs.8,9 After exiting the spinal
cord, sympathetic vasomotor
fibers pass through white rami
communicantes to join the
paravertebral sympathetic chain.4
Sweat glands are innervated
by unmyelinated C fibers, which
are mainly cholinergic. However,
evidence shows that human
sympathetic sudomotor neurons
can also coexpress markers of
FIGURE 7-1 noradrenergic neurons.10 Results
Thermoregulatory pathway. Central
thermoregulatory pathways are triggered in the
from animal studies suggest that
hypothalamus by warm-sensitive neurons of the a postnatal switch from adrenergic
medial preoptic nucleus, which tonically inhibit to cholinergic innervation of sweat
cold-responsive neurons in the dorsomedial glands occurs.11,12 While sweat
nucleus, periaqueductal gray, and nucleus raphe
pallidus. Efferent pathways descend from the
glands may maintain some dual
hypothalamus ipsilaterally through the brainstem innervation, activation of eccrine
and synapse on preganglionic sympathetic sweat glands is mediated
neurons in the intermediolateral cell column of primarily by acetylcholine acting
the spinal cord. Preganglionic neurons exit
via M3-type receptors. Activation
between T1 and L2 to synapse in the sympathetic
chain ganglia. Postganglionic sudomotor fibers of the cholinergic M3-type
travel with vasomotor fibers to the dermis to receptors triggers an increase of
synapse on sweat glands to regulate evaporative intracellular calcium concentration
heat loss and cutaneous arterioles to regulate
that increases the permeability of
radiant heat loss.
Data from Benarroch EE. 4 potassium and chloride channels
© 2014 Oxford University Press. and initiates the release of an

SWEATING DISORDERS
isotonic precursor fluid from the secretory cells. Other cotransmitters, such as
vasoactive intestinal polypeptide, elicit vasodilation, which promotes sweating.
Sympathetic fibers innervate 2 million to 4 million eccrine sweat glands
distributed over the body surface. The greatest density of eccrine sweat glands
associated with thermoregulation is on the forehead, followed by the upper limbs
and then the trunk and lower limbs. The palms and the soles have a high density
of sweat glands (600 glands/cm2 to 700 glands/cm2); however, these are not
chiefly involved in thermoregulation but mediate emotional sweating.13
HYPERHIDROSIS
Hyperhidrosis is defined as excessive sweating beyond what is needed to
maintain core temperature in response to a thermal stimulus. Hyperhidrosis is
considered more socially bothersome than medically worrisome but can interfere
TABLE 7-1 Disorders Associated With Hyperhidrosis
Generalized
◆ Essential generalized hyperhidrosis
◆ Secondary to central nervous system disorders
◇ Shapiro syndrome (episodic hypothermia with hyperhidrosis)
◇ Posttraumatic or posthemorrhagic
◇ Fatal familial insomnia
◇ Parkinson disease
◆ Secondary to central and peripheral nervous system disorders
◇ Familial dysautonomia
◇ Morvan fibrillary chorea
◆ Secondary to systemic illness
◇ Infection
◇ Neoplasm
→ Pheochromocytoma, lymphoma, leukemia, carcinoid, renal cell cancer, Castleman
disease
◇ Metabolic
→ Thyrotoxicosis, diabetes mellitus, hypopituitarism, menopause
◇ Drug withdrawal
→ Opiates, alcohol
◆ Nocturnal diaphoresis
◇ Tuberculosis
◇ Lymphoma
◇ Endocarditis
◇ Diabetes mellitus
◇ Acromegaly
118 FEBRUARY 2020

with some occupations, whereas heavy generalized sweating may lead to
hypovolemia and depletion of electrolytes.6 Disorders causing hyperhidrosis are
summarized in TABLE 7-1, and medications known to cause hyperhidrosis are
shown in TABLE 7-2.
Generalized Hyperhidrosis
Essential (or primary generalized) hyperhidrosis involves the entire body but is
typically most pronounced in areas of the highest sweat gland density, with
excessive sweating often noted over the face, neck, and upper trunk. Sweating
may occur at a lower temperature or exercise threshold than in people
without hyperhidrosis.
Secondary causes of generalized hyperhidrosis are often associated with a
systemic process or illness (TABLE 7-1). For example, nocturnal diaphoresis may
◇ Menopause
◇ Obstructive sleep apnea
◇ Prinzmetal angina
◆ Medication related
◇ Neuroleptic malignant syndrome, serotonin syndrome
Focal
◆ Essential focal hyperhidrosis
◇ Palmoplantar, axillary, craniofacial
◆ Secondary to central nervous system disorders
◇ Cerebral infarction
◇ Spinal cord injury
→ Autonomic dysreflexia, posttraumatic syringomyelia
◇ Cold-induced sweating syndrome
◇ Olfactory hyperhidrosis
◇ Chiari type I malformation
◆ Associated with peripheral nervous system disorders
◇ Autonomic neuropathy
◇ Dermatomal due to nerve trunk irritation
◆ Craniofacial disorders
◇ Gustatory sweating
◇ Lacrimal sweating
◇ Harlequin syndrome
◆ Associated with dermatologic disorders
◇ Pretibial myxedema
◇ POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell
disorder, skin changes)

SWEATING DISORDERS
be a manifestation of a neoplasm, infection, diabetes mellitus, or coronary

vasospasm, with improvement of the hyperhidrosis requiring treatment of the
underlying cause.13,14 Medications may also cause hyperhidrosis (TABLE 7-2).
Common offenders include opioids, antidepressants (selective serotonin
reuptake inhibitors [SSRIs]), and prostaglandin inhibitors.15,16 Hyperhidrosis is
noted in both acute and chronic opioid administration, likely related to histamine
release, yet may also be seen in opioid and alcohol withdrawal.17 Both serotonin
syndrome and neuroleptic malignant syndrome may manifest hyperthermia
with hyperhidrosis in addition to labile blood pressure, rigidity, agitation, and
confusion. Medication effects in the setting of CNS disorders may also contribute
to hyperhidrosis as seen in Parkinson disease (CASE 7-1).
SHAPIRO SYNDROME. CNS dysfunction may lead to generalized hyperhidrosis,

such as in Shapiro syndrome, which is characterized by episodic hypothermia
and hyperhidrosis. Radiographically, this syndrome is associated with
abnormalities of midline structures, such as agenesis of the corpus callosum.22
Episodes in Shapiro syndrome may respond to treatment with clonidine,23
glycopyrrolate,24 or antiepileptic medications.6
PAROXYSMAL SYMPATHETIC HYPERACTIVITY. Paroxysmal sympathetic

hyperactivity after acquired brain injury is the consensus term for the syndrome
characterized by paroxysmal sympathetic overreactivity leading to diaphoresis,
fever, flushing, shivering, hypertension, tachypnea, tachycardia, and, in some
cases, motor involvement such as dystonic posturing.25 The original case
described by Penfield26 as “diencephalic epilepsy” was due to a tumor at the
foramen of Monro; however, numerous causes of acquired CNS damage leading
to this syndrome have been described, including trauma, hemorrhage, tumors,
and hydrocephalus.27,28 Treatment is aimed at reducing sympathetic nervous
system activity by maintaining adequate hydration, and mimicking conditions
should be excluded. Pharmacologic treatment includes morphine, nonselective
beta-blockers, or gabapentin.29 For more information on paroxysmal
TABLE 7-2 Selected Medications Causing Hyperhidrosis
Antidepressants
◆ Tricyclics
◆ Serotonin norepinephrine reuptake inhibitors (SNRIs)
◆ Selective serotonin reuptake inhibitors (SSRIs)
Anticholinesterases
◆ Pyridostigmine
Muscarinic Receptor Agonists
◆ Pilocarpine
◆ Bethanechol
Opioids
Proton Pump Inhibitors
120 FEBRUARY 2020

sympathetic hyperactivity, refer to the article “Autonomic Hyperactivity” by
Alejandro A. Rabinstein, MD, FAAN,30 in this issue of Continuum.
Focal Hyperhidrosis
While thermoregulatory sweating is often accentuated in disorders with
generalized hyperhidrosis, focal hyperhidrosis may be independent of
thermoregulatory processes, with localized sweating occurring spontaneously or
precipitated by emotional stimuli.
PRIMARY FOCAL HYPERHIDROSIS. Essential (or primary focal) hyperhidrosis is

likely the most common cause of sweating dysfunction, with an estimated
prevalence of 2.8% in the United States.31 Primary focal hyperhidrosis affects the
palms, soles, axillae, and sometimes the craniofacial region. The hyperhidrosis is
independent of thermoregulatory needs, and sweating may be constant;
however, anxiety-inducing stimuli, elevated ambient temperature, or physical
exertion often exacerbates the hyperhidrosis.1,32 Sweating from the palms may
influence academic pursuits, as it may cause difficulty writing with pen and
paper; it may also impair fine motor tasks and present a potential risk of minor
electrical shock if the fingers come into contact with poorly insulated wires or
switches of electrical appliances. Sweating from the soles can render certain
footwear such as sandals slippery, and frequent exposure to sweat can cause
shoes to wear out more quickly. When severe, focal hyperhidrosis may interfere
with the patient’s quality of social and professional life because of the
embarrassing appearance of sweat and avoidance of shaking hands in greeting
and may lead to social anxiety.
Treatment of focal primary hyperhidrosis is based on the severity of
symptoms and the patient’s goals. Topical treatments are recommended for
initial treatment, with topical antiperspirants containing 6% to 25% aluminum
A 72-year-old man with a 6-year history of Parkinson disease treated with CASE 7-1
carbidopa/levodopa presented with generalized sweating episodes. The
episodes characteristically began with sweating over the forehead and
proceeded to involve his entire body, often necessitating a change in
clothing. The episodes occurred daily, leading to social isolation, and
followed a typical pattern: after taking carbidopa/levodopa, he
experienced mild dyskinesia when in the on state, but as dyskinesia
began to wane, sweating would begin. Sweating occurred roughly
30 minutes before his next scheduled dose of carbidopa/levodopa and
continued for about 20 minutes after taking the dose.
This patient demonstrated off state hyperhidrosis episodes that were COMMENT
significantly limiting his quality of life. Sweating abnormalities in Parkinson
disease were noted by Gowers18 but became more evident after the
introduction of levodopa.19 Hyperhidrosis episodes are more often
reported in the off period in Parkinson disease20 and may have a significant
negative impact on quality of life.21

SWEATING DISORDERS
chloride in alcohol applied nightly over affected areas. When topical treatments
fail, tap water iontophoresis is a safe and useful treatment. The patient immerses
the affected area in an electrolyte solution while a low-intensity current of 15 mA
to 30 mA is applied by a battery-powered unit. The suspected mechanism is
mechanical plugging of sweat pores at the stratum corneum. Since the effect is
temporary, patients repeat the procedure on a nightly basis or, after the desired
effect is achieved, every few days thereafter for continued benefit. Adding
crushed glycopyrrolate to the solution may enhance the results.
Systemic medications may also be tried. Anticholinergic medications such as
glycopyrrolate often lead to intolerable side effects, especially dry mouth, in the
doses necessary to ameliorate focal sweating. When anxiety or psychosocial
stressors trigger severe hyperhidrosis, anxiolytics may be useful.
After topical and medication treatments, intradermal botulinum toxin
injections may be useful.33 Botulinum toxin inhibits release of acetylcholine at the
CASE 7-2 A 21-year-old woman presented

with hyperhidrosis of the palms and
soles. Even as a toddler, the patient
had been noted to leave damp
handprints and footprints. The
symptoms became problematic for
the patient around puberty and
influenced her ability to write with
paper and pen, shake hands without
embarrassment, and put on gloves
during nursing classes. Examination
showed sweat beading from the
palms and soles. A thermoregulatory
sweat test confirmed resting sweat
activity with otherwise normal sweat
recruitment and distribution
(FIGURE 7-2). The patient had tried
topical therapies, which led to FIGURE 7-2
cracking of the palms, and tap water Palmoplantar hyperhidrosis. Alizarin
red indicator dye changes from yellow
iontophoresis and systemic therapies
to purple with sweating. This patient
of glycopyrrolate, which offered demonstrated palmar and plantar
only marginal benefit and led to sweating before heat exposure,
intolerable side effects. consistent with essential palmoplantar
hyperhidrosis.
COMMENT This case illustrates the typical features of essential palmoplantar

hyperhidrosis. The patient had tried multiple topical and systemic
therapies for hyperhidrosis with only marginal benefit. Since her
hyperhidrosis had failed to respond to multiple topical and systemic
therapies, she was referred to a neurosurgeon for endoscopic
transthoracic sympathotomy, which achieved lasting anhidrosis of the
palms.
122 FEBRUARY 2020

sympathetic nerve junction with the sweat gland. Multiple injections are KEY POINTS
necessary as the anhidrotic effect is localized to a square centimeter of the
● The highest density of
injection site. However, the effect may last as long as 6 months.34,35 When sweat glands involved in
injecting for palmar hyperhidrosis, patients must be made aware of the risk of thermoregulation is on the
intrinsic hand weakness.36 forehead, followed by the
Long-term success for palmar hyperhidrosis is often achieved with endoscopic upper limbs and then the
trunk and lower limbs,
transthoracic sympathotomy or sympathectomy (CASE 7-2). Surgical approaches
whereas acral (hands and
involve interruption of sympathetic outflow to the hands via resection, ablation, feet) sweating is chiefly
or clip placement to the sympathetic thoracic chain, with various success rates triggered by emotional stimuli.
and complications. Surgical sympathectomy involves removal of the stellate
ganglion, which may lead to Horner syndrome with associated pupillary and ● Hyperhidrosis is defined
as excessive sweating
eyelid dysfunction.37 Sympathotomy, which refers to cautery of the sympathetic beyond the need to maintain
chain at the level of the second thoracic ganglion, leads to a high success rate of core temperature; it tends
more than 95% for controlled palmar sweating with low risk of compensatory to be more socially limiting
hyperhidrosis.38,39 Surgical options for axillary hyperhidrosis are reserved for than medically worrisome.
severe cases and include axillary gland liposuction or resection.40 ● Medications frequently
cause hyperhidrosis, with
GUSTATORY AND OLFACTORY SWEATING. Sweating may normally be triggered by common offenders
eating hot and spicy foods and localized to the perioral area, forehead, scalp, and including selective serotonin
reuptake inhibitors, opioids,
nose. When pathologic, gustatory hyperhidrosis is asymmetric and intense and
and prostaglandin inhibitors.
may even include patches over the trunk and extremities. The etiology in pathologic
cases is aberrant regeneration of damaged nerves from facial parasympathetic ● Shapiro syndrome is
fibers originally destined for salivary glands that instead innervate facial sweat characterized by episodic
glands that have been sympathetically denervated. One cause is Frey syndrome, hypothermia and
hyperhidrosis with
with sweating occurring over the distribution of the auriculotemporal nerve after abnormalities of midline
injury such as abscess or surgery of the parotid region.41 Cases have also been structures, such as agenesis
reported due to diabetic neuropathy, cluster headache, and injury to the of the corpus callosum.
sympathetic trunk.42–44 Treatment may include subcutaneous botulinum toxin
● Paroxysmal sympathetic
injection in the symptomatic area.35 Olfactory hyperhidrosis syndrome is hyperactivity after acquired
characterized by profuse facial sweating precipitated by perfume smells but not brain injury is characterized
by gustatory or emotional stimuli; it has been treated with oral amitriptyline.45,46 by paroxysmal sympathetic
overreactivity leading to
diaphoresis, fever, flushing,
COLD-INDUCED SWEATING SYNDROME. Cold-induced sweating syndrome is a
shivering, hypertension,
genetic disorder associated with missense mutations in the CRLF1 or CLCF1 tachypnea, tachycardia,
gene; these genes are part of a cytokine signaling pathway involved in normal and, occasionally, motor
development of the nervous system.47,48 In cold temperatures, patients demonstrate involvement.
profuse truncal sweating, but, paradoxically, they do not sweat in the heat. The
● Primary focal
syndrome may also include a limited autonomic neuropathy with thermal and pain hyperhidrosis frequently
insensitivity and characteristic facial features and joint abnormalities. involves palms and soles
and may significantly
Compensatory Hyperhidrosis interfere with quality of life.
Secondary hyperhidrosis commonly occurs either adjacent or distant to areas of ● Treatment options for
anhidrosis or hypohidrosis as the body compensates for the area of reduced sweating. primary focal hyperhidrosis
Often, the areas of excessive sweating are what lead patients to seek medical include topical agents,
attention, while the region of hypohidrosis or anhidrosis is related to the pathologic systemic medications,
iontophoresis, or
cause. Both central and peripheral causes of anhidrosis may have accompanying
endoscopic thoracic
hyperhidrosis (refer to the Hypohidrosis and Anhidrosis section below). sympathotomy.
CNS DISORDERS. Strokes, particularly those affecting the insular and opercular
cortex, can lead to hemihyperhidrosis affecting the side contralateral to the

SWEATING DISORDERS
stroke, with the face and arm often more affected. Strokes involving the
hypothalamus, paramedian thalamus, pons, and medulla may also lead to acute
and transient hyperhidrosis. The putative mechanism involves interruption of
inhibitory pathways controlling contralateral sweating.49
In multiple sclerosis, involvement of the hypothalamus may lead to unilateral
sweating.1 Spinal cord involvement is more likely to cause abnormal sweating,
often with areas of anhidrosis related to myelopathy leading to compensatory
hyperhidrosis above the lesion.
AUTONOMIC DYSREFLEXIA. Patients with spinal cord injury may experience

segmental hyperhidrosis above the lesion, with episodes of profuse sweating
occurring in the acute stage as well as months to years after injury. When the
lowest segment of cord injury is above T6, autonomic dysreflexia is very
common.50 Autonomic dysreflexia is characterized by an elevation in blood
pressure with accompanying bradycardia, facial flushing, and profuse sweating
above the level of the lesion and pale cold skin and piloerection below the level of
the lesion. Patients may report severe headaches with risk for hypertensive
complications with frequent or prolonged elevations in blood pressure. The
mechanism is related to stimulation of sympathetic afferents below the lesion
CASE 7-3 A 60-year-old man was referred for evaluation of excessive facial
sweating. His history was notable for a double aortic arch, for which he
underwent repair 2 years before presentation. Following the procedure,
he noted increasing sweating
over the right half of his face,
which was sometimes
accompanied by marked
right hemifacial flushing.
Episodes were triggered by
exertion and mild increases
in ambient heat. On
examination, his pupils were
symmetric and reactive to
light. A thermoregulatory
sweat test showed anhidrosis
of the left face and neck, FIGURE 7-3
Findings of the patient in CASE 7-3. A,
with well-demarcated Thermoregulatory sweat test demonstrates
sweating occurring over the left-sided facial anhidrosis with normal sweating
right half of the face over the right half of the face. B, Marked flushing
(FIGURE 7-3). after exertion and heat exposure is seen over the
right half of the face.
COMMENT In this patient, harlequin syndrome was likely due to injury to the preganglionic
sympathetic fibers or ganglia during thoracotomy. Oculopupillary fibers,
which depart primarily at T1, were preserved, while vasomotor fibers, which
exit primarily at T2 to T3, were impaired. Both join the paravertebral
sympathetic chain and pass through the stellate ganglion.
124 FEBRUARY 2020

that leads to exaggerated sympathetic discharges due to disconnection from KEY POINTS
supraspinal regulation. As blood pressure rises, vagal responses triggered by the
● Cold-induced sweating
baroreflex lead to bradycardia, but baroreflex-mediated sympathoinhibition is syndrome is a genetic
disrupted due to interruption of descending inputs to the spinal cord. disorder characterized by
Vasoconstriction occurs below the level of the lesion and vasodilation above the profuse truncal sweating
lesion. Treatment involves urgent identification of the stimulus, such as bladder when exposed to cold with
paradoxical anhidrosis when
or bowel distension or skin or visceral irritation, while fast-acting
exposed to heat.
antihypertensives are used to control blood pressure.51 For more information on
autonomic dysreflexia, refer to the article “Autonomic Hyperactivity” by ● Autonomic dysreflexia
Alejandro A. Rabinstein, MD, FAAN,30 in this issue of Continuum. may occur in patients with
spinal cord injuries with
lesions above T6 and is
HYPERHIDROSIS IN CERVICAL SYMPATHETIC CHAIN LESIONS. Injury of the characterized by
cervical sympathetic chain ganglia or postganglionic sympathetic fibers leading hypertension with
to reduced or exaggerated activity may lead to sweating symptoms in the face, concomitant bradycardia
neck, and upper thorax before causing other symptoms. Encroachment by and facial flushing with
profuse sweating above the
neoplasms is commonly seen with Pancoast tumors, commonly due to level of the spinal cord
pulmonary adenocarcinoma,52,53 mesothelioma,54 and lymphoma55; occasionally lesion.
a cervical rib may also compress the sympathetic chain.56 Symptoms may include
hemifacial flushing and typically include Horner syndrome with unilateral ● Treatment for autonomic
dysreflexia involves fast-
ptosis, miosis, and facial anhidrosis. Pancoast syndrome refers to additional
acting antihypertensives
involvement of the brachial plexus with associated upper extremity weakness with urgent identification of
and sensory loss. the trigger, such as bowel or
Idiopathic unilateral circumscribed hyperhidrosis may be related to bladder distension or skin
irritation.
hyperfunction of the localized sympathetic chain ganglia. Patients with this
disorder present with profuse sweating in a defined area on the face and upper ● Harlequin syndrome is
extremities that is precipitated by heat and lasts between 15 and 60 minutes.1 characterized by hemifacial
Treatment may include application of topical aluminum chloride or a topical flushing and hyperhidrosis
anticholinergic, botulinum toxin injection, or oral anticholinergic or clonidine. contralateral to sympathetic
denervation and may
include Horner syndrome
HARLEQUIN SYNDROME. Harlequin syndrome denotes contralateral hemifacial when oculosympathetic
flushing and hyperhidrosis that is due to unilateral sympathetic denervation fibers are involved.
leading to ipsilateral anhidrosis. Harlequin syndrome has a number of different
● Patients with multiple
presentations and causes, which may include spinal cord involvement,
system atrophy typically
ganglionopathy, or iatrogenic causes.57 When oculosympathetic fibers are have a high degree of
involved, Horner syndrome accompanies the anhidrotic side. Sudomotor fibers anhidrosis, which is
destined for the head exit the spinal cord at T2 to T3 and join oculopupillary fibers predominantly due to a
central/preganglionic
exiting between C8 and T2 to pass through the stellate ganglion and ascend in the
lesion.
cervical sympathetic trunk to synapse on postganglionic neurons in the superior
cervical ganglion. Sudomotor fibers innervating the face follow the external
carotid artery, whereas oculosympathetic fibers and sudomotor fibers innervating
the medial supraorbital area continue with the internal carotid plexus through the
carotid canal and cavernous sinus to reach orbital structures. The presence of
Horner syndrome with anhidrosis helps to localize the site of the lesion (CASE 7-3).
ROSS SYNDROME. Ross syndrome consists of the triad of segmental anhidrosis,

areflexia, and tonic (Adie) pupil. Often, the most problematic feature is
compensatory hyperhidrosis.58 The areas of anhidrosis may be asymmetric and
progressive. Autonomic testing typically demonstrates a postganglionic lesion,
with skin biopsies showing absent or reduced cutaneous and autonomic
innervation underlying anhidrosis and loss of cutaneous blood flow regulation.59

SWEATING DISORDERS
HYPOHIDROSIS AND ANHIDROSIS

Anhidrosis is the absence of sweating, whereas hypohidrosis refers to reduced
sweating that is inadequate to dissipate body heat for thermoregulation. Central
and peripheral etiologies may contribute to anhidrosis (TABLE 7-3). Medication
effects may influence sweating at central or peripheral levels. Anticholinergic
medications are the most common drug-related cause of anhidrosis due to
muscarinic receptor antagonism at the junction between the sympathetic nerve
terminal and the eccrine sweat gland.15 Multiple classes of medication cause an
anticholinergic effect, although other mechanisms may also reduce sweating
(TABLE 7-4).
Synucleinopathies
Disorders due to abnormal intracellular accumulation of misfolded α-synuclein
have characteristic patterns of thermoregulatory dysfunction that range in
TABLE 7-3 Disorders Associated With Anhidrosis
Central Nervous System Disease

◆ Multiple system atrophy
◆ Dementia with Lewy bodies
◆ Parkinson disease
◆ Stroke
◆ Multiple sclerosis
◆ Spinal cord disease
Peripheral Nervous System Disease
◆ Pure autonomic failure
◆ Autoimmune autonomic ganglionopathy
◆ Autonomic neuropathy
◇ Diabetic neuropathy
◇ Paraneoplastic neuropathy
◇ Inherited neuropathy
◇ Amyloid neuropathy
◇ Lepromatous neuropathy
◆ Sjögren syndrome
◆ Ross syndrome
◆ Harlequin syndrome
◆ Fabry disease
Chronic Idiopathic Anhidrosis
Dermatologic Disorders
◆ Local skin injury
◆ Systemic sclerosis
◆ Congenital absence of sweat glands
126 FEBRUARY 2020

degree and distribution of anhidrosis and preganglionic or postganglionic site of
the thermoregulatory lesion (FIGURE 7-4).60
MULTIPLE SYSTEM ATROPHY. Multiple system atrophy is a neurodegenerative

disorder characterized by autonomic failure with parkinsonism or cerebellar
ataxia, or both. Neuropathologically, it is characterized by abnormal α-synuclein
accumulation as glial cytoplasmic inclusions in brainstem autonomic centers
involved in blood pressure control and thermoregulation, including the rostral
ventrolateral medulla and medullary raphe.61,62 As a manifestation of autonomic
failure, patients with multiple system atrophy often have extensive anhidrosis on
the thermoregulatory sweat test (FIGURE 7-5).60,63 The site of the lesion is
predominantly central/preganglionic (CASE 7-4), although evidence exists of
increasing peripheral involvement with disease duration, suggesting
involvement of postganglionic fibers or sweat glands later in the disease
course.63,65 Skin biopsies from patients with multiple system atrophy may also
show reduction in sweat gland innervation.66 Some patients may have preserved
sweating over the hands, which may be explained by preserved acral
sympathetic innervation similar to the cold hand sign in this disorder.67
PURE AUTONOMIC FAILURE. Previously known as Bradbury-Eggleston syndrome,

pure autonomic failure is a progressive degenerative disorder of the autonomic
nervous system characterized by orthostatic hypotension, often with widespread
autonomic dysfunction involving genitourinary, bowel, and thermoregulatory
functions.68 Pathophysiologically, pure autonomic failure is characterized by
α-synuclein deposition peripherally in autonomic ganglia and nerves.69 While,
by definition, no evidence of CNS dysfunction is seen in pure autonomic failure,
these patients may progress to other synucleinopathies, such as multiple system
Selected Medications Causing Anhidrosis TABLE 7-4
Mechanism Class Selected Examples
Anticholinergic effect via M3 receptor Anticholinergics Glycopyrrolate, doxepin, atropine,

antagonism cyproheptadine, hyoscyamine
Tricyclic antidepressants Amitriptyline
Antihistamines Diphenhydramine
Bladder antispasmodics Oxybutynin, tolterodine
Antipsychotics and Chlorpromazine, clozapine, quetiapine

antiemetics
Carbonic anhydrase inhibition Antiepileptics Topiramate, zonisamide
Central adrenergic effect Antihypertensives Clonidine
Hypothalamic μ-opioid receptor agonism Opioids Fentanyl, morphine, hydrocodone, oxycodone
Inhibiting presynaptic acetylcholine release Neuromuscular paralytics Botulinum toxins
Data from Cheshire WP, Fealey RD, Drug Saf.15

SWEATING DISORDERS
FIGURE 7-4
Pattern of anhidrosis in the synucleinopathies. Patients with Parkinson disease tend to have
the lowest degree of anhidrosis compared to patients with dementia with Lewy bodies and
multiple system atrophy on thermoregulatory sweat test, with predominantly distal anhidrosis
(A). Patients with dementia with Lewy bodies have a greater percentage of anhidrosis that
tends to follow a distal or length-dependent pattern (B), whereas patients with multiple
system atrophy have the greatest degree of anhidrosis, frequently seen in a global pattern (C).
atrophy, Parkinson disease, or dementia with Lewy bodies.70,71 Classically,

thermoregulatory dysfunction in pure autonomic failure is peripheral in origin
and may have striking degrees of anhidrosis, sometimes with compensatory
hyperhidrosis. However, one sign that patients may later progress to CNS disease
may be a central pattern of sweat loss showing anhidrosis on thermoregulatory
sweat testing in the presence of preserved QSART volumes.71
LEWY BODY DISORDERS. Patients with Parkinson disease may manifest symptoms
of thermoregulatory dysfunction such as heat or cold intolerance and may have
episodes of hyperhidrosis, which are often medication-related. Classically,
patients with Parkinson disease have evidence of mild distal anhidrosis that is
peripheral in origin. Patients with dementia with Lewy bodies tend to have a
similar pattern of postganglionic sudomotor failure, with a greater degree of
anhidrosis compared to patients with Parkinson disease.60
Peripheral Disorders
Thermoregulatory sweat output declines with normal aging. This decline may be
because of factors related to peripheral neural and eccrine glands as well as
physical conditioning levels and genetic predisposition.72 Any disruption of the
autonomic ganglia or peripheral sudomotor nerves leads to characteristic
patterns of peripheral hypohidrosis or anhidrosis.
128 FEBRUARY 2020

KEY POINTS
● Patients with Parkinson

disease typically have mild
distal anhidrosis that is
peripheral in origin, whereas
patients with dementia with
Lewy bodies also show a
peripheral pattern of sweat
loss that is to a greater
degree than in patients with
Parkinson disease.
● Patients with autoimmune

may manifest a high degree
of anhidrosis, which tends to
increase distally; the degree
of autonomic failure may
correlate with the antibody
titer.
FIGURE 7-5 ● Familial dysautonomia is

Thermoregulatory sweat patterns in multiple system atrophy. The most common patterns of characterized by episodes
anhidrosis in patients with multiple system atrophy are regional/widespread anhidrosis of orthostatic hypotension
(approximately 40% of patients) that tends to ascend. Global anhidrosis is seen in 35% of or hypertension in addition
patients and may show acral preservation (CASE 7-4). Length-dependent sweat loss may also to profuse sweating related
be present in about 10% of patients, whereas a minority (5%) demonstrates normal sweating. to underlying neuropathy
and central sudomotor
pathway hyperexcitability.
AUTOIMMUNE AUTONOMIC GANGLIONOPATHY. Autoimmune autonomic

ganglionopathy is a subacute or insidiously progressive disorder affecting
autonomic ganglia and their nerves and is commonly due to autoantibodies
to the neuronal ganglionic nicotinic acetylcholine receptor. Patients
may manifest severe autonomic dysfunction, including gastrointestinal
dysmotility, urinary retention, dilated pupils, reduced heart rate variability,
and orthostatic hypotension.73,74 The degree of autonomic failure may
correlate with the antibody titer.73,75 The percentage of anhidrosis in
patients with autoimmune autonomic ganglionopathy may be severe and
tends to increase distally (CASE 7-5).76 For more information on autoimmune
autonomic ganglionopathy, refer to the article “Autoimmune Autonomic
Disorders” by Steven Vernino, MD, PhD, FAAS, FAAN,77 in this issue of
Continuum.
AUTONOMIC NEUROPATHIES. A distal pattern of anhidrosis is a frequent

manifestation of length-dependent neuropathies. Patients are often unaware of
reduced distal sweating, which underscores the importance of testing sudomotor
function to determine small fiber involvement in neuropathies.78 Hereditary
sensory and autonomic neuropathies (HSAN) with small fiber involvement
(such as HSAN I, HSAN II, HSAN IV [congenital insensitivity to pain], and
HSAN V) have varying degrees of anhidrosis. HSAN II is characterized by
anhidrosis with distal acropathy.79
Familial dysautonomia (HSAN III, or Riley-Day syndrome) is characterized
by episodic orthostatic hypotension and hypertension with profuse sweating,
skin blotching, absence of emotional tears, gastrointestinal dysmotility, and

SWEATING DISORDERS
CASE 7-4 A 46-year-old man presented for evaluation of orthostatic hypotension.

He had a 4-year history of erectile dysfunction with urinary frequency and
urgency. During the few months before presentation, he endorsed
sloppier handwriting and gait imbalance.
Neurologic examination showed evidence of cerebellar ataxia. On
autonomic reflex screen, the patient had autonomic failure with
preserved quantitative sudomotor axon reflex test (QSART) volumes.
Thermoregulatory sweat test showed global anhidrosis with preserved
sweating over the hands (FIGURE 7-6).
FIGURE 7-6
Autonomic failure in multiple system atrophy with predominant cerebellar ataxia. This
patient’s quantitative sudomotor axon reflex test (QSART) showed normal sweat responses
at all sites. The thermoregulatory sweat test showed global anhidrosis with hypohidrosis over
the hands, neck, and forehead. The normal postganglionic sudomotor sweat volumes in the
context of anhidrosis on thermoregulatory sweat test indicate a central or preganglionic
lesion, characteristic of multiple system atrophy.
COMMENT This patient fulfills criteria for multiple system atrophy with predominant
cerebellar ataxia, with autonomic failure manifesting as orthostatic
hypotension with genitourinary dysfunction.64 The thermoregulatory sweat
test and QSART results interpreted together indicate a central/
preganglionic pattern of sweat loss.
130 FEBRUARY 2020

A 49-year-old man presented 2 months after developing nausea followed CASE 7-5
by diarrhea, urinary retention, erectile dysfunction, orthostatic
hypotension, and sicca symptoms (dry eyes and dry mouth). Neurologic
examination was normal other than slow pupillary responses to light.
Autonomic testing showed reduced or absent quantitative sudomotor
axon reflex test (QSART) volumes with blunted heart rate responses to
deep breathing and Valsalva maneuver. Beat-to-beat blood pressure
recording during Valsalva showed absent late phase II recovery and
phase IV overshoot with prolonged blood pressure recovery time, while
orthostatic hypotension was immediately detected on head-up tilt. The
thermoregulatory sweat test showed global anhidrosis with preserved
islands of sweating (FIGURE 7-7). Laboratory testing for ganglionic nicotinic
acetylcholine receptor antibodies was positive at 0.22 nmol/L (normal
less than 0.02 nmol/L).
FIGURE 7-7
Autonomic failure in autoimmune autonomic ganglionopathy. The patient’s thermoregulatory
sweat test at presentation showed 88% anhidrosis with circumscribed areas of preserved
sweating over the trunk and arms. Following treatment with IV immunoglobulin (IVIg), the
patient’s repeat testing showed improvement in sweating to 44% anhidrosis.
This case demonstrates severe autonomic failure and the characteristic COMMENT
sweating pattern in a patient with autoimmune autonomic ganglionopathy.
The patient was treated with a course of IV immunoglobulin (IVIg) with
improvement of all symptoms other than mild residual orthostatic
intolerance.

SWEATING DISORDERS
insensitivity to pain.80,81 On skin biopsy, significantly reduced epidermal

nerve fiber density and reduced innervation of sweat glands are seen. Testing
suggests that central sudomotor pathways and remaining peripheral sudomotor
axons are hyperexcitable in patients with familial dysautonomia.82
HSAN IV is congenital or infantile onset of fevers with widespread anhidrosis
and insensitivity to pain with lack of epidermal and sweat gland innervation on
skin biopsy.83
Acquired neuropathic disorders may also manifest anhidrosis. Lepromatous
neuropathy due to infection with Mycobacterium leprae leads to tender
enlargement of peripheral nerves with a predilection for cooler (often distal)
body parts. Testing may show sensory loss over affected regions, with multifocal,
well-circumscribed areas of anhidrosis.6 Small fiber involvement manifesting as
anhidrosis is often present in neuropathies such as in amyloid neuropathies,
Tangier disease, vasculitis, alcoholism, and Fabry disease.84
DIABETIC AUTONOMIC NEUROPATHY. Diabetes mellitus is the most common

cause of autonomic neuropathy, with neuropathy found in approximately
half of all patients with type 1 diabetes mellitus and nearly three-fourths of
those with type 2 diabetes mellitus.85 The most frequent pattern of sweat loss is
length-dependent, often in a stocking-glove distribution. In addition to distal
sweat loss, thoracic nerve roots may be involved, leading to asymmetric
sweat loss over affected areas; when severe, patients may manifest global
anhidrosis.6
SJÖGREN SYNDROME. Sjögren syndrome is an autoimmune exocrinopathy that

causes sicca symptoms of xerostomia (dry mouth) and xerophthalmia (dry
eyes). With lymphocytic infiltration of the eccrine glands, patients with Sjögren
syndrome may have accompanying hypohidrosis.86,87
CHRONIC IDIOPATHIC ANHIDROSIS. The syndrome of chronic idiopathic

anhidrosis was described in 1985 in patients with heat intolerance and
widespread anhidrosis without accompanying features of autonomic failure.88
Clinically, patients present with flushing, dyspnea, dizziness, and weakness
when exposed to elevated ambient temperatures. The pattern of the lesion
varies and may be preganglionic or postganglionic, and the prognosis is
favorable.88 An autoimmune etiology may account for some cases, as skin
biopsies may demonstrate perieccrine lymphocytic infiltrates over areas of
anhidrotic skin.
IDIOPATHIC PURE SUDOMOTOR FAILURE. Autoimmune mechanisms may

also underlie anhidrosis as seen in idiopathic pure sudomotor failure, which
clinically presents with the sudden onset of generalized anhidrosis with
concomitant sharp pain or cholinergic urticaria. No other features of
autonomic dysfunction are seen, and skin biopsy may not show morphologic
abnormalities; however, serum IgE levels are elevated and patients respond
well to steroids.89
DERMATOLOGIC DISORDERS. Primary dermatologic disorders in which disruption

of sweat gland integrity occurs, such as psoriasis, exfoliative dermatitis, lichen
sclerosus, ichthyosis, or miliaria, may lead to hypohidrosis. Hypohidrosis may
132 FEBRUARY 2020

also develop after dermatologic injury such as damage to sweat glands (burns, KEY POINTS
radiation, inflammation, scarring) or secondary to sweat gland necrosis
● Diabetic autonomic
following blistering from medication overdoses. neuropathy is the most
common cause of autonomic
TRENDS neuropathy and may
Historically, skin biopsies were performed in patients with metabolic diseases manifest as length-
dependent sweat loss and
such as lysosomal disorders. With the discovery of protein gene product 9.5
focal areas of anhidrosis or
as a component of axons, leading to the detection of unmyelinated nerve fibers lead to global anhidrosis
in the epidermis, it is now possible to perform qualitative and quantitative when severe.
studies of cutaneous nerve fiber density and morphology.90,91 The use of skin
biopsy has been expanded to peripheral autonomic disorders, and skin biopsy ● Chronic idiopathic
anhidrosis is characterized
is commonly used to quantify autonomic innervation in diabetic neuropathy.92 by heat intolerance and
The use of skin biopsies has also been extended to synucleinopathies with widespread anhidrosis in the
decreased sudomotor and pilomotor innervation demonstrated in Parkinson absence of accompanying
disease and pure autonomic failure.93,94 In multiple system atrophy, autonomic autonomic failure; the
pattern of anhidrosis may be
innervation is relatively preserved, which leads to the intriguing possibility preganglionic or
that skin biopsy may become a potential tool to differentiate the various postganglionic.
synucleinopathies.94,95 However, the current methodologies are variable, and
consensus does not yet exist for optimal reporting of α-synuclein quantification.
Additionally, histologic evaluation does not differentiate the etiology of the
disease and rarely changes clinical management.96
CONCLUSION
Any lesion along the thermoregulatory pathway, from central involvement to
peripheral structures, including autonomic nerves and eccrine sweat glands, may
manifest as abnormal sweating. Hyperhidrosis may interfere with quality of life,
whereas compensatory hyperhidrosis may be a red flag for hypohidrosis or
anhidrosis. Disorders with anhidrosis are often due to autonomic failure or
neuropathy, portending a more severe neurologic disorder.
REFERENCES
1 Cheshire WP, Freeman R. Disorders of sweating. 6 Fealey R. Thermoregulatory failure. In:

Semin Neurol 2003;23(4):399–406. doi:10.1055/ Appenzeller O, editor. Autonomic nervous
s-2004-817724. system: an introduction to basic and clinical
concepts. 4th ed. New York, NY: Elsevier Science
2 Low PA. Evaluation of sudomotor function. Clin
Ltd, 1990:53–84.
Neurophysiol 2004;115(7):1506–1513. doi:10.1016/j.
clinph.2004.01.023. 7 Nathan PW, Smith MC. The location of descending
fibres to sympathetic preganglionic vasomotor
3 Cheshire WP Jr. Thermoregulatory disorders and
and sudomotor neurons in man. J Neurol
illness related to heat and cold stress. Auton
Neurosurg Psychiatry 1987;50(10):1253–1262.
Neurosci 2016;196:91–104. doi:10.1016/j.autneu.
doi:10.1136/jnnp.50.10.1253.
2016.01.001.
8 List CF, Peet PM. Sweat secretion in man: I.
4 Benarroch EE. Central autonomic network. In:
Sweating responses in normal persons. Arch
Benarroch EE, editor. Autonomic neurology. New
Neurol Psychiatry 1938;39(6):1228–1237.
York, NY: Oxford University Press, 2014:3–4.
doi:10.1001/archneurpsyc.1938.02270060118005.
5 Morrison SF. Central neural control of
9 List CF, Peet MM. Sweat secretion in man. II.
thermoregulation and brown adipose tissue.
Anatomic distribution of disturbances in
Auton Neurosci 2016;196:14–24. doi:10.1016/j.
sweating associated with lesions of the
autneu.2016.02.010.
sympathetic nervous system. Arch Neurol
Psychiatry 1938;40(1):27–43. doi:10.1001/
archneurpsyc.1938.02270070037003.

SWEATING DISORDERS
10 Weihe E, Schütz B, Hartschuh W, et al. 25 Baguley IJ, Perkes IE, Fernandez-Ortega JF, et al.
Coexpression of cholinergic and noradrenergic Paroxysmal sympathetic hyperactivity after
phenotypes in human and nonhuman autonomic acquired brain injury: consensus on conceptual
nervous system. J Comp Neurol 2005;492(3): definition, nomenclature, and diagnostic criteria.
370–379. doi:10.1002/cne.20745. J Neurotrauma 2014;31(17):1515–1520. doi:10.1089/
neu.2013.3301.
11 Cui CY, Schlessinger D. Eccrine sweat gland
development and sweat secretion. Exp Dermatol 26 Penfield W. Diencephalic autonomic epilepsy.
2015;24(9):644–650. doi:10.1111/exd.12773. Arch Neurol Psychiatry 1929;22(2):358–374.
doi:10.1001/archneurpsyc.1929.0222002017401.
12 Schütz B, von Engelhardt J, Gördes M, et al.
Sweat gland innervation is pioneered by sympathetic 27 Rabinstein AA. Paroxysmal sympathetic
neurons expressing a cholinergic/noradrenergic hyperactivity in the neurological intensive care
co-phenotype in the mouse. Neuroscience 2008; unit. Neurol Res 2007;29:680–682. doi:10.1179/
156(2):310–318. doi:10.1016/j.neuroscience. 016164107X240071.
2008.06.074.
28 Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal
13 Sato K, Kang WH, Saga K, Sato KT. Biology of sympathetic hyperactivity: the storm after acute
sweat glands and their disorders. I. Normal sweat brain injury. Lancet Neurol 2017;16(9):721–729.
gland function. J Am Acad Dermatol 1989;20(4): doi:10.1016/S1474-4422(17)30259-4.
537–563. doi:10.1016/S0190-9622(89)70063-3.
29 Rabinstein AA, Benarroch EE. Treatment of
14 Quinton PM. Sweating and its disorders. Annu paroxysmal sympathetic hyperactivity. Curr
Rev Med 1983;34:429–452. doi:10.1146/annurev. Treat Options Neurol 2008;10(2):151–157.
me.34.020183.002241. doi:10.1007/s11940-008-0016-y.
15 Cheshire WP, Fealey RD. Drug-induced hyperhidrosis 30 Rabinstein AA. Autonomic hyperactivity. Continuum
and hypohidrosis: incidence, prevention and (Minneap Minn) 2020:26(1, Autonomic Disorders):
management. Drug Saf 2008;31(2):109–126. 138–153.
doi:10.2165/00002018-200831020-00002.
31 Strutton DR, Kowalski JW, Glaser DA, Stang PE.
16 Lindquist M, Edwards IR. Endocrine adverse US prevalence of hyperhidrosis and impact on
effects of omeprazole. BMJ 1992;305(6851): individuals with axillary hyperhidrosis: results
451–452. doi:10.1136/bmj.305.6851.451. from a national survey. J Am Acad Dermatol
2004;51(2):241–248. doi:10.1016/j.jaad.2003.
17 Ikeda T, Kurz A, Sessler DI, et al. The effect of
12.040.
opioids on thermoregulatory responses in
humans and the special antishivering action of 32 Eisenach JH, Atkinson JL, Fealey RD. Hyperhidrosis:
meperidine. Ann N Y Acad Sci 1997;813:792–798. evolving therapies for a well-established
doi:10.1111/j.1749-6632.1997.tb51783.x. phenomenon. Mayo Clin Proc 2005;80(5):
657–666. doi:10.4065/80.5.657.
18 Gowers WR. A manual of diseases of the nervous
system. 2nd ed. London, UK: J & A Churchill, 1893. 33 Cheshire WP. Subcutaneous botulinum toxin
type A inhibits regional sweating: an individual
19 Barbeau A. High-level levodopa therapy in
observation. Clin Auton Res 1996;6(2):123–124.
Parkinson’s disease: five years later. Trans Am
doi:10.1007/BF02291235.
Neurol Assoc 1974;99:160–163.
34 Heckmann M, Plewig G, Hyperhidrosis Study
20 Pursiainen V, Haapaniemi TH, Korpelainen JT,
Group. Low-dose efficacy of botulinum toxin
et al. Sweating in Parkinsonian patients with
A for axillary hyperhidrosis: a randomized,
wearing-off. Mov Disord 2007;22(6):828–832.
side-by-side, open-label study. Arch Dermatol
doi:10.1002/mds.21422.
2005;141(10):1255–1259. doi:10.1001/archderm.
21 Swinn L, Schrag A, Viswanathan R, et al. Sweating 141.10.1255.
dysfunction in Parkinson’s disease. Mov Disord
35 Glaser DA. The use of botulinum toxins to treat
2003;18(12):1459–1463. doi:10.1002/mds.10586.
hyperhidrosis and gustatory sweating syndrome.
22 Shapiro WR, Williams GH, Plum F. Spontaneous Neurotox Res 2006;9(2–3):173–177. doi:10.1007/
recurrent hypothermia accompanying agenesis BF03033936.
of the corpus callosum. Brain 1969;92(2):423–436.
36 Saadia D, Voustianiouk A, Wang AK, Kaufmann H.
doi:10.1093/brain/92.2.423.
Botulinum toxin type A in primary palmar
23 Walker BR, Anderson JA, Edwards CR. Clonidine hyperhidrosis: randomized, single-blind, two-dose
therapy for Shapiro’s syndrome. Q J Med 1992; study. Neurology 2001;57(11):2095–2099. doi:10.1212/
82(299):235–245. doi:10.1093/oxfordjournals. WNL.57.11.2095.
qjmed.a068665.
37 Ray BS. Sympathectomy of the upper
24 Klein CJ, Silber MH, Halliwill JR, Schreiner SA, extremity; evaluation of surgical methods.
Suarez GA, Low PA. Basal forebrain malformation J Neurosurg 1953;10(6):624–633. doi:10.3171/
with hyperhidrosis and hypothermia: variant of jns.1953.10.6.0624.
Shapiro’s syndrome. Neurology 2001;56:254–256.
doi:10.1212/WNL.56.2.254.
134 FEBRUARY 2020

38 Atkinson JL, Fealey RD. Sympathotomy instead of 51 Krassioukov A, Warburton DE, Teasell R, et al. A
sympathectomy for palmar hyperhidrosis: systematic review of the management of
minimizing postoperative compensatory autonomic dysreflexia after spinal cord injury.
hyperhidrosis. Mayo Clin Proc 2003;78(2): Arch Phys Med Rehabil 2009;90(4):682–695.
167–172. doi:10.4065/78.2.167. doi:10.1016/j.apmr.2008.10.017.
39 Atkinson JL, Fode-Thomas NC, Fealey RD, et al. 52 Walsh JC, Low PA, Allsop JL. Localized sympathetic
Endoscopic transthoracic limited sympathotomy overactivity: an uncommon complication of lung
for palmar-plantar hyperhidrosis: outcomes cancer. J Neurol Neurosurg Psychiatry 1976;39(1):
and complications during a 10-year period. Mayo 93–95. doi:10.1136/jnnp.39.1.93.
Clin Proc 2011;86(8):721–729. doi:10.4065/mcp.
53 Lindsay DC, Freeman JG, Record CO. Unilateral
2011.0199.
hyperhidrosis associated with underlying
40 Rompel R, Scholz S. Subcutaneous curettage vs. intrathoracic neoplasia. Thorax 1986;41(10):
injection of botulinum toxin A for treatment of 814–815. doi:10.1136/thx.41.10.814.
axillary hyperhidrosis. J Eur Acad Dermatol
54 Pleet DL, Mandel S, Neilan B. Paroxysmal unilateral
Venereol 2001;15(3):207–211. doi:10.1046/j.1468-
hyperhidrosis and malignant mesothelioma. Arch
3083.2001.00226.x.
Neurol 1983;40(4):256. doi:10.1001/archneur.
41 Laskawi R, Ellies M, Rödel R, Schoenebeck C. 1983.04050040086020.
Gustatory sweating: clinical implications and
55 Lambert M, Kanyinda JM, Richard F, Sindic C.
etiologic aspects. J Oral Maxillofac Surg 1999;
Unilateral hyperhidrosis associated with
57(6):642–648; discussion 648–649. doi:10.1016/
intrathoracic IgD lambda myelomatous tumour.
S0278-2391(99)90420-2.
Clin Oncol (R Coll Radiol) 1993;5(1):65–66.
42 Blair DI, Sagel J, Taylor I. Diabetic gustatory doi:10.1016/S0936-6555(05)80705-8.
sweating. South Med J 2002;95(3):360–362.
56 Telford ED. Cervical rib and hyperhidrosis.
43 Shaw JE, Parker R, Hollis S, et al. Gustatory Br Med J 1942;2(4255):96.
sweating in diabetes mellitus. Diabet Med
57 Tascilar N, Tekin NS, Erdem Z, et al. Unnoticed
1996;13(12):1033–1037. doi:10.1002/(SICI)1096-
dysautonomic syndrome of the face: Harlequin
9136(199612)13:12<1033::AID-DIA280>3.0.CO;2-B.
syndrome. Auton Neurosci 2007;137(1–2):1–9.
44 Friedman JH. Hemifacial gustatory doi:10.1016/j.autneu.2007.05.004.
sweating due to Pancoast’s tumor. Am J Med
58 Ross AT. Progressive selective sudomotor
1987;82(6):1269–1271. doi:10.1016/0002-9343(87)
denervation; a case with coexisting Adie's
90239-7.
syndrome. Neurology 1958;8(11):809–817.
45 Stier B, Schröder T, Matschke HJ, Haas W. doi:10.1212/WNL.8.11.809.
Olfactory and gustatory sweating—case report on
59 Nolano M, Provitera V, Perretti A, et al. Ross
reflex facial hyperhidrosis [in German]. Psychiatr
syndrome: a rare or a misknown disorder of
Neurol Med Psychol (Leipz) 1990;42(11):693–698.
thermoregulation? A skin innervation study on
46 Eedy DJ, Corbett JR. Clin Exp Dermatol 1987;12(4): 12 subjects. Brain 2006;129(pt 8):2119–2131.
298–299. doi:10.1111/j.1365-2230.1987.tb01929.x. doi:10.1093/brain/awl175.
47 Knappskog PM, Majewski J, Livneh A, et al. 60 Thaisetthawatkul P, Boeve BF, Benarroch EE,
Cold-induced sweating syndrome is caused et al. Autonomic dysfunction in dementia
by mutations in the CRLF1 gene. Am J with Lewy bodies. Neurology 2004;62(10):
Hum Genet 2003;72(2):375–383. doi: 1804–1809. doi:10.1212/01.WNL.0000125192.
10.1086/346120. 69777.6D.
48 Rousseau F, Gauchat JF, McLeod JG, et al. 61 Benarroch EE, Smithson IL, Low PA, Parisi JE.
Inactivation of cardiotrophin-like cytokine, a Depletion of catecholaminergic neurons of
second ligand for ciliary neurotrophic factor the rostral ventrolateral medulla in multiple
receptor, leads to cold-induced sweating systems atrophy with autonomic failure.
syndrome in a patient. Proc Natl Acad Sci Ann Neurol 1998;43(2):156–163. doi:10.1002/
U S A 2006;103(26):10068–10073. doi:10.1073/ ana.410430205.
pnas.0509598103.
62 Coon EA, Cutsforth-Gregory JK, Benarroch EE.
49 Korpelainen JT, Sotaniemi KA, Myllylä VV. Neuropathology of autonomic dysfunction in
Asymmetric sweating in stroke: a prospective synucleinopathies. Mov Disord 2018;33:349–358.
quantitative study of patients with hemispheral doi:10.1002/mds.27186.
brain infarction. Neurology 1993;43(6):1211–1214.
63 Coon EA, Fealey RD, Sletten DM, et al. Anhidrosis
doi:10.1212/WNL.43.6.1211.
in multiple system atrophy involves pre- and
50 Lee ES, Joo MC. Prevalence of autonomic postganglionic sudomotor dysfunction.
dysreflexia in patients with spinal cord injury Mov Disord 2017;32(3):397–404. doi:10.1002/
above T6. Biomed Res Int 2017;2017:2027594. mds.26864.
doi:10.1155/2017/2027594.

SWEATING DISORDERS
64 Gilman S, Wenning GK, Low PA, et al. Second 78 Low PA. Testing the autonomic nervous system.
consensus statement on the diagnosis of Semin Neurol 2003;23(4):407–421. doi:10.1055/
multiple system atrophy. Neurology 2008;71(9): s-2004-817725.
670–676. doi:10.1212/01.wnl.0000324625.
79 Axelrod FB, Gold-von Simson G. Hereditary
00404.15.
sensory and autonomic neuropathies: types II, III,
65 Lipp A, Sandroni P, Ahlskog JE, et al. Prospective and IV. Orphanet J Rare Dis 2007;2. doi:10.1186/
differentiation of multiple system atrophy from 1750-1172-2-39.
Parkinson disease, with and without autonomic
80 Axelrod FB, Nachtigal R, Dancis J. Familial
failure. Arch Neurol 2009;66(6):742–750.
dysautonomia: diagnosis, pathogenesis and
doi:10.1001/archneurol.2009.71.
management. Adv Pediatr 1974;21:75–96.
66 Provitera V, Nolano M, Caporaso G, et al.
81 Hilz MJ, Axelrod FB. Quantitative sensory testing
Postganglionic sudomotor denervation in
of thermal and vibratory perception in familial
patients with multiple system atrophy. Neurology
dysautonomia. Clin Auton Res 2000;10(4):177–183.
2014;82(24):2223–2229. doi:10.1212/WNL.
doi:10.1007/BF02291353.
0000000000000518.
82 Hilz MJ, Axelrod FB, Bickel A, et al. Assessing
67 Coon EA, Fealey RD, Benarroch EE, et al. Purple
function and pathology in familial dysautonomia:
hands in multiple system atrophy: global
assessment of temperature perception, sweating
anhidrosis with preserved acral sweating.
and cutaneous innervation. Brain 2004;127(pt 9):
Neurology 2016;86(24):2314. doi:10.1212/
2090–2098. doi:10.1093/brain/awh235.
WNL.0000000000002778.
83 Hilz MJ, Axelrod FB, Steingrueber M, Stemper B.
68 Consensus statement on the definition of
Valsalva maneuver suggests increased rigidity of
orthostatic hypotension, pure autonomic failure,
cerebral resistance vessels in familial
and multiple system atrophy. J Neurol Sci 1996;
dysautonomia. Clin Auton Res 2002;12(5):
144(1–2):218–219.
385–392. doi:10.1007/s10286-002-0027-9.
69 Kaufmann H, Hague K, Perl D. Accumulation of
84 Hovaguimian A, Gibbons CH. Diagnosis and
alpha-synuclein in autonomic nerves in pure
treatment of pain in small-fiber neuropathy.
autonomic failure. Neurology 2001;56(7):980–981.
Curr Pain Headache Rep 2011;15(3):193–200.
doi:10.1212/WNL.56.7.980.
doi:10.1007/s11916-011-0181-7.
70 Kaufmann H, Norcliffe-Kaufmann L, Palma JA,
85 Low PA, Benrud-Larson LM, Sletten DM, et al.
et al. Natural history of pure autonomic failure: a
Autonomic symptoms and diabetic neuropathy:
United States prospective cohort. Ann Neurol
a population-based study. Diabetes Care 2004;
2017;81(2):287–297. doi:10.1002/ana.24877.
27(12):2942–2947. doi:10.2337/diacare.27.
71 Singer W, Berini SE, Sandroni P, et al. Pure 12.2942.
autonomic failure: predictors of conversion
86 Wright RA, Grant IA, Low PA. Autonomic neuropathy
to clinical CNS involvement. Neurology
associated with sicca complex. J Auton Nerv Syst
2017;88(12):1129–1136. doi:10.1212/WNL.
1999;75(1):70–76. doi:10.1016/S0165-1838(98)00164-7.
0000000000003737.
87 Katayama I, Yokozeki H, Nishioka K. Impaired
72 Downey JA, Huckaba CE, Kelley PS, et al. Sweating
sweating as an exocrine manifestation in
responses to central and peripheral heating in
Sjögren’s syndrome. Br J Dermatol 1995;133(5):
spinal man. J Appl Physiol 1976;40(5):701–706.
716–720. doi:10.1111/j.1365-2133.1995.tb02744.x.
doi:10.1152/jappl.1976.40.5.701.
88 Low PA, Fealey RD, Sheps SG, et al. Chronic
73 Vernino S, Low PA, Fealey RD, et al. Autoantibodies
idiopathic anhidrosis. Ann Neurol 1985;18(3):
to ganglionic acetylcholine receptors in
344–348. doi:10.1002/ana.410180312.
autoimmune autonomic neuropathies. New Engl
J Med 2000;343(12):847–855. doi:10.1056/ 89 Nakazato Y, Tamura N, Ohkuma A, et al. Idiopathic
NEJM200009213431204. pure sudomotor failure: anhidrosis due to deficits
in cholinergic transmission. Neurology 2004;63(8):
74 Klein CM, Vernino S, Lennon VA, et al. The spectrum
1476–1480. doi:10.1212/01.WNL.0000142036.
of autoimmune autonomic neuropathies.
54112.57.
Ann Neurol 2003;53(6):752–758. doi:10.1002/
ana.10556. 90 Wang L, Hilliges M, Jernberg T, et al. Protein gene
product 9.5-immunoreactive nerve fibres and
75 Cutsforth-Gregory JK, McKeon A, Coon EA, et al.
cells in human skin. Cell Tissue Res 1990;261(1):
Ganglionic antibody level as a predictor of severity
25–33. doi:10.1007/BF00329435.
of autonomic failure. Mayo Clin Proc 2018;93(10):
1440–1447. doi:10.1016/j.mayocp.2018.05.033. 91 Kennedy WR, Wendelschafer-Crabb G. The
innervation of human epidermis. J Neurol Sci
76 Kimpinski K, Iodice V, Sandroni P, et al.
1993;115(2):184–190. doi:10.1016/0022-510X(93)
Sudomotor dysfunction in autoimmune autonomic
90223-L.
ganglionopathy. Neurology 2009;73(18):1501–1506.
doi:10.1212/WNL.0b013e3181bf995f. 92 Luo KR, Chao CC, Hsieh PC, et al. Effect of
glycemic control on sudomotor denervation in
77 Vernino S. Autoimmune autonomic disorders.
type 2 diabetes. Diabetes Care 2012;35(3):
Continuum (Minneap Minn) 2020:26(1, Autonomic
612–616. doi:10.2337/dc11-1607.
Disorders):44–57.
136 FEBRUARY 2020

93 Nolano M, Provitera V, Estraneo A, et al. Sensory 95 Gibbons CH, Garcia J, Wang N, Shih LC, Freeman
deficit in Parkinson’s disease: evidence of a R. The diagnostic discrimination of cutaneous
cutaneous denervation. Brain 2008;131(pt 7): α-synuclein deposition in Parkinson disease.
1903–1911. doi:10.1093/brain/awn102. Neurology 2016;87(5):505–512. doi:10.1212/
WNL.0000000000002919.
94 Donadio V, Cortelli P, Elam M, et al. Autonomic
innervation in multiple system atrophy and pure 96 Myers MI, Peltier AC. Uses of skin biopsy for
autonomic failure. J Neurol Neurosurg Psychiatry sensory and autonomic nerve assessment. Curr
2010;81(12):1327–1335. doi:10.1136/ Neurol Neurosci Rep 2013;13(1):323. doi:10.1007/
jnnp.2009.198135. s11910-012-0323-2.

REVIEW ARTICLE

Autonomic Hyperactivity
C O N T I N UU M A UD I O By Alejandro A. Rabinstein, MD, FAAN
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Autonomic hyperactivity is a relatively common
consequence of severe acute brain injury and can also be seen with
spinal cord and peripheral nerve disorders. This article reviews basic
pathophysiologic concepts regarding autonomic hyperactivity, its various
forms of clinical presentation, and practical management considerations.
RECENT FINDINGS:Paroxysmal sympathetic hyperactivity is most common

after traumatic brain injury but can also occur after other forms of severe
acute diffuse or multifocal brain injury. Formal criteria for the diagnosis and
severity grading of paroxysmal sympathetic hyperactivity have now been
proposed. A growing body of literature is beginning to elucidate the
mechanisms underlying this disorder, but treatment remains based on
observational data. Our mechanistic understanding of other distinct forms
of autonomic hyperactivity, such as autonomic dysreflexia after traumatic
spinal cord injury and dysautonomia after Guillain-Barré syndrome,
remains rudimentary, yet clinical experience shows that their appropriate
management can minimize the risk of serious complications.
SUMMARY: Syndromes of autonomic hyperactivity can result from injury at all

levels of the neuraxis. Much more research is needed to refine our
CITE AS:
understanding of these disorders and guide optimal management
C O N T I N U U M ( M I N N E AP M I N N ) decisions.
138–153.
Address correspondence to INTRODUCTION
A
Dr Alejandro A. Rabinstein, utonomic disorders are relatively common in patients with acute
Mayo Clinic, 200 First St SW,
neurologic disease at every level of the neuraxis. Most frequently,
Rochester, MN 55905, rabinstein.
alejandro@mayo.edu. these disorders manifest with signs and symptoms of autonomic
hyperactivity. Sympathetic manifestations typically predominate
Dr Rabinstein serves as an
and sometimes occur without any accompanying signs of excessive
associate editor of parasympathetic function. Dysregulation is a characteristic feature; autonomic
Neurocritical Care and on the responses to external or internal stimuli are exaggerated.
editorial board of Continuum and
receives publishing royalties Recognition of these disorders in practice is important because their
from Elsevier and Oxford mismanagement can provoke dangerous and even life-threatening
University Press. complications. Also, great potential exists for misdiagnosis, and this may result in
UNLABELED USE OF excessive testing and sometimes treatment of incorrect alternative diagnoses.
PRODUCTS/INVESTIGATIONAL Timely identification of the actual problem not only can prevent these mistakes
USE DISCLOSURE:
Dr Rabinstein reports no
but also allows for the initiation of effective preventive and therapeutic
disclosure. measures.
This article discusses basic pathophysiologic concepts, clinical features, and
management considerations of autonomic hyperactivity in patients with severe
of Neurology. neurologic disease, with a focus on acute diseases. Individual sections with
138 FEBRUARY 2020

illustrative cases are dedicated to a more detailed discussion of specific KEY POINTS
syndromes associated with critical brain disease, spinal cord injury, and the
● Recognition of autonomic
peripheral nervous system. hyperactivity is important
because it can provoke
PATHOPHYSIOLOGY OF AUTONOMIC HYPERACTIVITY dangerous complications.
Injury to the neuraxis at various levels may produce autonomic hyperactivity
● Injury at multiple levels of
(FIGURE 8-11). The precise pathophysiologic mechanisms are poorly defined, but,
the neuraxis can cause
in general terms, the autonomic (mainly sympathetic) overdrive could be autonomic hyperactivity.
explained by an injury causing increased activation of excitatory pathways, an
injury affecting descending inhibitory pathways and releasing excitatory
reflexes, or a combination of both of these mechanisms. Sympathetic activation
originates from the hypothalamus (paraventricular nucleus, dorsomedial
nucleus, and lateral hypothalamic area) and the rostral ventrolateral medulla.
FIGURE 8-1
Schematic representation of the levels of neuraxial injury and proposed mechanisms for the
development of autonomic hyperactivity.
CeA = central nucleus of the amygdala; IML = intermediolateral cell column; NMDA = N-methyl-D-aspartate;
NTS = nucleus of the solitary tract; PAG = periaqueductal gray; PVN = paraventricular nucleus; RVLM =
rostral ventrolateral medulla; SG = sympathetic ganglion; VGKC = voltage-gated potassium channel.
Reprinted with permission from Benarroch EE.1 © Oxford University Press.

AUTONOMIC HYPERACTIVITY
The paraventricular nucleus of the hypothalamus is responsible for acute stress

responses. The rostral ventrolateral medulla maintains blood pressure through
a tonic sympathetic output, which, in turn, is modulated by the baroreceptor
reflex. Injury directly involving these key sympathetic centers can produce
sympathetic hyperactivity, but similar manifestations can be observed with
damage to brainstem fibers connecting these hypothalamic and medullary
centers and with injury to cortical areas that connect with the hypothalamus
(such as the insula and mesial temporal lobe). Damage to inhibitory pathways
coming from the forebrain and rostral brainstem may also result in sympathetic
hyperactivity. Lack of inhibition releases spinal sympathoexcitatory reflexes that
then overreact to peripheral stimulation.
Multiple types of injury can cause autonomic hyperactivity, including
hypoxia, global and focal ischemia, trauma with diffuse axonal damage, other
causes of increased intracranial pressure (hemorrhage, hydrocephalus), spinal
cord injury, and severe denervation.2–5 Increase in glutamate or decrease in
γ-aminobutyric acid (GABA) transmission (the main excitatory and inhibitory
neurotransmitters in the central autonomic nervous system, respectively) can
also produce signs of autonomic hyperactivity.
GENERAL FEATURES OF AUTONOMIC HYPERACTIVITY IN ACUTE

BRAIN DISEASE
Most manifestations of autonomic hyperactivity in patients with acute
neurologic disease are related to sympathetic excess (TABLE 8-1). In isolation,
parasympathetic overactivity is very rare, although it can occur with seizures
(ictal bradycardia). Some disorders, such as autonomic dysreflexia after spinal
cord injury and autoimmune encephalitis, can manifest with a combination of
sympathetic and parasympathetic signs (TABLE 8-1); in some of these cases, the
TABLE 8-1 Manifestations of Autonomic Hyperactivity
Sympathetic Signs
◆ Tachycardia
◆ Hypertension
◆ Mydriasis
◆ Skin pallor and piloerection
◆ Hyperhidrosis
◆ Hyperthermia
◆ Muscle rigidity
Parasympathetic Signs
◆ Bradycardia
◆ Hypotension
◆ Miosis
◆ Skin flushing
◆ Increased oral and tracheobronchial secretions
140 FEBRUARY 2020

parasympathetic signs may predominate at times. However, sympathetic
hyperactivity characterizes acute autonomic disorders in the great majority of
patients who are critically ill (TABLE 8-2).3
Sinus tachycardia, hypertension (often with an increased pulse pressure),
hyperthermia (often severe and sustained), tachypnea (often with use of
accessory muscles and hyperventilation), diaphoresis, and muscle rigidity
(sometimes with dystonic posturing) are the prevailing features of sympathetic
hyperactivity. Other common manifestations are ileus and urinary retention.
Hypersympathetic states also exhibit pupillary dilation, tremors or shivering,
piloerection, hyperreflexia, and sometimes clonus.
Serious complications may develop in patients with very severe, persistent, or
frequent episodes of sympathetic hyperactivity. They include tachyarrhythmias,
stress-induced cardiomyopathy (also known as takotsubo cardiomyopathy or
apical ballooning syndrome), pulmonary edema (neurogenic, cardiogenic, or
both) with hypoxemic respiratory failure, posterior reversible encephalopathy
syndrome (PRES), worsening intracranial hypertension, intracranial
hemorrhage, rhabdomyolysis with acute tubular necrosis and renal failure,
dehydration, malnutrition, and muscle contractures, among others. Meanwhile,
severe parasympathetic hyperactivity may cause serious bradyarrhythmias and
even asystole or heart block in extreme cases. Patients with acute autonomic
dysfunction are very susceptible to medications; major and even life-threatening
iatrogenic complications may occur if medications that can affect heart function
or vascular tone are not used cautiously.
Several systemic disorders, such as sepsis, pulmonary embolism, and active
bleeding, are associated with hyperadrenergic features. Excluding these
Select Diseases That Can Present With Acute Sympathetic Hyperactivity TABLE 8-2
◆ Traumatic brain injury

◆ Global cerebral anoxia-ischemia
◆ Aneurysmal subarachnoid hemorrhage
◆ Intracerebral hemorrhage (especially with diencephalic or pontomesencephalic
involvement)
◆ Ischemic stroke with insular involvement
◆ Temporal lobe seizures
◆ Acute bacterial meningitis
◆ Viral encephalitis
◆ Cerebral malaria
◆ Autoimmune encephalitis
◆ Cerebral fat embolism syndrome
◆ Cerebral air embolism
◆ Toxic encephalopathies (eg, serotonin syndrome, neuroleptic malignant syndrome, alcohol
withdrawal, cocaine overdose)
◆ Cervical or upper thoracic spinal cord injury (as part of autonomic dysreflexia)
◆ Guillain-Barré syndrome

CASE 8-1 A 21-year-old man had a rollover car accident while driving unrestrained
and intoxicated with alcohol. At the scene, his Glasgow Coma Scale score
was 5, and he was intubated. Upon arrival at the emergency department,
a head CT did not show any intracranial hemorrhage. He had an
intraparenchymal intracranial pressure monitor placed in the intensive
care unit (ICU). His intracranial hypertension was treated with hypertonic
saline and improved after 2 days.
On day 5, he started having recurrent episodes of sinus tachycardia,
hypertension with high pulse pressure, tachypnea, fever, marked
sweating, and dystonic posturing. He had no associated hypoxemia. A
focused workup for sepsis was negative. The episodes were mostly
triggered by external stimulation (such as nursing care), but occasionally
they occurred without apparent trigger. He was diagnosed with
paroxysmal sympathetic hyperactivity, and his episodes were acutely
treated with 2 mg to 4 mg IV morphine sulfate with good response. He
was started on gabapentin 300 mg every 8 hours and propranolol 20 mg
every 6 hours as a preventive regimen. His brain MRI showed evidence of
diffuse axonal injury (FIGURE 8-2). Every 3 days, the dose of gabapentin was
increased until it reached 2700 mg/d. The episodes of paroxysmal
sympathetic hyperactivity became less frequent and less severe. By the
time of his discharge from the ICU 12 days after the injury, he was starting
to track with his eyes and his paroxysmal sympathetic hyperactivity was
well controlled.
FIGURE 8-2
Imaging of the patient in CASE 8-1. Axial gradient
recalled echo (GRE) MRI of the brain showing
hypointense microhemorrhages indicative of
diffuse axonal injury involving the brainstem
(A, arrow) and subcortical white matter (B, arrows).
COMMENT Manifestations of paroxysmal sympathetic hyperactivity can be observed

in the ICU within the first week after a traumatic brain injury, especially
among young patients with severe injury to connecting tracts. Early
diagnosis and prompt initiation of abortive and preventive therapies can
achieve control of paroxysmal sympathetic hyperactivity, thus allowing
earlier discharge from the ICU, preventing secondary complications (eg,
fluid loss, excessive energy expenditure, contractures), and facilitating
rehabilitation activities.
142 FEBRUARY 2020

alternative diagnoses may be necessary in the right clinical scenarios. However, KEY POINTS
these systemic complications do not need to be formally excluded in all patients
● Damage causing
with autonomic hyperactivity. Certain clinical signs can help with their disconnection of
discrimination from sympathetic hyperactivity from critical neurologic disease. sympathetic centers from
Patients with severe sepsis are uncommonly hypertensive and typically do not descending inhibitory
exhibit peripheral vasoconstriction. Pulmonary embolism manifests with pathways and maladaptive
changes in the spinal cord
hypoxemia, which is not expected in cases of sympathetic hyperactivity from
can result in excessive
primary neurologic disease. Active bleeding is not associated with fever. Of note, sympathetic responses.
severe muscle rigidity is not characteristically present with these systemic
disorders, but some degree of hypertonicity can be seen with any condition that ● Sympathetic signs
produces excessive adrenergic transmission. To the untrained eye, paroxysmal predominate in most
patients with central
sympathetic hyperactivity episodes may be confused with seizures. autonomic hyperactivity.
Differentiating features include excessive diaphoresis, longer duration, and the
absence of clonic movements. While none of these elements are fully ● Autonomic hyperactivity
discriminating in themselves, the entire appearance of a patient having an may cause exaggerated
responses to various
episode of paroxysmal sympathetic hyperactivity is quite distinctive and medications and therefore
different from a seizure. puts patients at risk of
serious iatrogenic
SPECIFIC SYNDROMES OF AUTONOMIC HYPERACTIVITY complications.
Autonomic dysfunction can occur with many neurologic disorders, and
● Careful attention can
manifestations of autonomic hyperactivity are fairly common in patients with reliably distinguish
acute brain disease. Yet, there are certain specific syndromes that deserve a more paroxysmal sympathetic
detailed discussion. These include paroxysmal sympathetic hyperactivity after hyperactivity caused by
severe traumatic brain injury, autonomic dysreflexia after spinal cord injury, and brain injury from adrenergic
manifestations of sepsis,
dysautonomia in patients with Guillain-Barré syndrome. pulmonary embolism, or
seizures.
Paroxysmal Sympathetic Hyperactivity in Traumatic Brain Injury
Paroxysmal sympathetic hyperactivity is a relatively common complication ● Paroxysmal sympathetic
hyperactivity can be seen in
among young patients with severe traumatic brain injury (TBI), occurring in up up to one-third of patients
to one-third of cases.6 It is characterized by the occurrence of repeated episodes with severe traumatic brain
of rapid-onset tachycardia, hypertension, tachypnea, fever, sweating, and injury.
rigidity with dystonic posturing (CASE 8-1).7–9 Not all of these features are
● Standardized criteria
present in all episodes, but several must be observed simultaneously for the
have been proposed for the
diagnosis to be considered.2 Parasympathetic features are absent. Episodes are diagnosis and severity
often provoked by some form of external stimulation10 but can occur assessment of paroxysmal
spontaneously as well. Paroxysms resolve spontaneously, but, if left untreated, sympathetic hyperactivity.
they can last for up to 20 to 30 minutes and result in profuse fluid loss and
marked energy expenditure.11
Research on paroxysmal sympathetic hyperactivity has been historically
hampered by the lack of a uniform definition. An international panel has
proposed a Paroxysmal Sympathetic Hyperactivity Assessment Measure
consisting of a clinical feature scale and a diagnostic likelihood tool (FIGURE 8-3).8
Use of this measure has been reported to reduce misdiagnosis of paroxysmal
sympathetic hyperactivity, with possible resulting favorable impacts on length of
hospital stay and hospitalization costs.12 Although previously considered only a
subacute complication of TBI seen in rehabilitation units, paroxysmal
sympathetic hyperactivity can develop within the first week after the trauma,
and early presentation in the intensive care unit (ICU) is not uncommon at all.3
Early appearance of fever in the ICU can herald the onset of paroxysmal
sympathetic hyperactivity.13,14 Persistent paroxysmal sympathetic hyperactivity

FIGURE 8-3
Paroxysmal Sympathetic Hyperactivity Assessment Measure.
PSH = paroxysmal sympathetic hyperactivity.
Reprinted with permission from Baguley IJ, et al, J Neurotrauma.8 ©2014 Mary Ann Liebert, Inc.
is associated with worse long-term course during rehabilitation,15 and early

treatment may be effective in preventing later complications.
Paroxysmal sympathetic hyperactivity is more common in young patients
with low Glasgow Coma Scale scores.2,3,13,16 In fact, it is a well-known major
complication in pediatric patients with severe TBI,15,17 although adolescents may
be at greater increased risk than children.18 Patients with paroxysmal
sympathetic hyperactivity may have more deep structural lesions on brain
MRI.16 It is believed that the risk of paroxysmal sympathetic hyperactivity may
correlate with the severity of diffuse axonal injury.2,19 Analysis of multimodality
MRI, including diffusion tensor imaging, indicates that decreased fractional
anisotropy (reflecting loss of connectivity) in the splenium of the corpus
callosum and posterior limb of the internal capsule is associated with the
occurrence of paroxysmal sympathetic hyperactivity among patients with severe
TBI.20 These radiologic findings support the prevailing hypothesis that
144 FEBRUARY 2020

paroxysmal sympathetic hyperactivity is caused by disconnection within higher KEY POINTS
sympathetic inhibitory regions (eg, insula, cingulate cortex) and lower
● Young age and coma are
sympathetic activating centers (from the hypothalamus to the lower associated with higher risk
brainstem).21 This disinhibition would also allow excessive activation of spinal of paroxysmal sympathetic
responses to peripheral stimuli.10,22–24 It is conceivable that maladaptive plastic hyperactivity.
changes in the spinal cord might underlie persistence of paroxysmal sympathetic
● Deep brain lesions
hyperactivity in refractory cases.2 An excessive increase in circulating
affecting connecting tracts,
catecholamines (and, to a lesser degree, adrenal hormones) have been as seen with diffuse axonal
documented during episodes of paroxysmal sympathetic hyperactivity.10 injury, are commonly seen in
Treatment of paroxysmal sympathetic hyperactivity consists of minimization patients with paroxysmal
of avoidable stimulation and the use of medications to abort paroxysms and sympathetic hyperactivity.
prevent further episodes. Pharmacologic options are presented in TABLE 8-3. ● Management of
Unfortunately, none of the medications are supported by solid evidence; paroxysmal sympathetic
however, clinical experience supports their value.2,13,25–29 In the author’s experience, hyperactivity includes
morphine sulfate is the most effective agent to abort ongoing episodes, and minimizing stimulation and
using abortive (eg,
gabapentin, often combined with propranolol or clonidine, is most useful in morphine) and preventive
preventing further episodes.3 Of note, dopamine antagonists (such as haloperidol (eg, gabapentin and
or chlorpromazine) are not useful to treat paroxysmal sympathetic hyperactivity propranolol) medications.
and may even worsen the disorder and cause other serious side effects.30,31
● Paroxysmal sympathetic
Most available evidence suggests that paroxysmal sympathetic hyperactivity is
hyperactivity can negatively
associated with worse short- and long-term outcomes after TBI.2,15,16,32,33 Some affect the outcome of
series have reported no differences in functional outcomes in association with traumatic brain injury.
paroxysmal sympathetic hyperactivity,2,20,34,35 but, in most of those studies,
paroxysmal sympathetic hyperactivity was nonetheless related to other negative ● Although primarily a
complication of traumatic
end points, such as length of hospital stay34,35 and higher rate of tracheostomy.35 brain injury, paroxysmal
It has been reported that persistent episodes of paroxysmal sympathetic sympathetic hyperactivity
hyperactivity can be seen as long as 1 year after TBI in up to 20% of patients who can occur after other
experience this complication during the acute and subacute phases.35 However, forms of acute brain injury,
most notably global
early treatment with the correct medications is usually quite effective except in a anoxia-ischemia.
small subgroup of recalcitrant cases (often patients in whom traumatic injury
was combined with diffuse anoxic damage).3 ● Autonomic dysreflexia
Although paroxysmal sympathetic hyperactivity is primarily a complication of occurs after severe spinal
cord injury at the cervical or
severe TBI, it can be encountered after various other forms of critical brain
upper thoracic (T5 and
disease. Examples include global anoxia-ischemia (which may actually result in above) levels.
the most severe and refractory forms of paroxysmal sympathetic hyperactivity),3,7
autoimmune encephalitis,36 cerebral fat embolism,37 subarachnoid hemorrhage,3 ● Episodes of autonomic
intracerebral hemorrhage,3 and meningoencephalitis in children,38 among others. dysreflexia are often
triggered by urinary
retention, fecal impaction,
Autonomic Dysreflexia in Spinal Cord Injury or nursing care.
Patients with severe acute spinal cord injury can have neurogenic hypotension
for the first few days after the injury.39 During this early phase, other autonomic
disturbances are uncommon. However, patients with complete lesions to the
cervical or upper thoracic cord (ie, no motor or sensory function below the level
of the injury) may subsequently develop autonomic dysreflexia. This
complication, which may emerge any time after resolution of the acute period of
spinal shock but most often appears weeks after the trauma, is characterized by
overresponsiveness to visceral or somatic stimuli below the level of the cord
lesion.5 Common triggers include bladder or bowel distension, pressure sores,
and nursing care. Whether somatic stimuli precipitating dysreflexic responses
are transmitted by small- or large-diameter fibers continues to be debated.40 The

clinical manifestations are the result of disinhibited sympathetic responses and

secondary parasympathetic reflexes. Maladaptive changes in the spinal cord after
loss of supraspinal modulation is thought to be responsible for the pathogenesis
of autonomic dysreflexia.5 Very frequent episodes of autonomic dysreflexia
could produce peripheral adrenergic hypersensitization, with worsening of the
dysreflexia over time.41
Abrupt and severe hypertension is the hallmark and most dangerous
component of this disorder (CASE 8-2). Cases of hypertensive encephalopathy
and intracranial hemorrhage have been reported with extreme hypertension in
these patients.42 Autonomic dysreflexia may also be associated with tachycardia
TABLE 8-3 Abortive and Preventive Medications for Paroxysmal Sympathetic

Hyperactivity
Drug Mechanism Dose Clinical Effect Side Effects
Morphine sulfate Opioid agonista 2–8 mg IV bolus Abortive; improves Respiratory depression,
most features sedation, hypotension,
ileus, emesis, histamine
release, development of
tolerance (requiring
dose escalation)
Propofol GABAA agonist 10–20 mg IV bolus or Abortive (bolus) or Deep sedation (only
continuous infusion preventive (infusion); permissible in patients
(up to 80 mcg/kg/min) improves most who are intubated and
features ventilated), propofol
infusion syndrome (in
sustained high doses)
Benzodiazepines GABAA agonists Diazepam 5–10 mg IV Abortive (diazepam, Sedation, respiratory

bolus lorazepam, midazolam) depression,
or preventive development of
Lorazepam 1–4 mg IV
(clonazepam); can tolerance (requiring
bolus
improve most features dose escalation)
Midazolam 2–5 mg IV but less effectively
bolus than morphine;
diazepam is most
Clonazepam 0.5–2 mg
useful for hypertonicity
every 8 hours by
enteral route
Dexmedetomidine Central α2-adrenergic 0.2–1.5 mcg/kg/h by Abortive and Bradycardia,

receptor agonist IV infusion preventive; improves hypotension, sedation
mostly tachycardia and
hypertension but may
improve other features
as well
Clonidine Central α2-adrenergic 0.1–0.3 mg every Abortive and Bradycardia,

receptor agonist 6–8 hours by enteral preventive; improves hypotension, sedation
route (subcutaneous mostly tachycardia and
option also available) hypertension but may
improve other features
as well
146 FEBRUARY 2020

or baroreflex-mediated bradycardia. Severe headache often accompanies the
hypertension. Examination often demonstrates flushing, sweating, nasal
congestion, excess oral and respiratory secretions (ie, from exaggerated
compensatory increase in parasympathetic activation above the level of the cord
lesion), and pale, cool limbs with piloerection below the level of the cord lesion
(from excessive sympathetic activation).
Management of autonomic dysreflexia is best achieved by preventing possible
triggers, such as bladder catheter obstruction and fecal impaction. Once an
episode has begun, the patient should be placed upright to minimize the potential
risk of sudden hypertension. If pharmacologic treatment is necessary, it is most
Drug Mechanism Dose Clinical Effect Side Effects
Propranololb Noncardioselective 20–80 mg every Preventive; improves Bradycardia,

beta-blocker 4–6 hours by enteral tachycardia, hypotension, sleep
route hypertension, and disturbances
diaphoresis and might
improve dystonia; less
effective for fever
Gabapentin Interacts with α2δ 100–300 mg every Preventive; improves Mild sedation
subunit of voltage-gated 8 hours by enteral most features
calcium channels in brain route; can rapidly
and spinal cord titrate up to 3600 or
4800 mg total daily
dose
Bromocriptine Dopamine D2 receptor 1.25 mg every 12 hours Preventive; effect Confusion, agitation,
agonist by enteral route; can tends to be modest dyskinesia, nausea/
titrate up to 20–40 mg and delayed emesis, orthostatic
total daily dose hypotension; could
reduce seizure threshold
Baclofen GABAB agonist 5 mg every 8 hours by Preventive; improves Sedation, muscle

enteral route; can hypertonicity and weakness, risk of
titrate up to 80 mg dystonia withdrawal (mostly with
total daily dose intrathecal
(intrathecal option administration)
available through
implanted pump)
Dantrolene Ryanodine receptors in 0.5–2 mg/kg IV every Abortive; improves Hepatotoxicity (can be
myocytes 6–12 hours, up to hypertonicity and severe), respiratory
10 mg/kg total daily dystonia depression, muscle
dose weakness
GABAA = γ-aminobutyric acid A; GABAB = γ-aminobutyric acid B; IV = intravenous.

a
Other opioids, such as fentanyl, can be used, but they are usually less effective than morphine.
b
Can be replaced with IV labetalol (combined alpha-blocker and beta-blocker) if enteral route is unavailable. Cardioselective beta-blockers (such
as metoprolol) are usually much less effective.

prudent to use short-acting direct vasodilators (such as nitrates, hydralazine, or

calcium channel blockers without negative chronotropic effect) or prazosin
(blocker of α1-adrenergic receptors on peripheral vessels) and to avoid beta-
blockers because they can dangerously exacerbate the associated bradycardia.
Pretreatment with prazosin may dampen the hypertensive response seen in some
patients with spinal cord injury during sexual stimulation.43 In patients with
neurogenic detrusor muscle overactivity, intradetrusor injection of botulinum
toxin may prevent episodes of autonomic dysreflexia triggered by bladder
distension.44 Maintenance doses of antihypertensive medications are generally
unnecessary and avoided because patients with chronic spinal cord injury often
develop orthostatic hypotension from impaired baroreflex regulation.45
Dysautonomia in Guillain-Barré Syndrome

Dysautonomia is a frequent complication during the acute phase of Guillain-Barré
syndrome (GBS).4,46 The disorder is thought to be caused by an imbalance in
autonomic activation related to blocked peripheral nerve transmission of vascular
and visceral afferents and efferent autonomic fibers. Signs of sympathetic and
parasympathetic hyperactivity or hypoactivity can be encountered in the same
patient at various times, and, consequently, autonomic responses become
dangerously unpredictable.47 Dysautonomia is more frequent in patients with
severe weakness and can occur with demyelinating or axonal disease.4,48
CASE 8-2 A 32-year-old woman sustained an American Spinal Injury Association

(ASIA) A (ie, complete loss of motor and sensory function) C5 spinal cord
injury after falling from a horse. She remained quadriplegic and was
undergoing slow weaning from mechanical ventilation when she began
experiencing episodes of severe hypertension with pronounced facial
flushing. She was diagnosed with autonomic dysreflexia. The episodes
were managed conservatively by keeping her trunk upright and
minimizing lower body stimulation. When this failed, she occasionally
received pharmacologic treatment with sublingual nitrate or short-acting
nifedipine. It was then noticed that she had been more constipated than
usual despite her usual cathartic regimen. Rectal examination disclosed a
fecal impaction. After treatment of this problem, her episodic
hypertension nearly resolved.
COMMENT Autonomic dysreflexia is a delayed complication of cervical and upper

thoracic cord injuries. Its most serious manifestation is hypertension, which
can be extreme in some cases. Episodes of autonomic dysreflexia are
characteristically triggered by a visceral or somatic afferent from below
the level of the cord lesion. Because of lack of sensation, the patient is
typically unaware of the trigger. It is crucial to look for urinary retention,
detrusor muscle hyperactivity, fecal impaction or other forms of intestinal
distension, and pressure sores on the back in patients with dysreflexia,
because removal of the precipitating factor may be very effective in
preventing further episodes of autonomic hyperactivity.
148 FEBRUARY 2020

Sinus tachycardia is the most common finding, and hypertension occurs often, KEY POINTS
but sudden acute hypotension and severe bradycardia can be particularly
● Sudden hypertension is
threatening and can even result in cardiac arrest. Rapid fluctuations in blood the most common and most
pressure can be associated with the development of PRES, and sympathetic serious manifestation of
surges can cause stress-induced cardiomyopathy.49 Adynamic ileus is another autonomic dysreflexia.
major complication of dysautonomia in GBS, and it can become a very refractory
● Close attention to
problem.50 Urinary retention (often an early manifestation), sudomotor changes,
potential triggers is the key
and fever (rarely hypothermia) can also occur. Patients with dysautonomia most element in the management
often also have relentless neuropathic pain. of autonomic dysreflexia.
Use of medications that can affect autonomic function can have catastrophic
consequences in patients with dysautonomia from GBS.51 Manifestations of ● The clinical presentation
of dysautonomia in
dysautonomia are best managed conservatively. Avoiding precipitating causes, Guillain-Barré syndrome is
such as pain, is the safest and most effective strategy. Drugs known to be unpredictable and
effective for neuropathic pain, such as gabapentin or pregabalin, should be potentially life-threatening.
preferred, and opiates should be used sparingly because they can provoke or
● Rapid fluctuations in
exacerbate ileus. In case of hypotension, Trendelenburg positioning and
blood pressure and heart
administration of IV fluids are useful strategies; vasopressors must be used very rate, urinary retention, and
cautiously because exaggerated blood pressure responses may result from adynamic ileus are the most
denervation hypersensitivity. Similarly, hypertension should be treated prevalent expressions of
dysautonomia in Guillain-
judiciously; infusion of short-acting drugs, such as clevidipine or nicardipine,
Barré syndrome.
without aggressive targets is a prudent approach. Adrenergic blockade is
ill-advised because of the risk of serious bradyarrhythmias and profound ● Dysautonomic signs in
hypotension. Symptomatic bradycardia may require the administration of IV patients with Guillain-Barré
atropine and sometimes use of a temporary transcutaneous pacemaker. syndrome are best managed
conservatively to prevent
Treatment of adynamic ileus can be particularly challenging (CASE 8-3). iatrogenic complications.
Naltrexone can be tried when opiate effect is suspected. However, neostigmine
should be either avoided or used in low doses and under very close monitoring
because of the risk of inducing extreme bradycardia in these patients.
Nasogastric and rectal tubes can be used for abdominal decompression, and some
cases require therapeutic colonoscopy or even decompressive colostomy.
The long-term evolution of dysautonomia after GBS is not well studied.
Limited available data as well as clinical experience indicate that orthostatic
hypotension is the most lasting manifestation and may remain present for weeks
to months after resolution of the acute phase.4 Persistent orthostatic symptoms
can hinder progress during rehabilitation. For the most part, clinical
dysautonomia resolves over time, and long-term follow-up studies have found
only subclinical manifestations on sympathetic indices of cardiovascular
function.52 However, it remains unknown whether subtle autonomic changes
could contribute to the symptoms of fatigue and poor endurance commonly
reported by patients with GBS months or even years after the acute disease.
CONCLUSION
Our understanding of autonomic hyperactivity syndromes remains incomplete,
and much more research in this field is necessary. However, awareness of the
frequency of these disorders is growing, particularly in patients with acute brain
injury. Once confined to the rehabilitation literature and thought to occur
exclusively after trauma, paroxysmal sympathetic hyperactivity is now broadly
known as a possible acute complication of various forms of critical brain disease
in the ICU. It is hoped that consensus criteria for the definition and severity

CASE 8-3 A 48-year-old man developed rapidly ascending paralysis 2 weeks after a
respiratory illness and was diagnosed with Guillain-Barré syndrome.
Nerve conduction studies and EMG showed changes consistent with a
severe demyelinating polyradiculoneuropathy. He was admitted to the
intensive care unit for close neurologic and cardiopulmonary monitoring
and was preemptively intubated as he showed worsening weakness of
bulbar and respiratory muscles. He also exhibited labile heart rate and
blood pressure and had urinary retention. Despite being started on
scheduled doses of cathartic agents, he showed signs of progressive
abdominal distention. Abdominal x-ray findings were consistent with
adynamic ileus. Nasogastric and rectal tubes were used for
decompression, but efficacy was limited. He had not received opiates
and, consequently, naloxone was not administered. A trial with a low
dose of neostigmine failed to substantially improve the abdominal
distention and caused a marked drop in heart rate. Serial abdominal films
demonstrated further progression of the intestinal dilation, maximal at
the cecum (FIGURE 8-4).
Because of the severity of the ileus, the consulting gastroenterology
team decided to pursue a therapeutic colonoscopy. The degree of
abdominal distention decreased markedly following this intervention.
FIGURE 8-4
Abdominal x-ray of the patient in CASE 8-3 showing
severe adynamic ileus with maximal cecal
diameter exceeding 10 cm.
COMMENT Acute dysautonomia can be a major problem in patients with Guillain-Barré

syndrome. Clinical features may include blood pressure and heart rate
lability, urinary retention, and adynamic ileus, among others. This case
illustrates that ileus may require invasive interventions (such as therapeutic
colonoscopies or sometimes even colostomy for decompression) and that
administration of medications with autonomic effects can result in
exaggerated responses and should therefore be used with great caution.
150 FEBRUARY 2020

grading of paroxysmal sympathetic hyperactivity will facilitate interventional
clinical trials in the near future. New treatments are being investigated for the
prevention and control of autonomic dysreflexia after spinal cord injury, and
research on mechanisms of spinal cord neuroplasticity promises to accelerate our
understanding of this problem. Dysautonomia in GBS remains poorly studied,
despite being a common and potential life-threatening complication. Better
insight into the mechanisms of GBS-related dysautonomia could potentially
facilitate improvements in acute management and perhaps reduce persistent
symptoms during the rehabilitation phase.
REFERENCES
1 Benarroch EE. Autonomic hyperactivity. In: 11 Caldwell SB, Smith D, Wilson FC. Impact of
Benarroch EE, ed. Autonomic neurology. New paroxysmal sympathetic hyperactivity on
York, NY: Oxford University Press, 2014:170–186. nutrition management after brain injury: a case
series. Brain Inj 2014;28(3):370–373.
2 Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal
doi:10.3109/02699052.2013.865265.
sympathetic hyperactivity: the storm after acute
brain injury. Lancet Neurol 2017;16(9):721–729. 12 Samuel S, Lee M, Brown RJ, et al. Incidence of
doi:10.1016/S1474-4422(17)30259-4. paroxysmal sympathetic hyperactivity following
traumatic brain injury using assessment tools.
3 Hughes JD, Rabinstein AA. Early diagnosis of
Brain Inj 2018;32(9):1115–1121. doi:
paroxysmal sympathetic hyperactivity in the ICU.
10.1080/02699052.2018.1482002.
Neurocrit Care 2014;20(3):454–459. doi:10.1007/
s12028-013-9877-3. 13 Rabinstein AA, Sandhu K. Non-infectious fever in
the neurological intensive care unit: incidence,
4 Zaeem Z, Siddiqi ZA, Zochodne DW. Autonomic
causes and predictors. J Neurol Neurosurg
involvement in Guillain–Barré syndrome: an
Psychiatry 2007;78(11):1278–1280. doi:10.1136/
update. Clin Auton Res 2019;29(3):289–299.
jnnp.2006.112730.
doi:10.1007/s10286-018-0542-y.
14 Hinson HE, Schreiber MA, Laurie AL, et al. Early
5 Eldahan KC, Rabchevsky AG. Autonomic
fever as a predictor of paroxysmal sympathetic
dysreflexia after spinal cord injury: systemic
hyperactivity in traumatic brain injury. J Head
pathophysiology and methods of management.
Trauma Rehabil 2017;32(5):E50–E54. doi:10.1097/
Auton Neurosci 2018;209:59–70. doi:10.1016/j.
HTR.0000000000000271.
autneu.2017.05.002.
15 Pozzi M, Conti V, Locatelli F, et al. Paroxysmal
6 Rabinstein AA. Paroxysmal sympathetic
sympathetic hyperactivity in pediatric
hyperactivity in the neurological intensive care
rehabilitation: clinical factors and acute
unit. Neurol Res 2007;29(7):680–682.
pharmacological management. J Head Trauma
doi:10.1179/016164107X240071.
Rehabil 2015;30(5):357–363. doi:10.1097/
7 Perkes I, Baguley IJ, Nott MT, Menon DK. A review HTR.0000000000000084.
of paroxysmal sympathetic hyperactivity after
16 Lv LQ, Hou LJ, Yu MK, et al. Prognostic influence
acquired brain injury. Ann Neurol 2010;68(2):
and magnetic resonance imaging findings in
126–135. doi:10.1002/ana.22066.
paroxysmal sympathetic hyperactivity after
8 Baguley IJ, Perkes IE, Fernandez-Ortega JF, et al. severe traumatic brain injury. J Neurotrauma
Paroxysmal sympathetic hyperactivity after 2010;27(11):1945–1950. doi:10.1089/neu.2010.1391.
acquired brain injury: consensus on conceptual
17 Pozzi M, Locatelli F, Galbiati S, et al. Clinical
definition, nomenclature, and diagnostic criteria.
scales for paroxysmal sympathetic hyperactivity
J Neurotrauma 2014;31(17):1515–1520. doi:10.1089/
in pediatric patients. J Neurotrauma 2014;31(22):
neu.2013.3301.
1897–1898. doi:10.1089/neu.2014.3540.
9 Blackman JA, Patrick PD, Buck ML, Rust RS Jr.
18 Alofisan TO, Algarni YA, Alharfi IM, et al.
Paroxysmal autonomic instability with dystonia
Paroxysmal sympathetic hyperactivity after
after brain injury. Arch Neurol 2004;61(3):321–328.
severe traumatic brain injury in children:
doi:10.1001/archneur.61.3.321.
prevalence, risk factors, and outcome. Pediatr
10 Fernandez-Ortega JF, Baguley IJ, Gates TA, et al. Crit Care Med 2019;20(3):252–258. doi:10.1097/
Catecholamines and paroxysmal sympathetic PCC.0000000000001811.
hyperactivity after traumatic brain injury.
19 Huang P, Lin WC, Huang PK, Khor GT.
J Neurotrauma 2017;34(1):109–114. doi:10.1089/
Susceptibility weighted imaging in a patient with
neu.2015.4364.
paroxysmal sympathetic storms. J Neurol 2009;
256(2):276–278. doi:10.1007/s00415-009-0957-4.

20 Hinson HE, Puybasset L, Weiss N, et al. 32 Fernández-Ortega JF, Prieto-Palomino MA,

Neuroanatomical basis of paroxysmal Muñoz-López A, et al. Prognostic influence and
sympathetic hyperactivity: a diffusion tensor computed tomography findings in dysautonomic
imaging analysis. Brain Inj 2015;29(4):455–461. crises after traumatic brain injury. J Trauma 2006;
doi:10.3109/02699052.2014.995229. 61(5):1129–1133. doi:10.1097/01.ta.0000197634.
83217.80.
21 Baguley IJ, Heriseanu RE, Cameron ID, et al.
A critical review of the pathophysiology of 33 Mathew MJ, Deepika A, Shukla D, et al. Paroxysmal
dysautonomia following traumatic brain injury. sympathetic hyperactivity in severe traumatic
Neurocrit Care 2008;8(2):293–300. doi:10.1007/ brain injury. Acta Neurochir (Wien) 2016;158(11):
s12028-007-9021-3. 2047–2052. doi:10.1007/s00701-016-2934-x.
22 Baguley IJ. The excitatory:inhibitory ratio model 34 Laxe S, Terré R, León D, Bernabeu M. How does
(EIR model): an integrative explanation of acute dysautonomia influence the outcome of
autonomic overactivity syndromes. traumatic brain injured patients admitted in a
Med Hypotheses 2008;70(1):26–35. doi:10.1016/j. neurorehabilitation unit? Brain Inj 2013;27(12):
mehy.2007.04.037. 1383–1387. doi:10.3109/02699052.2013.823648.
23 Baguley IJ, Heriseanu RE, Nott MT, et al. 35 Fernandez-Ortega JF, Prieto-Palomino MA,
Dysautonomia after severe traumatic brain injury: Garcia-Caballero M, et al. Paroxysmal
evidence of persisting overresponsiveness to sympathetic hyperactivity after traumatic brain
afferent stimuli. Am J Phys Med Rehabil 2009; injury: clinical and prognostic implications.
88(8):615–622. doi:10.1097/PHM.0b013e3181aeab96. J Neurotrauma 2012;29(7):1364–1370. doi:10.1089/
neu.2011.2033.
24 Takahashi C, Hinson HE, Baguley IJ. Autonomic
dysfunction syndromes after acute brain injury. 36 Mittal MK, Rabinstein AA, Hocker SE, et al.
Handb Clin Neurol 2015;128:539–551. doi:10.1016/ Autoimmune encephalitis in the ICU: analysis of
B978-0-444-63521-1.00034-0. phenotypes, serologic findings, and outcomes.
25 Rabinstein AA, Benarroch EE. Treatment of
s12028-015-0196-8.
paroxysmal sympathetic hyperactivity. Curr
Treat Options Neurol 2008;10(2):151–157. 37 Godoy DA, Di Napoli M, Rabinstein AA. Cerebral
doi:10.1007/s11940-008-0016-y. fat embolism: recognition, complications, and
prognosis. Neurocrit Care 2018;29(3):358–365.
26 Ley EJ, Leonard SD, Barmparas G, et al. Beta
doi:10.1007/s12028-017-0463-y.
blockers in critically ill patients with traumatic
brain injury: results from a multicenter, 38 Farias-Moeller R, Carpenter JL, Dean N, Wells EM.
prospective, observational American Association Paroxysmal sympathetic hyperactivity in
for the Surgery of Trauma study. J Trauma Acute critically ill children with encephalitis and
Care Surg 2018;84(2):234–244. doi:10.1097/ meningoencephalitis. Neurocrit Care 2015;23(3):
TA.0000000000001747. 380–385. doi:10.1007/s12028-015-0124-y.
27 Thomas A, Greenwald BD. Paroxysmal 39 Rabinstein AA. Traumatic spinal cord injury.
sympathetic hyperactivity and clinical Continuum (Minneap Minn) 2018;24(2, Spinal
considerations for patients with acquired brain Cord Disorders):551–566. doi:10.1212/CON.
injuries: a narrative review. Am J Phys Med 0000000000000581.
Rehabil 2019;98(1):65–72. doi:10.1097/
40 Brown R, Burton AR, Macefield VG. Autonomic
PHM.0000000000000990.
dysreflexia: somatosympathetic and
28 Patel MB, McKenna JW, Alvarez JM, et al. viscerosympathetic vasoconstrictor responses
Decreasing adrenergic or sympathetic to innocuous and noxious sensory stimulation
hyperactivity after severe traumatic brain injury below lesion in human spinal cord injury. Auton
using propranolol and clonidine (DASH after TBI Neurosci 2018;209:71–78. doi:10.1016/j.
study): study protocol for a randomized autneu.2017.07.003.
controlled trial. Trials 2012;13:177. doi:10.1186/
41 West CR, Popok D, Crawford MA, Krassioukov AV.
1745-6215-13-177.
Characterizing the temporal development of
29 Lump D, Moyer M. Paroxysmal sympathetic cardiovascular dysfunction in response to spinal
hyperactivity after severe brain injury. Curr cord injury. J Neurotrauma 2015;32(12):922–930.
Neurol Neurosci Rep 2014;14(11):494. doi:10.1007/ doi:10.1089/neu.2014.3722.
s11910-014-0494-0.
42 Dolinak D, Balraj E. Autonomic dysreflexia and
30 Baguley IJ, Cameron ID, Green AM, et al. sudden death in people with traumatic spinal
Pharmacological management of dysautonomia cord injury. Am J Forensic Med Pathol 2007;28(2):
following traumatic brain injury. Brain Inj 2004; 95–98. doi:10.1097/PAF.0b013e3180600f99.
18(5):409–417. doi:10.1080/02699050310001645775.
43 Phillips AA, Elliott SL, Zheng MM, Krassioukov AV.
31 Wilkinson R, Meythaler JM, Guin-Renfroe S. Selective alpha adrenergic antagonist reduces
Neuroleptic malignant syndrome induced by severity of transient hypertension during
haloperidol following traumatic brain injury. Brain sexual stimulation after spinal cord injury.
Inj 1999;13(12):1025–1031. doi:10.1080/ J Neurotrauma 2015;32(6):392–396. doi:10.1089/
026990599121034. neu.2014.3590.
152 FEBRUARY 2020

44 Fougere RJ, Currie KD, Nigro MK, et al. Reduction 48 Asahina M, Kuwabara S, Suzuki A, Hattori T.
in bladder-related autonomic dysreflexia after Autonomic function in demyelinating and axonal
onabotulinumtoxinA treatment in spinal cord subtypes of Guillain–Barre syndrome. Acta
injury. J Neurotrauma 2016;33(18):1651–1657. Neurol Scand 2002;105(1):44–50. doi:10.1034/
doi:10.1089/neu.2015.4278. j.1600-0404.2002.00099.x.
45 Draghici AE, Taylor JA. Baroreflex autonomic 49 Fugate JE, Wijdicks EF, Kumar G, Rabinstein AA.
control in human spinal cord injury: Physiology, One thing leads to another: GBS complicated by
measurement, and potential alterations. Auton PRES and Takotsubo cardiomyopathy. Neurocrit
Neurosci 2018;209:37–42. doi:10.1016/j. Care 2009;11:395–397. doi:10.1007/s12028-009-
autneu.2017.08.007. 9279-8.
46 Anandan C, Khuder SA, Koffman BM. Prevalence 50 Burns TM, Lawn ND, Low PA, et al. Adynamic ileus
of autonomic dysfunction in hospitalized in severe Guillain–Barre syndrome. Muscle Nerve
patients with Guillain–Barré syndrome. Muscle 2001;24(7):963–965. doi:10.1002/mus.1095.
Nerve 2017;56(2):331–333. doi:10.1002/mus.25551.
51 Rabinstein AA. Acute neuromuscular respiratory
47 Pfeiffer G, Schiller B, Kruse J, Netzer J. Indicators failure. Continuum (Minneap Minn) 2015;
of dysautonomia in severe Guillain–Barré 21(5 Neurocritical Care):1324–1345. doi:10.1212/
syndrome. J Neurol 1999;246(11):1015–1022. CON.0000000000000218.
doi:10.1007/s004150050506.
52 Koeppen S, Kraywinkel K, Wessendorf TE, et al.
Long-term outcome of Guillain–Barré syndrome.
NCC:5:3:235.

REVIEW ARTICLE
Management of
Orthostatic Hypotension

ONLINE
By Jose-Alberto Palma, MD, PhD; Horacio Kaufmann, MD, FAAN
CITE AS: ABSTRACT

PURPOSE OF REVIEW: This article reviews the management of orthostatic
154–177. hypotension with emphasis on neurogenic orthostatic hypotension.
Address correspondence to RECENT FINDINGS: Establishing whether the cause of orthostatic hypotension
Dr Horacio Kaufmann, NYU
Langone Health, 530 First Ave,
is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic
Suite 9Q–Dysautonomia Center, hypotension) or secondary to other medical causes (ie, non-neurogenic
New York, NY 10016, Horacio. orthostatic hypotension) can be achieved by measuring blood pressure and
Kaufmann@nyulangone.org.
heart rate at the bedside. Whereas fludrocortisone has been extensively
RELATIONSHIP DISCLOSURE: used as first-line treatment in the past, it is associated with adverse events
Dr Palma serves as managing including renal and cardiac failure and increased risk of all-cause
editor for Clinical Autonomic
Research and as a consultant for hospitalization. Distinguishing whether neurogenic orthostatic hypotension
Biogen, Dr Reddy’s Laboratories is caused by central or peripheral dysfunction has therapeutic
Ltd, Lundbeck, and PTC
Therapeutics. Dr Palma receives
implications. Patients with peripheral sympathetic denervation respond
research/grant support from better to norepinephrine agonists/precursors such as droxidopa, whereas
the Familial Dysautonomia patients with central autonomic dysfunction respond better to
Foundation, Inc; the Michael J.
Fox Foundation for Parkinson’s
norepinephrine reuptake inhibitors.
Research; the Multiple System
Atrophy Coalition; and the SUMMARY: Management of orthostatic hypotension is aimed at improving
National Institute of Neurological
Disorders and Stroke quality of life and reducing symptoms rather than at normalizing blood
(R01NS107596, U54NS065736). pressure. Nonpharmacologic measures are the key to success.
Dr Kaufmann serves as
Pharmacologic options include volume expansion with fludrocortisone and
editor-in-chief of Clinical
Autonomic Research and as a sympathetic enhancement with midodrine, droxidopa, and norepinephrine
consultant for and on the reuptake inhibitors. Neurogenic supine hypertension complicates
scientific advisory boards
of Biogen, Biohaven
management of orthostatic hypotension and is primarily ameliorated by
Pharmaceuticals, Lundbeck, and avoiding the supine position and sleeping with the head of the bed
Pfizer Inc. Dr Kaufmann receives elevated.
Continued on page 177
INTRODUCTION
O
UNLABELED USE OF rthostatic hypotension is defined as a sustained reduction in
USE DISCLOSURE: systolic blood pressure of at least 20 mm Hg or a reduction in
Drs Palma and Kaufmann discuss diastolic blood pressure of at least 10 mm Hg, usually within the
the unlabeled/investigational
first 3 minutes of standing or head-up tilt on a tilt table.1 Thus,
use of acarbose, ampreloxetine,
atomoxetine, erythropoietin, a diagnosis of orthostatic hypotension requires blood pressure
fludrocortisone, octreotide, and measurements. Orthostatic hypotension is not a symptom but a sign that usually
pyridostigmine for the treatment
of orthostatic hypotension.
indicates volume depletion, impaired peripheral vasoconstriction, or both. When
orthostatic hypotension impairs perfusion to organs above the level of the heart,
most notably the brain, it causes disabling symptoms that reduce quality of
of Neurology. life and increase morbidity and mortality.
154 FEBRUARY 2020

Orthostatic hypotension is frequent in the elderly due to a variety of KEY POINTS
medical conditions, such as intravascular volume depletion, blood pooling (ie,
● Diagnosing orthostatic
varicose veins2), severe anemia, antihypertensive medications, and physical hypotension requires blood
deconditioning; in these patients, orthostatic hypotension improves dramatically pressure measurements.
or resolves after the underlying cause is treated. In a minority of patients, The presence of orthostatic
orthostatic hypotension is due to reduced norepinephrine release from intolerance is not sufficient
or necessary to diagnose
postganglionic sympathetic nerves, resulting in defective vasoconstriction when
assuming the upright position.1 This is referred to as neurogenic orthostatic
hypotension3 and is most frequently seen in patients with diabetes mellitus; ● Orthostatic hypotension
neurodegenerative disorders caused by abnormal accumulation of α-synuclein is very common in the
(ie, synucleinopathies); and small fiber neuropathies caused by amyloid, elderly, usually due to drug
effects, volume depletion,
autoimmune, or paraneoplastic diseases.3,4 Patients with high spinal cord lesions or cardiovascular
can experience neurogenic orthostatic hypotension when sitting or when placed deconditioning.
in an upright position for rehabilitation due to lack of baroreflex-mediated
activation of spinal sympathetic neurons.5 Complicating the management of ● Neurogenic orthostatic
hypotension is a feature of
neurogenic orthostatic hypotension is neurogenic supine hypertension, which neurologic disorders
occurs in approximately 50% of patients with neurogenic orthostatic hypotension.6 affecting sympathetic
pathways, including
EPIDEMIOLOGY AND PUBLIC HEALTH IMPACT diabetes mellitus,
neurodegenerative
In the general population, the prevalence of orthostatic hypotension increases
synucleinopathies, and
with age, and the numbers vary according to different clinical settings.1,7,8 In amyloid neuropathies.
large epidemiologic studies, such as the Cardiovascular Health Study, the
prevalence of orthostatic hypotension in patients older than 65 years of age was
approximately 20%, although only 2% had symptoms.9 One factor influencing
the high prevalence of orthostatic hypotension in the elderly is the frequency of
use of antihypertensive medications.10 Vasodilators (eg, α-adrenergic blockers,
calcium channel blockers, nitrates), opioids, tricyclic antidepressants, and
alcohol are frequently associated with orthostatic hypotension. In elderly
patients, orthostatic hypotension frequently causes or contributes to
hospitalization, and it is present in 25% of patients presenting with syncope in the
emergency department.11 The estimated orthostatic hypotension–related
hospitalization rate is 36 per 100,000 adults and can be as high as 233 per 100,000
patients older than 75 years of age, with a median length of stay of 3 days and an
overall in-hospital mortality rate of 0.9%.7 In inpatient series, the prevalence of
orthostatic hypotension in elderly patients is as high as 60%.12,13 Orthostatic
hypotension increases the risk of falls, cardiovascular disease, and all-cause
mortality.14–21
Neurogenic orthostatic hypotension affects approximately 20% of unselected
patients with type 1 or type 2 diabetes mellitus, but it can be as high as 65% (ie,
23 million people in the United States) with increasing age and duration of
diabetes mellitus.22–24 Neurogenic orthostatic hypotension is also common in
patients with neurodegenerative synucleinopathies, disorders characterized by
the abnormal accumulation of the misfolded protein α-synuclein in the central
and peripheral nervous systems, such as Parkinson disease, dementia with Lewy
bodies, pure autonomic failure, and multiple system atrophy. The prevalence of
neurogenic orthostatic hypotension is 50% in Parkinson disease (ie, 500,000
people in the United States), 70% in multiple system atrophy, and 100% in pure
autonomic failure. Other rare causes of neurogenic orthostatic hypotension
include a number of genetic and autoimmune disorders. Neurogenic orthostatic
hypotension is associated with increased morbidity, including poorer

MANAGEMENT OF ORTHOSTATIC HYPOTENSION
prognosis25; development of cardiovascular,26 renal,26,27 and cerebrovascular

disease26,28,29; and cognitive impairment.28–30
Neurogenic orthostatic hypotension occurs in up to 80% of patients with
spinal cord injury resulting in quadriplegia and 50% of those with paraplegia
immediately after the injury.31 Position changes during physical therapy induce
orthostatic hypotension in 74% of patients with high spinal cord injury, which
is symptomatic in 59%.31,32
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

Orthostatic hypotension can be symptomatic or asymptomatic. Symptoms are a
consequence of hypoperfusion of the brain (causing dizziness, lightheadedness,
cognitive slowing,33 [FIGURE 9-1] and syncope), the retina and visual pathways
(causing blurry, dimmed vision), the upper body muscles (causing “coat hanger”
pain), the lungs (causing fatigue and dyspnea due to hypoperfusion of the
FIGURE 9-1
Blood pressure and cerebral blood flow in a patient with neurogenic orthostatic hypotension.
The upper tracing shows blood flow velocity as measured by middle cerebral artery (MCA)
transcranial Doppler ultrasound, which indicates cerebral blood flow. The lower tracing
shows continuous blood pressure acquired with plethysmography. When the patient is in the
supine position, both blood pressure (121/84 mm Hg) and mean velocity (Vm) of MCA blood
flow (54 cm/s) are normal. When the patient stands up, blood pressure plummets rapidly to
66/54 mm Hg and cerebral blood flow falls by nearly 50% (Vm, 29 cm/s). The patient becomes
symptomatic, feels lightheaded and about to faint, and is unable to remain standing. Patient
sits down and his blood pressure increases to 93/62 mm Hg. Although this blood pressure is
still low, the patient is not symptomatic anymore because the Vm increased to 44 cm/s,
indicating almost normal cerebral blood flow. The blood pressure of a patient with
symptomatic orthostatic hypotension does not have to return to normal values for the patient to
become asymptomatic but only to increase above the lower limit of cerebral autoregulation.
Vm = mean velocity.
156 FEBRUARY 2020

apices), and, rarely, the heart (causing angina even with patent coronary KEY POINTS
arteries). Symptoms appear exclusively upon standing up and abate when sitting
● Exercise, meals
and lying down. Severely afflicted patients are unable to leave the supine position (postprandial hypotension),
without experiencing presyncopal symptoms or losing consciousness. prolonged bed rest (physical
In patients with neurogenic orthostatic hypotension, symptoms worsen deconditioning), and hot and
during exercise and after meals (postprandial hypotension). Marked worsening humid environments
typically worsen symptoms
occurs after prolonged bed rest that results in striatal and myocardial muscle
of neurogenic orthostatic
atrophy. These muscle changes of physical deconditioning impair both the hypotension.
skeletal “muscle pump” that helps venous return to the heart during active
movements and left ventricular contraction reducing cardiac output.34 ● Patients with cognitive
Symptoms are worse in the morning because of overnight pressure natriuresis impairment may not
accurately identify
causing intravascular volume depletion in the morning. symptoms of orthostatic
In patients with neurogenic orthostatic hypotension, it is imperative to perform hypotension, despite low
a careful neurologic examination with particular attention to subtle signs of blood pressure when
parkinsonism or cerebellar ataxia as well as cognitive impairment or standing.
dream-enactment behavior indicative of probable rapid eye movement (REM)
sleep behavior disorder. Any of these neurologic findings suggest that, in addition
to autonomic failure, the patient has central nervous system (CNS) abnormalities
and that autonomic failure is likely the presenting feature of a more widespread
CNS synucleinopathy: Parkinson disease, dementia with Lewy bodies, or multiple
system atrophy. Patients with chronic autonomic failure without motor, cognitive,
or sensory symptoms receive a diagnosis of pure autonomic failure; this may
remain as a restricted autonomic syndrome or patients may develop a CNS
synucleinopathy years later.4 In rare cases, patients with isolated autonomic failure
have a chronic form of an autoimmune autonomic neuropathy.35,36 If sensory
symptoms accompany neurogenic orthostatic hypotension, a small fiber
neuropathy should be suspected.37 Most commonly, as in diabetes mellitus or
amyloidosis, sensory symptoms are length dependent (affecting the distal areas of
extremities) and can include burning pain or absent/reduced pain and
temperature sensation. Less commonly, as in paraneoplastic and immune-
mediated neuropathies or ganglionopathies, sensory symptoms can be patchy
and diffuse, sometimes severe and widespread, resulting in devastating sensory
proprioceptive ataxia.38 A family history of neurogenic orthostatic hypotension
and sensory symptoms suggests hereditary transthyretin amyloidosis.
In patients presenting with “orthostatic intolerance” (ie, difficulty maintaining the
upright position), it is necessary to determine whether symptoms are due to
orthostatic hypotension or to other causes. In patients reporting typical symptoms but
without a fall in blood pressure within 3 minutes of standing, a more prolonged
orthostatic stress with a tilt-table test may be necessary to define the condition.
Patients with milder or earlier forms of autonomic failure may experience orthostatic
hypotension after a longer time of standing (ie, delayed orthostatic hypotension). In
patients with vasovagal syncope, prolonged tilt may reproduce an episode.39,40 Not
infrequently, patients may present with symptoms mimicking those of orthostatic
hypotension but without an identified fall in blood pressure, including patients with
vestibular disorders, gait abnormalities, CNS depression from alcohol and drug use,
and “the inebriationlike syndrome” (in which patients with parkinsonism report
feeling imbalanced and unsteady, as if they were slightly inebriated, but unrelated to
alcohol intake).41 Conversely, patients with cognitive impairment may not accurately
identify symptoms of organ hypoperfusion, despite low blood pressure
when standing.42

If sustained orthostatic hypotension is confirmed, it is key to establish whether

the cause is a pathologic lesion in sympathetic neurons (ie, neurogenic
orthostatic hypotension) or if it is secondary to other medical causes (ie, non-
neurogenic orthostatic hypotension), such as anemia- or dehydration-related
volume depletion, excessive venous pooling sometimes aggravated by
varicose veins, or medication side effects (eg, from alpha-blockers for benign
prostate hyperplasia, antihypertensive agents, diuretics, tricyclic antidepressants,
opioids, benzodiazepines, and antiparkinsonian agents).
TABLE 9-1 lists features that are useful to distinguish neurogenic versus non-
neurogenic orthostatic hypotension. A heart rate increase of at least 0.5 beats/min
for each mm Hg fall in systolic blood pressure (ie, change in heart rate [ΔHR]/
change in systolic blood pressure [ΔSBP] ratio of ≥0.5 beats per minute/mm Hg)
has very high sensitivity and specificity to diagnose non-neurogenic orthostatic
TABLE 9-1 Distinguishing Features of Neurogenic and Non-neurogenic Orthostatic

Hypotension
Non-neurogenic Orthostatic Hypotension Neurogenic Orthostatic Hypotension
Age at presentation Typically 65 years and older Typically 40–60 years
Onset Variable Usually chronic; acute or subacute with

immune-mediated etiology
Causes Physical deconditioning, antihypertensive Reduced norepinephrine release from

medications, intravascular volume loss (eg, sympathetic postganglionic nerves
dehydration, anemia), blood pooling (eg, large when standing up
varicose veins, skeletal muscle atrophy),
advanced heart failure, adrenal insufficiency
Prognosis Resolves when underlying cause is corrected Chronic disorder
Sympathetic activation upon Increased Low or absent

standing
Increase in heart rate upon Pronounced Mild or absent

standing
Change in heart rate (ΔHR)/ >0.5 beats per minute/mm Hg <0.5 beats per minute/mm Hg
change in systolic blood
pressure (ΔSBP) ratio
Blood pressure overshoot Present Absent

(phase IV) in Valsalva maneuver
Increase in plasma Normal or enhanced (at least 2) Reduced or absent (less than 2)
norepinephrine levels upon
standing
Other symptoms of autonomic None Gastrointestinal dysfunction, urinary

failure dysfunction, sudomotor abnormalities,
erectile dysfunction (men)
Concomitant neurologic deficits None (or, if present, they are unrelated to May have none, or may have
orthostatic hypotension) parkinsonism, cerebellar signs, cognitive
impairment, sensory neuropathy
158 FEBRUARY 2020

hypotension (CASE 9-1). Conversely, a ΔHR/ΔSBP ratio of <0.5 beats per KEY POINTS
minute/mm Hg strongly suggests neurogenic orthostatic hypotension.43
● A heart rate increase of at
least 0.5 beats/min for each
GENERAL PRINCIPLES OF MANAGEMENT 1 mm Hg fall in systolic blood
Because normalizing blood pressure is not possible, the goal of treatment in pressure (ΔHR/ΔSBP ratio
patients with orthostatic hypotension is to attenuate symptom burden and ≥0.5 beats per minute/mm
Hg) is sensitive and specific
reduce target organ damage and mortality. Expert consensus guidelines for the
to diagnose non-neurogenic
treatment of neurogenic orthostatic hypotension are available.44 Approximately orthostatic hypotension.
50% of patients with neurogenic orthostatic hypotension also have neurogenic
supine hypertension (a systolic blood pressure of at least 140 mm Hg or a ● Treatment of orthostatic
diastolic blood pressure of at least 90 mm Hg after at least 5 minutes in the supine hypotension should be
geared to the patients’
resting position), which poses a therapeutic challenge as treating one exacerbates symptoms and their impact
the other.6 The steps of management include correcting aggravating factors and on daily function rather than
initiating nonpharmacologic measures before using pharmacologic therapies a target blood pressure.
(FIGURE 9-3).44
● The initial treatment of
Patients with asymptomatic neurogenic orthostatic hypotension usually require orthostatic hypotension
education and nonpharmacologic measures only. An exception to this might be patients focuses on
with cognitive impairment who might not recognize symptoms of neurogenic nonpharmacologic
orthostatic hypotension.42 Patients with hypotension-related symptoms of brain measures first: removing
offending medications,
hypoperfusion do require treatment to increase standing blood pressure above the
increasing salt and fluid
lower limit of cerebral autoregulation, ideally without aggravating neurogenic supine intake, using compression
hypertension.45,46 The degree of tolerable hypertension when supine is unknown. garments, and instituting
physical maneuvers and
Correction of Aggravating Factors exercise.
Correction of aggravating factors can increase blood pressure sufficiently to ● Drugs that reduce
improve orthostatic tolerance in some patients and should be the first step in the intravascular volume
management of neurogenic orthostatic hypotension. (eg, diuretics) or induce
vasodilatation (eg,
α-adrenergic blockers,
DRUGS. Medications that reduce intravascular volume or trigger vasodilatation
nitrates, phosphodiesterase-5
can cause or worsen orthostatic hypotension. These drugs include nitrates, inhibitors, tricyclic
tricyclic antidepressants, diuretics, calcium channel blockers, alpha-blockers antidepressants, centrally
(usually prescribed for benign prostatic hypertrophy), phosphodiesterase-5 acting α-adrenergic
inhibitors (eg, sildenafil for erectile dysfunction), centrally acting α2-agonists (eg, agonists) exacerbate
orthostatic hypotension and
clonidine or tizanidine), and beta-blockers, as illustrated in CASE 9-1. Levodopa worsen symptoms; thus,
and dopamine agonists may also lower blood pressure, and a dose adjustment may they should be reduced or
be considered based on an individual risk-benefit assessment.10,16,18,47 discontinued.
● In patients with
ANEMIA. Anemia of chronic disease is common in patients with neurogenic
orthostatic hypotension.48 Anemia reduces blood viscosity and oxygen-carrying anemia should be
capacity and, consequently, worsens orthostatic hypotension. Hemoglobin investigated and treated.
scavenges nitric oxide, which is a potent vasodilator49; it is therefore possible that
nitric oxide–mediated mechanisms enhance vasodilation in patients with
orthostatic hypotension and anemia.50 Therefore, anemia must be investigated
and treated appropriately. Increasing the red cell mass with recombinant
erythropoietin improves orthostatic hypotension.51
Nonpharmacologic Management
Patient education on nonpharmacologic measures is the cornerstone of
successful management of orthostatic hypotension. Nonpharmacologic
treatments for orthostatic hypotension are listed in TABLE 9-2.52–54

CASE 9-1 A 72-year-old man presented with a 6-month history of orthostatic

lightheadedness, which he first noticed after mild exercise.
Lightheadedness was often accompanied by blurry vision and a
dull pain in both shoulders and the back of his neck, shortness of
breath, and, rarely, chest discomfort. He was taking furosemide
40 mg/d for “swollen legs,” amitriptyline 200 mg/d for depression,
diazepam 5 mg 3 times a day for anxiety, and tamsulosin 0.8 mg
in the morning for benign prostatic hyperplasia.
His neurologic examination was normal. His blood pressure in the
supine position was 139/91 mm Hg with a heart rate of 89 beats/min.
After 3 minutes standing, his blood pressure fell to 79/48 mm Hg with a
heart rate of 123 beats/min, and he was severely lightheaded (change in
heart rate [ΔHR]/change in systolic blood pressure [ΔSBP] ratio
of 0.56 beats per minute/mm Hg) (FIGURE 9-2).
His ECG, complete blood
cell count, and metabolic
panel were normal. His
plasma norepinephrine level
when supine was normal
at 198 pg/mL and increased
to 491 pg/mL after 3 minutes
of standing. The patient was
instructed to discontinue
furosemide and tamsulosin
and switch amitriptyline to
fluoxetine 20 mg/d.
At 4-week follow-up, his
blood pressure in the supine
FIGURE 9-2
position was 142/87 mm Hg
Blood pressure and heart rate of the patient in
with a heart rate of 81 beats/ CASE 9-1 supine and standing. The tracing shows
min. After 3 minutes of severe orthostatic hypotension with a significant
standing, his blood pressure compensatory increase in heart rate, with a
was 131/79 mm Hg with a heart change in heart rate (ΔHR)/change in systolic
blood pressure (ΔSBP) ratio above 0.5 beats per
rate of 92 beats/min. He was minute/mm Hg, indicative of non-neurogenic
asymptomatic. orthostatic hypotension.
COMMENT This is a case of non-neurogenic orthostatic hypotension, a problem

frequently caused by drugs with well-known hypotensive side effects,
including the diuretic furosemide, the α-adrenergic blocker tamsulosin, and
the tricyclic antidepressant amitriptyline. General physical and neurologic
examination are normal, with the exception of severe orthostatic
hypotension with a significant increase in heart rate, a ΔHR/ΔSBP ratio
above 0.5 beats per minute/mm Hg, and plasma norepinephrine levels that
more than doubled upon standing up.
160 FEBRUARY 2020

FIGURE 9-3
Flowchart of the management of neurogenic orthostatic hypotension. Removal of
aggravating factors and initiation of nonpharmacologic measures must always precede the
use of pharmacologic agents.
ΔHR = change in heart rate; ΔSBP = change in systolic blood pressure.
a
Supine.
LIFESTYLE, PHYSICAL ACTIVITY, AND MEALS. Hot, humid weather and

environments cause vasodilatation and exacerbate orthostatic intolerance.
Consequently, hot showers and saunas should be avoided. Short periods of bed
rest worsen neurogenic orthostatic hypotension by causing cardiovascular
deconditioning. The symptomatic burden can result in reluctance to stand up
and avoidance of physical activity; physical immobility and skeletal muscle loss,
in turn, worsen the severity of orthostatic hypotension. This results in a vicious
cycle of deconditioning.55 It is therefore important for patients not to stop
exercising, but to exercise in a recumbent or seated position (eg, using a
stationary bicycle or a rowing machine) as those positions are better tolerated
than the standing position. Exercise in a swimming pool is recommended, as the
hydrostatic pressure of water counteracts the gravity-induced fall in blood
pressure and improves orthostatic tolerance. Of note, patients must be very
careful when getting out of the swimming pool, as the sudden decrease of
hydrostatic pressure when exiting the pool can trigger venous pooling and
worsen symptoms of orthostatic hypotension.
Food digestion is associated with blood pooling within the gastrointestinal
(splanchnic) circulation.56 Normally, this is compensated for by increases in
sympathetic nerve traffic causing splanchnic vasoconstriction. In patients with

neurogenic orthostatic hypotension, however, vasoconstriction is deficient, and

some patients become hypotensive within 2 hours of eating.1,57 This is referred to
as postprandial hypotension, and it is particularly pronounced after high
glycemic index carbohydrate-rich meals. Low glycemic index carbohydrates are
preferable, and frequent smaller meals should be implemented. Alcohol should
be avoided during the daytime as it is a vasodilator. Alternatively, a high-
carbohydrate treat or a glass of alcohol can be reserved for before bedtime, as
these could contribute to managing supine hypertension.
VOLUME EXPANSION. Less intravascular volume causes reduced circulating

blood volume and aggravates the blood pressure drop when standing. This is
particularly relevant in elderly patients who are chronically volume depleted.58 It
is important that patients and families understand the diuretic effects of caffeine
and alcohol, a potent vasodilator. Patients should avoid sugary beverages (eg,
sodas, bottled juices) as high glycemic index carbohydrates can induce or
worsen hypotension.59 Water and salt liberalization are necessary to expand
intravascular volume. Ideally, daily fluid intake should be 2 L to 2.5 L of water. In
patients with neurogenic orthostatic hypotension, bolus water drinking (500 mL
[16 oz]) produces a marked increase in blood pressure.60,61 Bolus water drinking
has a fast pressor effect (the blood pressure increases within 5 to 10 minutes),
which can be useful as a rescue measure, although the effect is relatively short
(30 to 45 minutes). Patients should increase salt intake by adding 1 teaspoon of
salt to a healthy diet. Some patients prefer using salt tablets (0.5 g to 1.0 g),
although they may cause abdominal discomfort.
PHYSICAL COUNTERMANEUVERS. A number of physical countermaneuvers can

help maintain blood pressure and reduce orthostatic symptoms during daily
activities, including leg crossing, standing on tiptoes, stooping, squatting, and
buttock clenching.52 Making sure that patients understand the effect of
gravitational fluid shifts on blood pressure and orthostatic symptoms is key.
Patients should be instructed to change positions gradually and briefly sit before
standing. Straining with a closed glottis and other Valsalva-like maneuvers cause
a sudden and severe fall in blood pressure and should be avoided.
TABLE 9-2 Nonpharmacologic Treatments for Orthostatic Hypotension
◆ Liberalization of salt consumption

◆ Liberalization of water intake (up to 2.5 L/d)
◆ Acute water bolus (drinking 500 mL water)
◆ Sleeping with the head of the bed raised 30 to 45 degrees with the help of an electric bed or
mattress
◆ Physical activity with recumbent exercises (eg, stationary bicycle, rowing machine) or in a
swimming pool
◆ Physical countermaneuvers (eg, standing up slowly, leg crossing, buttock clenching)52
◆ Abdominal binder53
◆ Waist-high compression stockings producing at least 15 mm Hg to 20 mm Hg pressure54
(knee-high or thigh-high stockings are typically not useful)
162 FEBRUARY 2020

COMPRESSION GARMENTS. Elastic compression stockings apply counterpressure KEY POINTS
to the lower limbs and abdomen, reducing venous pooling.54 High-waist
● Because
stockings producing at least 15 mm Hg to 20 mm Hg compression are effective to carbohydrate-rich meals
increase venous return and increase blood pressure. However, a major problem trigger insulin, a potent
with the use of compression stockings is noncompliance. Elderly patients, vasodilator, patients with
patients with movement disorders, and those with sensory neuropathy may neurogenic orthostatic
hypotension should reduce
struggle to put the stockings on, which limits their applicability in everyday
carbohydrate content, eat
life.61 Elastic abdominal binders can be a good alternative.53,62 A recently smaller and more frequent
developed abdominal binder that inflates automatically only on standing and meals, and choose low
provides sustained splanchnic venous compression (40 mm Hg) showed glycemic index
carbohydrates.
promising results in patients with neurogenic orthostatic hypotension.63
● Bolus water drinking
SLEEPING WITH THE HEAD OF THE BED RAISED. Neurogenic supine hypertension produces a marked, albeit
is frequent in patients with neurogenic orthostatic hypotension.6 It is a side short-lived, increase in
effect of antihypotensive treatment, but it also occurs in untreated patients. blood pressure in patients
with neurogenic orthostatic
Managing neurogenic supine hypertension in patients with neurogenic hypotension.
orthostatic hypotension can be challenging, as treating one usually exacerbates
the other. During the daytime, the best treatment is to avoid the supine position. ● Waist-high compression
Patients can sit in a reclining chair with their feet on the floor if they need to nap stockings are effective to
increase blood pressure in
or rest. At night, elevating the head of the bed at least 30 to 45 degrees
patients with neurogenic
(accomplished with an electric bed or mattress) is effective to lower the blood orthostatic hypotension,
pressure.64 Avoiding nocturnal supine hypertension with postural changes reduces although compliance is very
the exaggerated nocturnal diuresis and natriuresis characteristic of these patients, low. Elastic abdominal
binders are a good
therefore reducing the overnight fluid loss and ameliorating orthostatic hypotension
alternative.
in the morning. The use of pressor agents should be avoided within at least 4 hours
before bedtime. Eating high glycemic index carbohydrate snacks or drinking a glass ● Sleeping with the head
of wine right before going to bed contributes to hypotension and can therefore be of the bed raised 30 to
harnessed to decrease nocturnal supine hypertension. 45 degrees reduces
nocturnal hypertension,
thus decreasing natriuresis,
Pharmacologic Management which, in turn, prevents
Despite removal of aggravating factors and implementing nonpharmacologic volume depletion overnight
methods, many patients remain symptomatic and require pharmacologic and improves orthostatic
tolerance the next morning.
treatment.44 Current pharmacologic approaches are based on two complementary
strategies: (1) expanding intravascular volume with fludrocortisone and (2) ● When medications for
increasing peripheral vascular resistance with midodrine, droxidopa, or neurogenic orthostatic
norepinephrine reuptake inhibitors. Selection of one strategy or the other or both hypotension are used,
patients should be taught to
strategies depends on the specific features and needs of each patient as well as the
avoid the flat position, sleep
degree of peripheral sympathetic denervation. Pharmacologic strategies can be with the head of the bed
combined (TABLE 9-3). When medications for neurogenic orthostatic hypotension raised 30 to 45 degrees, and
are implemented, patients should be taught to avoid the horizontal position, sleep measure their own blood
with the head of the bed raised 30 to 45 degrees, and measure their own blood pressure.
pressure. They should provide a series of blood pressure recordings taken over
several days to their clinician, including blood pressure taken when supine, sitting,
and standing upon awakening; before and 1 hour after lunch; and before retiring to
bed. Alternatively, ambulatory blood pressure monitors can be employed.
Ambulatory monitors also measure blood pressure during sleep and can define the
circadian blood pressure patterns before and after pharmacologic treatment.
LOCALIZING THE LESION. When planning therapeutic strategies in patients

with neurogenic orthostatic hypotension, localization of the autonomic

lesion is important and has therapeutic implications (TABLE 9-4). Peripheral

sympathetic neurons are affected in Lewy body disorders (Parkinson
disease, dementia with Lewy bodies, pure autonomic failure) as well as
in amyloidosis and autoimmune autonomic neuropathies but typically
are spared in multiple system atrophy. More accurate than the clinical diagnosis
is to determine the degree of sympathetic denervation by measuring plasma
norepinephrine levels. Because norepinephrine is released by postganglionic
sympathetic neurons, low levels of plasma norepinephrine in a patient with
neurogenic orthostatic hypotension indicates sympathetic denervation (ie, a
peripheral lesion), whereas normal or elevated norepinephrine levels indicate
decentralization (ie, a central lesion),65 although considerable overlap exists.
Determination of norepinephrine levels should be made in patients who are not
taking norepinephrine precursor or reuptake inhibitors.
VOLUME EXPANSION. Two strategies can be used to expand intravascular volume

in patients with orthostatic hypotension: fludrocortisone and erythropoietin.
FLUDROCORTISONE. Fludrocortisone is a synthetic mineralocorticoid that

increases renal sodium and water reabsorption, therefore expanding
intravascular volume and increasing blood pressure in all positions. It also
enhances the pressor effect of adrenergic agonists. Fludrocortisone is perhaps the
most frequently prescribed agent for the treatment of orthostatic hypotension
TABLE 9-3 Mainstream Pharmacologic Treatments for Neurogenic Orthostatic

Hypotension
Treatment Recommended Dosage Mechanism of Action Side Effects
Specifically approved for orthostatic hypotension
Midodrine 2.5–15 mg 2 or 3 times a day Direct α1-adrenergic receptor Supine hypertension,

(dosed morning, midday, and 3–4 agonist piloerection (“goose bumps”),
hours before bedtime) or tailored scalp itching, urinary retention;
to the patient’s needs caution in congestive heart
failure and chronic renal failure
Droxidopa 100–600 mg 3 times a day (dosed Synthetic norepinephrine Supine hypertension, headache,
morning, midday, and 3–4 hours precursor nausea, fatigue; caution in
before bedtime) or tailored to the congestive heart failure and
patient’s needs chronic renal failure
Not specifically approved for orthostatic hypotension
Atomoxetine 10–18 mg 2 times a day Norepinephrine reuptake inhibitor Supine hypertension, insomnia,
irritability, decreased appetite
Fludrocortisone 0.05–0.2 mg once a day; no Synthetic mineralocorticoid, Supine hypertension, hypokalemia,

benefit with dosages higher than volume expander that increases renal failure, edema, target
0.2 mg/d sodium and water reabsorption organ damage; caution in
congestive heart failure
Pyridostigmine 30–60 mg 2 or 3 times a day Acetylcholinesterase inhibitor Abdominal cramps, diarrhea,

sialorrhea, excessive sweating,
urinary incontinence
164 FEBRUARY 2020

despite the fact that it is not approved by the US Food and Drug Administration
(FDA) for this indication. Because activation of renal mineralocorticoid
receptors results in inflammation and fibrosis and may have a direct nephrotoxic
effect leading to a faster decline in renal function and hypertension,66
fludrocortisone should be used with extreme caution in the treatment of
orthostatic hypotension, preferably for short-term periods, and the dosage
should never be higher than 0.2 mg/d. Higher dosages do not improve
therapeutic effects but intensify side effects. Fludrocortisone usually requires at
least 7 days of treatment to exert significant clinical effect. Short-term side
effects are frequent and include supine hypertension, hypokalemia, and ankle
edema.67 Patients receiving fludrocortisone must eat potassium-rich foods or
take potassium supplements (potassium chloride 20 mEq/d) to reduce the risk of
hypokalemia. Long-term use exacerbates hypertension and organ damage,66
including left ventricular hypertrophy68 and renal failure,66 and is associated
with a higher risk of all-cause hospitalization in patients with orthostatic
hypotension.69
ERYTHROPOIETIN. It is important to test for and treat anemia as it is common in

patients with cardiovascular autonomic failure and frequently contributes to
hypotension.48,51 If anemia is deemed to be idiopathic (ie, anemia of chronic
disease), treatment with erythropoietin should be considered. Erythropoietin
increases standing blood pressure and improves orthostatic tolerance in patients
with orthostatic hypotension. Recombinant human erythropoietin is administered
subcutaneously at doses between 25 U/kg and 75 U/kg 3 times a week until the
Distinguishing Features of Peripheral and Central Autonomic Lesions TABLE 9-4

Causing Neurogenic Orthostatic Hypotension
Central Autonomic Lesion

Peripheral Autonomic
Lesiona Multiple System Atrophy Spinal Cord Injury
Plasma norepinephrine levels Usually low Usually normal or high Depends on the level
(<200 pg/mL) (>200 pg/mL) of the lesion
Cardiac MIBG or fluorodopamine Reduced sympathetic Preserved sympathetic Preserved sympathetic

positron emission tomography innervation innervation in most patients innervation
(PET) scan
Hypotension-induced vasopressin Present Absent Present

release
Hypotensive response to Minor Pronounced Unknown

trimethaphan
Pressor response to yohimbine Less pronounced Pronounced Unknown
Pressor response to droxidopa Pronounced Less pronounced Present
Pressor response to atomoxetine Less pronounced Pronounced Unknown
MIBG = metaiodobenzylguanidine.
a
Diabetes mellitus, Parkinson disease, pure autonomic failure, dementia with Lewy bodies, amyloidosis, autoimmune and other causes of
autonomic neuropathy.

patient’s hematocrit returns to normal levels. Lower maintenance doses (25 U/kg
3 times a week) may then be used. Concurrent iron supplementation is typically
required during the period when the hematocrit is increasing.
SYMPATHETIC ENHANCEMENT. Commonly used pharmacologic strategies to

induce vasoconstriction and increase peripheral vascular resistance include the
α1-adrenoceptor agonist midodrine, the norepinephrine precursor droxidopa,
and norepinephrine reuptake inhibitors.
MIDODRINE. Midodrine is an oral prodrug converted peripherally into the

active metabolite desglymidodrine, a selective α1-adrenoceptor agonist that
constricts arteriolar and venous vasculature, thus increasing blood pressure.
The FDA approved midodrine in 1996 for the treatment of symptomatic
orthostatic hypotension after clinical trials showed efficacy to increase standing
blood pressure and improve orthostatic tolerance.70 As with other drugs for
orthostatic hypotension, administration of midodrine increases blood pressure
in all positions. In contrast to fludrocortisone, midodrine is a short-acting
agent. Standing systolic blood pressure increases by 10 mm Hg to 30 mm Hg
approximately 1 hour after a 10-mg dose, with some effect persisting up to
3 hours. Treatment should begin with 2.5 mg or 5 mg, which can then be
increased up to 10 mg 3 times a day. As with other pressor agents, supine
hypertension is common with midodrine; hence, patients should not take it
within 3 to 4 hours before bedtime. Other common side effects are piloerection
(goose bumps), scalp itching, and urinary retention. Midodrine has no effect
on heart rate as it does not stimulate cardiac β-adrenergic receptors and, owing to its
poor diffusion across the blood-brain barrier, has no CNS side effects.
DROXIDOPA. Droxidopa is an oral synthetic amino acid that converts to

norepinephrine.71 Droxidopa is decarboxylated to norepinephrine by
the enzyme aromatic L-amino acid decarboxylase, the same enzyme that
converts levodopa to dopamine. Conversion of droxidopa to norepinephrine
occurs in the remaining sympathetic postganglionic terminals as well as
in non-neuronal tissues, particularly the kidney.72 Droxidopa was approved
in Japan in 1989 for the treatment of neurogenic orthostatic hypotension in
hereditary amyloidosis, Parkinson disease, and multiple system atrophy.71
The FDA approved droxidopa in 2014 after clinical trials showed its efficacy
to improve symptoms of orthostatic dizziness, lightheadedness, or “feeling
about to faint” in adult patients with symptomatic neurogenic orthostatic
hypotension caused by Parkinson disease, multiple system atrophy, pure
autonomic failure, and other rare disorders affecting norepinephrine production,
such as dopamine β-hydroxylase deficiency characterized by defective
norepinephrine release from sympathetic nerves upon standing.73–76
Similar to midodrine, droxidopa is a short-acting agent (FIGURE 9-477,78).
The peak pressor response occurs within approximately 3.5 hours after oral
administration. The recommended dosage varies from 100 mg to 600 mg up to
3 times a day. To identify the best dose for each patient, supervised titration
by a clinician is recommended.79,80 Although in clinical trials droxidopa was
administered 3 times a day, clinical experience shows that the dose of droxidopa
should be individualized to each patient’s needs, taking into account when the
patient is standing and active. For example, in a patient with a movement
166 FEBRUARY 2020

KEY POINTS
● Determining the site of

the autonomic lesion
(central versus peripheral) in
patients with neurogenic
orthostatic hypotension has
important therapeutic
implications. Patients with
central autonomic
dysfunction (ie,
decentralization) have a
more pronounced pressor
response to norepinephrine
reuptake inhibitors, whereas
patients with peripheral
autonomic dysfunction (ie,
denervation) have a more
pronounced pressor
response to norepinephrine
FIGURE 9-4 enhancers and agonists.
Pressor effect of midodrine and droxidopa versus placebo. Midodrine (A) and droxidopa (B)
have a similar short-acting pressor effect profile. Both medications have a fast pressor effect ● For patients who still
beginning approximately 1 hour after oral administration (green arrows). The pressor effect of remain symptomatic despite
midodrine remains for 4 to 5 hours, whereas the pressor effect of droxidopa is slightly longer nonpharmacologic
at 5 to 6 hours. The peak standing systolic blood pressure occurs 1 hour after midodrine measures, stepwise
administration, whereas the peak standing mean blood pressure occurs 3.5 hours after pharmacologic treatment
droxidopa administration. begins with low-dose
Panel A modified with permission from Wright RA, et al, Neurology.77 © 1998 American Academy of fludrocortisone (0.1 mg/d),
Neurology. Panel B modified with permission from Kaufmann H, et al, Circulation.78 © 2003 American Heart
particularly in patients with
Association, Inc.
volume depletion.
● Frequently used
disorder and orthostatic hypotension who is active for only a few hours in the fludrocortisone dosages
range from 0.05 mg/d to
morning (eg, showering, preparing breakfast), it is reasonable to use a single 0.2 mg/d. There is little
morning droxidopa dose and skip the afternoon and evening doses. Other benefit in increasing
patients with different needs may receive droxidopa only 2 times a day or take fludrocortisone to dosages
a higher dose in the morning with lower doses in the afternoon and evening. The higher than 0.2 mg/d.
Common short-term
most robust pressor response occurs in patients with low plasma norepinephrine side effects include
levels, indicating loss of peripheral sympathetic neurons.65 A supine plasma hypokalemia; long-term
norepinephrine level lower than 220 pg/mL in patients with neurogenic side effects include left
orthostatic hypotension has high sensitivity and specificity to predict a pressor ventricular hypertrophy and
renal failure.
response to droxidopa.65
Droxidopa may be less effective in patients with neurogenic orthostatic ● In patients with anemia
hypotension and parkinsonism receiving high dosages of carbidopa (higher than of chronic disease and
200 mg/d) as carbidopa blocks the conversion of droxidopa to norepinephrine.75,76,78,79 orthostatic hypotension,
The most common side effects of droxidopa are hypertension, headache, and subcutaneous recombinant
human erythropoietin
nausea. Although no specific studies have been done, concomitant use of increases blood pressure
droxidopa with norepinephrine reuptake inhibitors (eg, atomoxetine, venlafaxine) and improves orthostatic
or adrenergic agonists (eg, midodrine) may enhance the pressor effect; caution tolerance.
is advised.
● When starting droxidopa,
a careful titration is required
NOREPINEPHRINE REUPTAKE INHIBITORS. An emerging approach in the treatment to identify the best dose for
of neurogenic orthostatic hypotension is the use of inhibitors of the each patient and prevent
norepinephrine membrane transporter, which inhibit norepinephrine excessive supine
hypertension.
reuptake and increase its availability in the neurovascular junction.

In healthy subjects, norepinephrine reuptake inhibition has little effect on

blood pressure. Although norepinephrine reuptake inhibitors enhance
noradrenergic vasoconstriction at the level of the sympathetic postganglionic
fibers, this is counteracted by norepinephrine-mediated stimulation of central
α2-receptors in the CNS, which has a vasodilator effect. However, in patients
with central autonomic dysfunction, norepinephrine reuptake inhibitors result in
only peripheral vasoconstriction, making them particularly suitable for patients
with multiple system atrophy.
Short-term controlled clinical trials have shown that atomoxetine (10 mg to
18 mg, 2 times a day), a short-acting norepinephrine reuptake inhibitor, increases
standing blood pressure and reduces the burden of symptoms compared to
placebo in patients with neurogenic orthostatic hypotension.81–83 The higher
CASE 9-2 A 68-year-old woman with Parkinson disease presented with a 9-month
history of dizziness, lightheadedness, and shortness of breath after
walking for 100 yards and climbing stairs. She had been diagnosed with
Parkinson disease 2 years earlier and was taking carbidopa/levodopa
25 mg/100 mg 3 times a day with excellent response and remaining very
active.
Her blood pressure in the supine position was 148/92 mm Hg with a
heart rate of 69 beats/min. After 3 minutes in the standing position, her
blood pressure was 84/59 mm Hg with a heart rate of 71 beats/min
(change in heart rate [ΔHR]/change in systolic blood pressure [ΔSBP]
ratio of 0.03 beats per minute/mm Hg), and she reported feeling severely
dizzy and lightheaded (FIGURE 9-5). ECG, complete blood cell count, and
metabolic panel were normal. Autonomic testing confirmed neurogenic
orthostatic hypotension with plasma norepinephrine levels of
102 pg/mL when supine and 138 pg/mL when standing.
She was educated on nonpharmacologic measures, including
liberalization of salt and water intake, wearing compression garments
(waist-high stockings), and sleeping with the head of the bed raised 30
to 45 degrees with the help of an electric bed or mattress.
She returned 2 months later reporting symptomatic improvement,
although she still reported dizziness when standing for a few minutes. Her
blood pressure in the supine position was 147/82 mm Hg with a heart rate
of 69 beats/min. After 3 minutes in the standing position, her blood
pressure was 91/79 mm Hg with a heart rate of 72 beats/min, and she
reported feeling moderately dizzy and lightheaded.
Based on her low plasma norepinephrine levels indicating
postganglionic sympathetic denervation, an in-office titration with
droxidopa was performed, after which the patient was started on 300 mg
3 times a day and reminded to avoid the supine position and sleep with
the head of the bed raised 30 to 45 degrees. She returned 1 month later
reporting a significant abatement in her symptoms. Her blood pressure in
the supine position was 151/92 mm Hg with a heart rate of 68 beats/min.
After 3 minutes in the standing position, her blood pressure was 101/81 mm Hg
with a heart rate of 72 beats/min and she remained asymptomatic.
168 FEBRUARY 2020

the norepinephrine level, the greater the pressor effect and symptomatic
improvement with atomoxetine, which makes it a particularly attractive option
for patients with neurogenic orthostatic hypotension caused by autonomic
decentralization (eg, multiple system atrophy).84 A multicenter controlled trial
to confirm the efficacy of atomoxetine in patients with neurogenic orthostatic
hypotension is under way.85 A phase 2 trial with ampreloxetine (TD-9855), a
long-acting investigational norepinephrine reuptake inhibitor, showed that this
compound was safe and increased blood pressure and orthostatic tolerance in
patients with neurogenic orthostatic hypotension; a large multicenter phase
3 study to confirm its efficacy is ongoing.86
Conversely, lower supine plasma norepinephrine levels appear to predict a
greater symptomatic and pressor response to droxidopa, a synthetic oral
FIGURE 9-5
Blood pressure and heart rate of the patient in
CASE 9-2 supine and standing. The tracing shows
severe orthostatic hypotension with no
compensatory increase in heart rate, with a
change in heart rate (ΔHR)/change in systolic
blood pressure (ΔSBP) ratio below 0.5 beats per
minute/mm Hg, indicative of neurogenic
Symptomatic neurogenic orthostatic hypotension afflicts approximately COMMENT

20% of patients with Parkinson disease. The neurogenic origin of orthostatic
hypotension was confirmed in this patient by a ΔHR/ΔSBP ratio below
0.5 beats per minute/mm Hg and a blunted norepinephrine release when
standing up. The stepwise approach for patients with neurogenic orthostatic
hypotension begins with nonpharmacologic measures and, when these are
not sufficient, implementing pharmacologic therapy. Droxidopa, a synthetic
norepinephrine precursor, was expected to produce a pressor response
in this patient given her low plasma norepinephrine levels indicative of
peripheral sympathetic denervation, and as anticipated, it resulted in
significant symptomatic improvement.

CASE 9-3 A 63-year-old man presented for evaluation 10 days after an episode of
brief unresponsiveness and collapse. After a large and typical
Thanksgiving dinner, he stood up, walked a few steps, and suddenly
collapsed to the floor. He was unresponsive but came to in a few
seconds, startled but not confused. His wife was with him and reported
that he had no involuntary movements, loss of urine, or tongue biting. He
was taken by ambulance to a local hospital, where his blood pressure was
160/95 mm Hg. ECG, echocardiogram, complete blood cell count,
metabolic panel, urinalysis, and a 24-hour Holter monitor were normal.
He was diagnosed at that hospital with arterial hypertension, and
antihypertensive treatment was recommended, which he did not take.
On questioning during the current visit, he recalled having brief episodes
of mild lightheadedness and blurry vision when standing up after meals,
mostly after breakfast, for about 2 years. His wife measured his blood
pressure on one of these occasions, and it was approximately 80/60 mm
Hg. His symptoms abated after sitting or lying down, and he had never lost
consciousness until the episode that took him to the hospital. He reported
moderate constipation, erectile dysfunction, and nocturia.
On physical examination, he appeared healthy. He had preserved
cognition, intact cranial nerves, normal deep tendon reflexes, flexor
plantar responses, and no sensory deficits. His supine blood pressure was
157/102 mm Hg with a heart rate of 72 beats/min and after standing for
3 minutes was 119/75 mm Hg with a heart rate of 79 beats/min (change in
heart rate [ΔHR]/change in systolic blood pressure [ΔSBP] ratio of
0.18 beats per minute/mm Hg). He had no orthostatic symptoms in
the office.
He was given an ambulatory 24-hour blood pressure monitor, which
showed symptomatic drops in blood pressure associated with breakfast,
lunch, and dinner, consistent with postprandial hypotension (FIGURE 9-6).
After these findings were reviewed, the patient was contacted over the
phone and instructed to eat smaller and more frequent meals, to decrease
carbohydrate-rich meals during daytime, and to start taking acarbose
100 mg before breakfast, lunch, and dinner for the off-label indication of
lessening his postprandial hypotension. He was instructed to recognize
symptoms of orthostatic hypotension, to quickly sit down to prevent
syncope, and to follow nonpharmacologic measures to increase his
orthostatic tolerance. One month later, the patient came for a follow-up
visit reporting marked improvement in his postprandial symptoms.
170 FEBRUARY 2020

FIGURE 9-6
Ambulatory 24-hour blood pressure monitor results of the patient in CASE 9-3. The orange
horizontal dashed lines denote arbitrary limits for normal blood pressure (140/90 mm Hg during
daytime, 120/70 mm Hg during nighttime). The red tracing denotes systolic and the blue tracing
denotes diastolic blood pressure readings throughout one day. A significant drop in blood pressure
is seen right after breakfast, lunch, and dinner (arrows), consistent with postprandial hypotension.
The tracing also shows nocturnal hypertension while the patient was sleeping, except for an
episode of hypotension when standing as the patient got up to urinate (nocturia).
OH = orthostatic hypotension.
This patient had asymptomatic neurogenic orthostatic hypotension in the COMMENT

office (his blood pressure fell 38/27 mm Hg and his ΔHR/ΔSBP ratio was
below 0.5 beats per minute/mm Hg) with supine hypertension. He became
symptomatic only after meals, consistent with postprandial hypotension. His
autonomic failure (orthostatic hypotension, constipation, erectile dysfunction,
bladder dysfunction) in the absence of motor or sensory deficits is suggestive
of pure autonomic failure. Treatment of postprandial hypotension includes
reducing high glycemic index carbohydrates, eating smaller and more
frequent meals, and using the α-glucosidase inhibitor acarbose. These
patients require close follow-up as they may develop worsening symptoms
of orthostatic hypotension at times other than after meals.

norepinephrine precursor.65 These responses can be explained by denervation

supersensitivity of adrenergic receptors.87 Consequently, patients with low
plasma norepinephrine levels (usually seen in Lewy body disorders [CASE 9-2] or
peripheral autonomic neuropathies) may respond better to droxidopa and
midodrine,65 whereas patients with normal or high norepinephrine levels
(usually multiple system atrophy) may respond better to norepinephrine
reuptake inhibitors.
In patients with refractory neurogenic orthostatic hypotension,
norepinephrine reuptake inhibition could theoretically be combined with
droxidopa or midodrine, with or without fludrocortisone or pyridostigmine.
However, no safety data are available on the combined use of most of these
agents, and extreme caution is advised.
OTHER MEDICATIONS. Pyridostigmine, a cholinesterase inhibitor, enhances

cholinergic neurotransmission in sympathetic and parasympathetic ganglia.
A double-blind study showed that pyridostigmine increases systolic blood pressure,
on average, by only 4 mm Hg.88 The combination of 5 mg midodrine with 60 mg
pyridostigmine was slightly more effective than pyridostigmine alone. Similarly, the
combination of pyridostigmine with atomoxetine appears to have a synergistic
effect to increase blood pressure and improve orthostatic tolerance.89
POSTPRANDIAL HYPOTENSION
Hypotension after meals regularly occurs in patients with sympathetic failure and can
be its only manifestation, even in patients without overt orthostatic hypotension.90
Postprandial hypotension is defined as a fall of at least 10 mm Hg in systolic blood
pressure within 2 hours of eating.1,56,57,90,91 Management starts by eating smaller
and more frequent meals with low carbohydrate content and avoiding alcohol.
Drugs that delay or block the release of insulin, a known vasodilator, such as the
α-glucosidase inhibitor acarbose (50 mg to 100 mg before meals), decrease
gastrointestinal absorption of glucose and are useful to treat postprandial
hypotension (CASE 9-3).59 Midodrine taken right before or during meals may also
help. The somatostatin analogue octreotide induces vasoconstriction of
splanchnic vessels; it is administered subcutaneously (0.2 mcg/kg to 0.4 mcg/kg)
and is very effective to attenuate postprandial hypotension, although it can
induce nausea and abdominal pain.92
NEUROGENIC SUPINE HYPERTENSION

The prevalence of neurogenic supine hypertension is 30% to 50% in Parkinson
disease, 40% in multiple system atrophy, and 50% to 70% in pure autonomic
failure. The frequency of neurogenic supine hypertension in diabetes mellitus
and amyloid neuropathy is unknown.6
Treatment of supine hypertension focuses on reducing blood pressure to
lower the risk of target organ damage without worsening hypotension.
Achieving this goal is challenging. Patients should avoid the supine position. For
daytime naps, patients should sit in a reclining chair with their feet on the floor.
At night, tilting the head of the bed to a 30- or 45-degree angle lowers blood
pressure.64 This is best accomplished with an electric bed or mattress. A
carbohydrate-rich snack or an alcoholic drink before bedtime lowers blood
pressure. The application of an abdominal heating pad to lower blood pressure
by inducing splanchnic vasodilation is being currently studied in a clinical trial.93
172 FEBRUARY 2020

In patients with severe prolonged supine hypertension at night despite KEY POINTS
elevation of the head of the bed (systolic blood pressure of at least 180 mm Hg or
● Treatment with
diastolic blood pressure of at least 110 mm Hg), short-acting antihypertensives norepinephrine reuptake
(eg, captopril 25 mg, losartan 50 mg, or nitroglycerin patch 0.1 mg/h) at bedtime inhibition is emerging as a
could be considered, particularly in patients who already have target organ potentially effective option
damage, although none of these approaches has been studied in large controlled for patients with neurogenic
trials.94–96 Patients should be advised about the augmented risk of hypotension
particularly those with
and falls if they stand up at nighttime (eg, to urinate). To avoid this, the use of a autonomic dysfunction from
urinal or bedside commode should be encouraged. damage to the central
nervous system (eg,
decentralization).
CONCLUSION ● Pyridostigmine alone has
Orthostatic hypotension is a disabling disorder that occurs frequently in the little effect to increase
elderly as a consequence of drug effects, volume depletion, or cardiovascular blood pressure. It appears
deconditioning. Neurogenic orthostatic hypotension is common in patients with to have synergistic effects
when combined with
diseases affecting central or peripheral sympathetic neurons. Patients with
midodrine or atomoxetine.
orthostatic hypotension with no or minor symptoms can be treated with
nonpharmacologic measures only. Patients with a moderate burden of symptoms ● Neurogenic supine
typically require a combination of nonpharmacologic and pharmacologic hypertension is best treated
therapies (eg, the synthetic mineralocorticoid fludrocortisone and the pressor with postural measures, ie,
avoiding the flat position
agents midodrine, droxidopa, or atomoxetine). and sleeping with the head
of the bed raised 30 to
45 degrees with the help of
an electric bed or mattress.
REFERENCES
In patients with refractory
supine hypertension and
1 Freeman R, Wieling W, Axelrod FB, et al. 7 Shibao C, Grijalva CG, Raj SR, et al. Orthostatic high risk of organ damage,
Consensus statement on the definition of hypotension-related hospitalizations in the short-acting
orthostatic hypotension, neurally mediated United States. Am J Med 2007;120(11):975–980.
antihypertensives at
syncope and the postural tachycardia syndrome. doi:10.1016/j.amjmed.2007.05.009.
bedtime might be
Clin Auton Res 2011;21(2):69–72. doi:10.1007/
8 Masaki KH, Schatz IJ, Burchfiel CM, et al. considered.
s10286-011-0119-5.
Orthostatic hypotension predicts mortality in
2 Arenander E. Hemodynamic effects of varicose elderly men: the Honolulu Heart Program.
veins and results of radical surgery. Acta Chir Circulation 1998;98(21):2290–2295. doi.10.1161/
Scand Suppl 1960;(suppl 260):1–76. 01.CIR.98.21.2290.
3 Kaufmann H, Biaggioni I. Autonomic failure in 9 Rutan GH, Hermanson B, Bild DE, et al.
neurodegenerative disorders. Semin Neurol Orthostatic hypotension in older adults. The
2003;23(4):351–363. doi:10.1055/s-2004-817719. Cardiovascular Health Study. CHS Collaborative
Research Group. Hypertension 1992;19(6 pt 1):
4 Kaufmann H, Norcliffe-Kaufmann L, Palma JA,
508–519. doi:10.1161/01.HYP.19.6.508.
et al. Natural history of pure autonomic failure:
a United States prospective cohort. Ann Neurol 10 Fotherby MD, Potter JF. Orthostatic hypotension
2017;81(2):287–297. doi:10.1002/ana.24877. and anti-hypertensive therapy in the elderly.
Postgrad Med J 1994;70(830):878–881.
5 Weaver LC, Fleming JC, Mathias CJ, Krassioukov AV.
Disordered cardiovascular control after spinal 11 Sarasin FP, Louis-Simonet M, Carballo D, et al.
cord injury. Handb Clin Neurol 2012;109:213–233. Prevalence of orthostatic hypotension among
doi:10.1016/B978-0-444-52137-8.00013-9. patients presenting with syncope in the ED. Am J
Emerg Med 2002;20(6):497–501. doi:10.1053/
6 Fanciulli A, Jordan J, Biaggioni I, et al. Consensus
ajem.2002.34964.
statement on the definition of neurogenic supine
hypertension in cardiovascular autonomic failure 12 Feldstein C, Weder AB. Orthostatic hypotension:
by the American Autonomic Society (AAS) and a common, serious and underrecognized
the European Federation of Autonomic Societies problem in hospitalized patients. J Am Soc Hypertens
(EFAS): endorsed by the European Academy of 2012;6(1):27–39. doi:10.1016/j.jash.2011.08.008.
Neurology (EAN) and the European Society of
Hypertension (ESH). Clin Auton Res 2018;28(4):
355–362. doi:10.1007/s10286-018-0529-8.

13 Aung AK, Corcoran SJ, Nagalingam V, et al. 25 Goldstein DS, Holmes C, Sharabi Y, Wu T. Survival
Prevalence, associations, and risk factors for in synucleinopathies: a prospective cohort
orthostatic hypotension in medical, surgical, and study. Neurology 2015;85(18):1554–1561. doi:10.
trauma inpatients: an observational cohort study. 1212/WNL.0000000000002086.
Ochsner J 2012;12(1):35–41. doi:10.1016/j.hlc.
26 Milazzo V, Di Stefano C, Milan A, et al.
2011.05.044.
Cardiovascular complications in patients with
14 Ooi WL, Hossain M, Lipsitz LA. The association autonomic failure. Clin Auton Res 2015;25(3):
between orthostatic hypotension and recurrent 133–140. doi:10.1007/s10286-015-0275-0.
falls in nursing home residents. Am J Med 2000;
27 Garland EM, Gamboa A, Okamoto L, et al.
108(2):106–111. doi:10.1016/S0002-9343(99)00425-8.
Renal impairment of pure autonomic failure.
15 Luukinen H, Koski K, Laippala P, Airaksinen KE. Hypertension 2009;54(5):1057–1061. doi:10.1161/
Orthostatic hypotension and the risk of HYPERTENSIONAHA.109.136853.
myocardial infarction in the home-dwelling
28 Pilleri M, Facchini S, Gasparoli E, et al. Cognitive
elderly. J Intern Med 2004;255(4):486–493.
and MRI correlates of orthostatic hypotension
doi:10.1111/j.1365-2796.2004.01313.x.
in Parkinson’s disease. J Neurol 2013;260(1):
16 Rose KM, Tyroler HA, Nardo CJ, et al. Orthostatic 253–259. doi:10.1007/s00415-012-6627-y.
hypotension and the incidence of coronary heart
29 Kim JS, Oh YS, Lee KS, et al. Association of
disease: the Atherosclerosis Risk in Communities
cognitive dysfunction with neurocirculatory
study. Am J Hypertens 2000;13(6 pt 1):571–578.
abnormalities in early Parkinson disease.
doi:10.1016/S0895-7061(99)00257-5.
Neurology 2012;79(13):1323–1331. doi:10.1212/
17 Angelousi A, Girerd N, Benetos A, et al. Association WNL.0b013e31826c1acd.
between orthostatic hypotension and cardiovascular
30 Jones JD, Jacobson C, Murphy M, et al. Influence
risk, cerebrovascular risk, cognitive decline and
of hypertension on neurocognitive domains in
falls as well as overall mortality: a systematic
nondemented Parkinson's disease patients.
review and meta-analysis. J Hypertens 2014;
Parkinsons Dis 2014;2014:507529. doi:10.1155/
32(8):1562–1571; discussion 1571. doi:10.1097/
2014/507529.
HJH.0000000000000235.
31 Illman A, Stiller K, Williams M. The prevalence of
18 Rose KM, Eigenbrodt ML, Biga RL, et al.
orthostatic hypotension during physiotherapy
Orthostatic hypotension predicts mortality in
treatment in patients with an acute spinal cord
middle-aged adults: the Atherosclerosis Risk In
injury. Spinal Cord 2000;38(12):741–747. doi:10.
Communities (ARIC) Study. Circulation 2006;
1038/sj.sc.3101089.
114(7):630–636. doi:10.1161/CIRCULATIONAHA.
105.598722. 32 Krassioukov A, Eng JJ, Warburton DE, et al. A
systematic review of the management of
19 Xin W, Lin Z, Mi S. Orthostatic hypotension and
orthostatic hypotension after spinal cord injury.
mortality risk: a meta-analysis of cohort studies.
Arch Phys Med Rehabil 2009;90(5):876–885.
Heart 2014;100(5):406–413. doi:10.1136/heartjnl-
doi:10.1016/j.apmr.2009.01.009.
2013-304121.
33 Centi J, Freeman R, Gibbons CH, et al. Effects
20 Verwoert GC, Mattace-Raso FU, Hofman A, et al.
of orthostatic hypotension on cognition in
Orthostatic hypotension and risk of cardiovascular
Parkinson disease. Neurology 2017;88(1):17–24.
disease in elderly people: the Rotterdam study.
doi:10.1212/WNL.0000000000003452.
J Am Geriatr Soc 2008;56(10):1816–1820. doi:10.1111/
j.1532-5415.2008.01946.x. 34 Levine BD, Zuckerman JH, Pawelczyk JA. Cardiac
atrophy after bed-rest deconditioning: a
21 Mol A, Bui Hoang PTS, Sharmin S, et al.
nonneural mechanism for orthostatic intolerance.
Orthostatic hypotension and falls in older adults:
Circulation 1997;96(2):517–525. doi:10.1161/01.
a systematic review and meta-analysis. J Am
CIR.96.2.517.
Med Dir Assoc 2019;20(5):589–597. doi:10.1016/
j.jamda.2018.11.003. 35 Isonaka R, Holmes C, Cook GA, et al. Pure
autonomic failure without synucleinopathy. Clin
22 Spallone V, Ziegler D, Freeman R, et al.
Auton Res 2017;27(2):97–101. doi:10.1007/
Cardiovascular autonomic neuropathy in diabetes:
s10286-017-0404-z.
clinical impact, assessment, diagnosis, and
management. Diabetes Metab Res Rev 2011; 36 Coon EA, Low PA. Pure autonomic failure
27(7):639–653. doi:10.1002/dmrr.1239. without alpha-synuclein pathology: an evolving
understanding of a heterogeneous disease. Clin
23 Vinik AI, Erbas T, Casellini CM. Diabetic cardiac
Auton Res 2017;27(2):67–68. doi:10.1007/s10286-
autonomic neuropathy, inflammation and
017-0410-1.
cardiovascular disease. J Diabetes Investig 2013;
4(1):4–18. doi:10.1111/jdi.12042. 37 Terkelsen AJ, Karlsson P, Lauria G, et al. The
diagnostic challenge of small fibre neuropathy:
24 Zhou Y, Ke SJ, Qiu XP, Liu LB. Prevalence, risk
clinical presentations, evaluations, and causes.
factors, and prognosis of orthostatic hypotension
Lancet Neurol 2017;16(11):934–944. doi:10.1016/
in diabetic patients: a systematic review and
S1474-4422(17)30329-0.
meta-analysis. Medicine (Baltimore) 2017;96(36):
e8004. doi:10.1097/MD.0000000000008004.
174 FEBRUARY 2020

38 Koike H, Atsuta N, Adachi H, et al. Clinicopathological 51 Perera R, Isola L, Kaufmann H. Effect of
features of acute autonomic and sensory recombinant erythropoietin on anemia and
neuropathy. Brain 2010;133(10):2881–2896. doi:10. orthostatic hypotension in primary autonomic
1093/brain/awq214. failure. Clin Auton Res 1995;5(4):211–213. doi:10.
1007/BF01824009.
39 Gibbons CH, Freeman R. Clinical implications of
delayed orthostatic hypotension: a 10-year 52 Krediet CT, van Lieshout JJ, Bogert LW, et al.
follow-up study. Neurology 2015;85(16):1362–1367. Leg crossing improves orthostatic tolerance in
doi:10.1212/WNL.0000000000002030. healthy subjects: a placebo-controlled
crossover study. Am J Physiol Heart Circ Physiol
40 Cheshire WP Jr. Clinical classification of orthostatic
2006;291(14):H1768–H1772. doi:10.1152/
hypotensions. Clin Auton Res 2017;27(3):133–135.
ajpheart.00287.2006.
doi:10.1007/s10286-017-0414-x.
53 Smit AA, Wieling W, Fujimura J, et al. Use of lower
41 Palma JA, Norcliffe-Kaufmann L, Kaufmann H. An
abdominal compression to combat orthostatic
orthostatic hypotension mimic: the inebriation-
hypotension in patients with autonomic
like syndrome in Parkinson disease. Mov D 2016;
dysfunction. Clin Auton Res 2004;14(3):167–175.
31(4):598–600. doi:10.1002/mds.26516.
doi:10.1007/s10286-004-0187-x.
42 Bengtsson-Lindberg M, Larsson V, Minthon L,
54 Diedrich A, Biaggioni I. Segmental orthostatic
et al. Lack of orthostatic symptoms in dementia
fluid shifts. Clin Auton Res 2004;14(3):146–147.
patients with orthostatic hypotension. Clin Auton
doi:10.1007/s10286-004-0188-9.
Res 2015;25(2):87–94. doi:10.1007/s10286-014-
0244-z. 55 Freeman R. Clinical practice. Neurogenic
orthostatic hypotension. N Engl J Med 2008;
43 Norcliffe-Kaufmann L, Kaufmann H, Palma JA,
358(6):615–624. doi:10.1056/NEJMcp074189.
et al. Orthostatic heart rate changes in patients
with autonomic failure caused by neurodegenerative 56 Kooner JS, Raimbach S, Watson L, et al.
synucleinopathies. Ann Neurol 2018;83(3):522–531. Relationship between splanchnic vasodilation
doi:10.1002/ana.25170. and postprandial hypotension in patients with
primary autonomic failure. J Hypertens Suppl
44 Gibbons CH, Schmidt P, Biaggioni I, et al. The
1989;7(6):S40–S41. doi:10.1097/00004872-
recommendations of a consensus panel for
198900076-00017.
the screening, diagnosis, and treatment of
neurogenic orthostatic hypotension and associated 57 Jansen RW, Lipsitz LA. Postprandial hypotension:
supine hypertension. J Neurol 2017;264(8): epidemiology, pathophysiology, and clinical
1567–1582. doi:10.1007/s00415-016-8375-x. management. Ann Intern Med 1995;122(4):
286–295. doi:10.7326/0003-4819-122-4-
45 Palma JA, Gomez-Esteban JC, Norcliffe-
199502150-00009.
Kaufmann L, et al. Orthostatic hypotension in
Parkinson disease: how much you fall or how low 58 Weinberg AD, Minaker KL. Dehydration. Evaluation
you go? Mov Dis 2015;30(5):639–645. doi:10.1002/ and management in older adults. Council on
mds.26079. Scientific Affairs, American Medical Association.
JAMA 1995;274(19):1552–1556. doi:10.1001/
46 Palma JA, Kaufmann H. Epidemiology, diagnosis,
jama.1995.03530190066035.
and management of neurogenic orthostatic
hypotension. Mov Disord Clin Pract 2017;4(3): 59 Shibao C, Gamboa A, Diedrich A, et al. Acarbose,
298–308. doi:10.1002/mdc3.12478. an alpha-glucosidase inhibitor, attenuates
postprandial hypotension in autonomic failure.
47 Kamaruzzaman S, Watt H, Carson C, Ebrahim S.
Hypertension 2007;50(1):54–61. doi:10.1161/
The association between orthostatic hypotension
HYPERTENSIONAHA.107.091355.
and medication use in the British Women’s Heart
and Health Study. Age Ageing 2010;39(1):51–56. 60 May M, Jordan J. The osmopressor response to
doi:10.1093/ageing/afp192. water drinking. Am J Physiol Regul Integr Comp
Physiol 2011;300(1):R40–R46. doi:10.1152/
48 Biaggioni I, Robertson D, Krantz S, et al. The
ajpregu.00544.2010.
anemia of primary autonomic failure and its
reversal with recombinant erythropoietin. 61 Newton JL, Frith J. The efficacy of
Ann Intern Med 1994;121(3):181–186. doi:10. nonpharmacologic intervention for orthostatic
7326/0003-4819-121-3-199408010-00004. hypotension associated with aging. Neurology
2018;91(7):e652–e656. doi:10.1212/WNL.
49 Azarov I, Huang KT, Basu S, et al. Nitric oxide
0000000000005994.
scavenging by red blood cells as a function of
hematocrit and oxygenation. J Biol Chem 2005; 62 Fanciulli A, Goebel G, Metzler B, et al. Elastic
280(47):39024–39032. doi:10.1074/jbc. abdominal binders attenuate orthostatic
M509045200. hypotension in Parkinson's disease. Mov Dis Clin
Pract 2016;3(2):156–160. doi:10.1002/mdc3.12270.
50 Allen BW, Piantadosi CA. How do red blood
cells cause hypoxic vasodilation? The SNO- 63 Okamoto LE, Diedrich A, Baudenbacher FJ, et al.
hemoglobin paradigm. Am J Physiol Heart Circ Efficacy of servo-controlled splanchnic venous
Physiol 2006;291(4):H1507–1512. doi:10.1152/ compression in the treatment of orthostatic
ajpheart.00310.2006. hypotension: a randomized comparison with
midodrine. Hypertension 2016;68(2):418–426.
doi:10.1161/HYPERTENSIONAHA.116.07199.

64 MacLean AR, Allen EV. Orthostatic hypotension 75 Hauser RA, Biaggioni I, Hewitt LA, Vernino S.
and orthostatic tachycardia: treatment with the Integrated analysis of droxidopa for the
“head-up” bed. JAMA 1940;115:2162–2167. doi:10. treatment of neurogenic orthostatic hypotension
1001/jama.1940.02810510038010. in patients with Parkinson disease. Mov Disord
Clin Pract 2018;5(6):627–634. doi:10.1002/
65 Palma JA, Norcliffe-Kaufmann L, Martinez J,
mdc3.12695.
Kaufmann H. Supine plasma NE predicts the
pressor response to droxidopa in neurogenic 76 Biaggioni I, Arthur Hewitt L, Rowse GJ, Kaufmann
orthostatic hypotension. Neurology 2018; H. Integrated analysis of droxidopa trials for
91(16):e1539–e1544. doi:10.1212/WNL. neurogenic orthostatic hypotension. BMC Neurol
0000000000006369. 2017;17(1):90. doi:10.1186/s12883-017-0867-5.
66 Norcliffe-Kaufmann L, Axelrod FB, Kaufmann H. 77 Wright RA, Kaufmann HC, Perera R, et al. A
Developmental abnormalities, blood pressure double-blind, dose-response study of midodrine
variability and renal disease in Riley Day syndrome. in neurogenic orthostatic hypotension.
J Hum Hypertens 2013;27(1):51–55. doi:10.1038/ Neurology 1998;51(1):120–124. doi:10.1212/
jhh.2011.107. WNL.51.1.120.
67 Chobanian AV, Volicer L, Tifft CP, et al. 78 Kaufmann H, Saadia D, Voustianiouk A, et al.
Mineralocorticoid-induced hypertension in Norepinephrine precursor therapy in neurogenic
patients with orthostatic hypotension. N Engl J orthostatic hypotension. Circulation 2003;108(6):
Med 1979;301(2):68–73. doi:10.1056/ 724–728. doi:10.1161/01.CIR.0000083721.49847.D7.
NEJM197907123010202.
79 Kaufmann H. Droxidopa for symptomatic
68 Vagaonescu TD, Saadia D, Tuhrim S, et al. neurogenic orthostatic hypotension: what can
Hypertensive cardiovascular damage in patients we learn? Clin Auton Res 2017;27(7 suppl 1):1–3.
with primary autonomic failure. Lancet 2000; doi:10.1007/s10286-017-0426-6.
355(9205):725–726. doi:10.1016/S0140-6736(99)
80 Claassen D, Lew M. Initiating droxidopa for
05320-9.
neurogenic orthostatic hypotension in a patient
69 Grijalva CG, Biaggioni I, Griffin MR, Shibao CA. with Parkinson disease. Clin Auton Res 2017;
Fludrocortisone is associated with a higher risk of 27(suppl 1):13–14. doi:10.1007/s10286-017-0429-3.
all-cause hospitalizations compared with
81 Okamoto LE, Shibao C, Gamboa A, et al.
midodrine in patients with orthostatic hypotension.
Synergistic effect of norepinephrine transporter
J Am Heart Assoc 2017;6:pii: e006848. doi:10.1161/
blockade and α-2 antagonism on blood pressure
JAHA.117.006848.
in autonomic failure. Hypertension 2012;59(3):
70 Smith W, Wan H, Much D, et al. Clinical benefit 650–656. doi:10.1161/HYPERTENSIONAHA.
of midodrine hydrochloride in symptomatic 111.184812.
orthostatic hypotension: a phase 4,
82 Shibao C, Raj SR, Gamboa A, et al. Norepinephrine
double-blind, placebo-controlled, randomized,
transporter blockade with atomoxetine induces
tilt-table study. Clin Auton Res 2016;26(4):
hypertension in patients with impaired autonomic
269–277. doi:10.1007/s10286-016-0363-9.
function. Hypertension 2007;50(1):47–53. doi:10.
71 Kaufmann H, Norcliffe-Kaufmann L, Palma JA. 1161/HYPERTENSIONAHA.107.089961.
Droxidopa in neurogenic orthostatic hypotension.
83 Ramirez CE, Okamoto LE, Arnold AC, et al.
Expert Rev Cardiovasc Ther 2015;13(8):875–891.
Efficacy of atomoxetine versus midodrine for
doi:10.1586/14779072.2015.1057504.
the treatment of orthostatic hypotension in
72 Lamotte G, Holmes C, Sullivan P, Goldstein DS. autonomic failure. Hypertension 2014;64(6):
Substantial renal conversion of L-threo-3,4- 1235–1240. doi:10.1161/HYPERTENSIONAHA.
dihydroxyphenylserine (droxidopa) to 114.04225.
norepinephrine in patients with neurogenic
84 Shibao C, Martinez J, Palma JA, et al.
orthostatic hypotension. Clin Auton Res 2019;
Norepinephrine levels predicts the improvement
29(1):113–117. doi:10.1007/s10286-018-0564-5.
in orthostatic symptoms after atomoxetine in
73 Kaufmann H, Freeman R, Biaggioni I, et al. patients with neurogenic orthostatic hypotension
Droxidopa for neurogenic orthostatic hypotension: (P5.320). Poster presented at 69th American
a randomized, placebo-controlled, phase 3 trial. Academy of Neurology Annual Meeting,
Neurology 2014;83(4):328–335. doi:10.1212/ April 22–28, 2017; Boston, Massachusetts.
WNL.0000000000000615.
85 ClinicalTrials.gov. Norepinephrine Transporter
74 Elgebaly A, Abdelazeim B, Mattar O, et al. Meta- Blockade, Autonomic Failure (NETAF).
analysis of the safety and efficacy of droxidopa clinicaltrials.gov/ct2/show/NCT02784535?
for neurogenic orthostatic hypotension. Clin cond=02784535&rank=1. Accessed
Auton Res 2016;26(3):171–180. doi:10.1007/s10286- January 7, 2020.
016-0349-7.
86 ClinicalTrials.gov. Clinical Effect of
Ampreloxetine (TD-9855) for Treating snOH
in Subjects With Primary Autonomic Failure.
clinicaltrials.gov/ct2/show/NCT03750552?
cond=NCT03750552&rank=1. Accessed
January 7, 2020.
176 FEBRUARY 2020

87 Jordan J, Shibao C, Biaggioni I. Multiple system 92 Hoeldtke RD, Israe BC. Treatment of orthostatic
atrophy: using clinical pharmacology to reveal hypotension with octreotide. J Clin Endocrinol
pathophysiology. Clin Auton Res 2015;25(1):53–59. Metab 1989;68(6):1051–1059. doi:10.1210/jcem-68-
doi:10.1007/s10286-015-0271-4. 6-1051.
88 Singer W, Sandroni P, Opfer-Gehrking TL, et al. 93 ClinicalTrials.gov. Local Heat Stress in Autonomic
Pyridostigmine treatment trial in neurogenic Failure Patients With Supine Hypertension.
orthostatic hypotension. Arch Neurol 2006;63(4): clinicaltrials.gov/ct2/show/NCT02417415?cond=
513–518. doi:10.1001/archneur.63.4.noc50340. NCT02417415&rank=1. Accessed October 14, 2019.
89 Okamoto LE, Shibao CA, Gamboa A, et al. 94 Arnold AC, Biaggioni I. Management approaches
Synergistic pressor effect of atomoxetine and to hypertension in autonomic failure. Curr Opin
pyridostigmine in patients with neurogenic Nephrol Hypertens 2012;21:481–485. doi:10.1097/
orthostatic hypotension. Hypertension 2019; MNH.0b013e328356c52f.
73(1):235–241. doi:0.1161/HYPERTENSIONAHA.
95 Kaufmann H, Palma JA. Neurogenic orthostatic
118.11790.
hypotension: the very basics. Clin Auton Res
90 Pavelić A, Krbot Skorić M, Crnošija L, Habek M. 2017;27:39–43. doi:10.1007/s10286-017-0437-3.
Postprandial hypotension in neurological
96 Di Stefano C, Maule S. Treatment of supine
disorders: systematic review and meta-analysis.
hypertension in autonomic failure: a case series.
s10286-017-0440-8.
s10286-017-0437-3.
91 Abbas R, Tanguy A, Bonnet-Zamponi D, et al. New
simplified screening method for postprandial
hypotension in older people. J Frailty Aging 2018;
7(1):28–33. doi:10.14283/jfa.2018.2.
DISCLOSURE
Continued from page 154
the Familial Dysautonomia Foundation, Inc; the

Michael J. Fox Foundation for Parkinson's Research;
the Multiple System Atrophy Coalition; the National
Institutes of Health (R01HL103988, U54NS065736);
Theravance Biopharma; and the US Food and Drug
Administration (FDR3731-01) and publishing royalties
from UpToDate, Inc. Dr Kaufmann has served as an
expert witness for the Department of Justice
regarding the alleged relationship between human
papilloma virus vaccination and autonomic
disorders.

REVIEW ARTICLE

Lower Urinary Tract
ONLINE
and Bowel Dysfunction
in Neurologic Disease
By Jalesh N. Panicker, MD, DM, FRCP; Ryuji Sakakibara, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of the clinical
presentation, investigations, and treatment options for lower urinary tract
and bowel dysfunction in patients with neurologic diseases.
RECENT FINDINGS: The site of the neurologic lesion influences the pattern
of lower urinary tract dysfunction. Antimuscarinic agents are first-line
management for urinary incontinence; however, the side effect profile should
be considered when prescribing them. β3-Receptor agonists are a promising
CITE AS: alternative oral medication. Botulinum toxin injections into the detrusor
C O N T I N U U M ( M I N N E AP M I N N ) have revolutionized the management of neurogenic detrusor overactivity.
Bowel dysfunction commonly presents as constipation and fecal
178–199.
incontinence. Gastrointestinal emergencies may arise, including intestinal
Address correspondence to pseudoobstruction, intussusception, volvulus, and stercoral ulcer (ulcer of
Dr Jalesh Panicker, Department the colon due to pressure and irritation resulting from severe, prolonged
of Uro-Neurology, The National
Hospital for Neurology and
constipation). Bowel function tests in neurologic patients often show a
Neurosurgery and UCL Queen combination of slow transit and anorectal dysfunction. Management for
Square Institute of Neurology, slow transit constipation includes bulking agents, softening agents,
London, United Kingdom,
j.panicker@ucl.ac.uk. yogurt/probiotics, and prokinetic agents. Suppositories, botulinum toxin
injections, and transanal irrigation are options for managing anorectal
constipation.
Dr Panicker has received
personal compensation for
speaking engagements from SUMMARY: Functions of the lower urinary tract and bowel are commonly
Astellas Pharma Inc and
Wellspect HealthCare and
affected in neurologic disease. Neurologists play an important role
receives research/grant support in assessing lower urinary tract and bowel symptoms in their patients
from the United Kingdom’s and planning treatment strategies, often in collaboration with
Department of Health National
Institute of Health Research specialist teams.
Biomedical Research Centres
funding scheme and publishing
royalties from Cambridge
University Press. Dr Sakakibara INTRODUCTION
L
reports no disclosure.
ower urinary tract and bowel dysfunction commonly accompany
UNLABELED USE OF neurologic disease and have a significant impact on quality of life.
PRODUCTS/INVESTIGATIONAL The high prevalence of symptoms reflects the complex distribution of
USE DISCLOSURE:
Drs Panicker and Sakakibara
neural control of the lower urinary tract and bowel across the central
report no disclosures. and peripheral nervous systems. This article presents an overview of
the evaluation of patients with neurologic diseases who report lower urinary
© 2020 American Academy tract and bowel symptoms and reviews treatment options that are currently
of Neurology. available.
178 FEBRUARY 2020

THE NEUROGENIC BLADDER KEY POINT
The term neurogenic bladder is an oversimplification of lower urinary tract
● The site of the neurologic
dysfunction occurring following neurologic disease. Depending upon the site of lesion influences the pattern
the lesion in the neuraxis, different patterns of dysfunction may occur of lower urinary tract
(FIGURE 10-1).1 Suprapontine lesions affect the ability of the bladder to store dysfunction. Symptoms of
urine because of reduced bladder wall compliance and spontaneous involuntary an overactive bladder
(urinary urgency, increased
contractions of the detrusor, termed detrusor overactivity. Urinary incontinence
daytime frequency,
following neurologic disease is most commonly due to detrusor overactivity. nocturia, and, often,
Injury to the suprasacral pathways in the spinal cord also results in storage incontinence) are the most
dysfunction. Additionally, the normally coordinated activity between the common presentation.
detrusor and urethral sphincters during voiding becomes impaired, and the
detrusor and urethral sphincters contract simultaneously, a condition termed
detrusor sphincter dyssynergia. Voiding dysfunction results in incomplete
emptying of the bladder and urinary retention. Injury to the conus medullaris,
sacral roots of the cauda equina, or peripheral nerves results primarily in voiding
dysfunction from poorly sustained detrusor contractions or a nonrelaxing
sphincter, or both. Variations from these expected patterns of dysfunction
warrant a search for additional urologic pathologies or even additional neurologic
sites of localization.
Lower Urinary Tract Dysfunction in Specific Neurologic Disorders

Lower urinary tract dysfunction is commonly reported in various
neurologic disorders.
FIGURE 10-1
Patterns of lower urinary tract dysfunction following neurologic disease. The pattern
depends upon the site of the lesion. Schematic diagrams of the bladder on the right show the
expected pattern of dysfunction of the detrusor and sphincter.
a
Reprinted with permission from Panicker JN, et al, Lancet Neurol.1 © 2015 Elsevier Ltd.

LOWER URINARY TRACT AND BOWEL DYSFUNCTION
PARKINSON DISEASE AND MULTIPLE SYSTEM ATROPHY. The prevalence of

lower urinary tract symptoms in Parkinson disease ranges between 38% and 71%
and is influenced by the extent of neurologic disease, the presence of urologic
comorbidities, and the presence of other manifestations of autonomic
dysfunction.2–4 Lower urinary tract symptoms are the most common nonmotor
symptoms reported in Parkinson disease5 and are associated with an increased
risk for falls,6 early institutionalization, and escalating health-related costs.7
Both an overactive bladder and nocturnal polyuria can contribute to nocturia.8,9
Lower urinary tract symptoms in multiple system atrophy (MSA) may
precede other neurologic manifestations. In the early stages of MSA,
incontinence usually arises from detrusor overactivity and external sphincter
weakness; however, as the disease progresses, incomplete bladder emptying
begins to manifest.10 The finding of an open bladder neck in video urodynamic
studies in men who have not undergone surgery to the bladder outlet is a
suggestive sign of the sympathetic denervation of the bladder neck seen
in MSA.11
MULTIPLE SCLEROSIS AND OTHER DEMYELINATING DISORDERS. Lower urinary

tract symptoms are reported in 32% to 96% of patients with multiple sclerosis
(MS) and increase with the duration of disease. The first symptoms are reported,
on average, 6 years into the illness, and more than 90% of patients report
symptoms if the duration of disease exceeds 10 years.12 However, nearly 10% of
patients report lower urinary tract symptoms at the time of initial diagnosis.12
Symptoms most often result from lesions of the spinal cord, and a correlation
exists between lower urinary tract symptoms and lower limb pyramidal
findings.13 Symptoms may be overlooked, however; the results of a 2010 survey
suggest that only 43% of patients with MS with moderate to severe overactive
bladder symptoms had their symptoms evaluated by a urologist.14 Urinary
incontinence is considered by patients to be one of the worst aspects of the
disease, with most patients classifying the impact symptoms have on their life as
moderate or high.15 Most commonly, both storage and voiding symptoms are
reported. The most common findings in urodynamic testing are detrusor
overactivity and detrusor sphincter dyssynergia.16
Lower urinary tract dysfunction is common following acute disseminated
encephalomyelitis (ADEM), and, as in MS, the severity of symptoms is
associated with the degree of lower limb pyramidal involvement.17 Findings of
detrusor sphincter dyssynergia and detrusor overactivity are reported in patients
with neuromyelitis optica (NMO) spectrum disorder; the extent of lower urinary
tract symptoms is influenced by the severity of the disease18 and can significantly
impact quality of life.19
Urinary Retention
Urinary retention may occur in various neurologic conditions (TABLE 10-1) and
may occur due to either an impairment of contractility of the detrusor or a failure
of relaxation of the sphincter.20 Medications such as opiates,21 drugs with
anticholinergic properties (eg, antipsychotics, antidepressants, respiratory
agents with anticholinergic effects, and antimuscarinic agents for the bladder),
and α-adrenoceptor agonists may be associated with different degrees of voiding
dysfunction ranging from incomplete bladder emptying to complete urinary
retention.
180 FEBRUARY 2020

Urinary retention is relatively uncommon in young women, and if no
underlying urologic or neurologic disease can be established, a primary disorder
of urethral sphincter relaxation known as Fowler syndrome should be considered.
Women typically present with painless urinary retention, often with volumes
exceeding 1 liter in the absence of a sensation of bladder fullness. They often
experience difficulty performing intermittent catheterization, especially when
attempting to remove the catheter. Urethral sphincter EMG reveals a
characteristic pattern of abnormal activity, and the urethral pressure profile is
usually elevated. Sacral neuromodulation, a proven treatment option for bladder
and bowel control involving an implanted neurostimulator and lead that
electrically stimulates the sacral nerve root and, more recently, sphincter
injections of botulinum toxin have been shown to be effective treatments.22,23
The Risk for Upper Urinary Tract Damage

Detrusor overactivity and detrusor sphincter dyssynergia can result in high
pressures within the lower urinary tract, which may subsequently affect the
upper urinary tract, resulting in vesicoureteric reflux, hydronephrosis, and, in
some instances, renal impairment and end-stage renal disease. Patients with
spinal cord injury or spina bifida are more likely to develop these problems,24
whereas the prevalence of upper urinary tract damage and renal failure is much
Differential Diagnosis for Urinary Retention in a Patient When a Structural TABLE 10-1
Urologic Lesion Has Been Excludeda
Lesions of the Conus Medullaris or Cauda Equina

◆ Compressive lesions
◇ Spinal fracture
◇ Intervertebral disk prolapse
◇ Space-occupying lesions (tumor, granuloma, abscess)
◆ Noncompressive lesions
◇ Vascular (infarction, arteriovenous malformation)
◇ Inflammation (myelitis, meningitis retention syndrome)
◇ Infection (herpes simplex, varicella-zoster, cytomegalovirus, Elsberg syndrome [viral
aseptic meningitis])
Other Neurologic Conditions
◆ Spina bifida
◆ Multiple system atrophy
◆ Autonomic failure (pure autonomic failure, autonomic neuropathies)
◆ Nerve injury following radical pelvic surgery
Miscellaneous
◆ Medications (opiates, anticholinergics)
◆ Fowler syndrome (females)
a
Data from Smith, MD, et al, Pract Neurol.20 © 2013 BMJ Publishing Group Limited.

lower in patients with slowly progressive nontraumatic neurologic disorders such

as MS (in which the risk for urinary tract complications is related to the length of
disease and severity of disability),25 Parkinson disease, and hereditary spastic
paraplegia.26 The reasons for this are unclear; however, the management of
neurogenic lower urinary tract dysfunction should include an assessment of the
risk of developing upper urinary tract damage. Whereas those at high risk of upper
urinary tract damage require close lifelong urologic supervision, patients with
progressive neurologic disease who are at lower risk of developing upper urinary
tract damage are much more troubled by poor lower urinary tract control and are
most often being followed by neurologists; this article focuses on the management
of lower urinary tract dysfunction in this group of patients with low risk.
Evaluation and Management of Lower Urinary Tract Dysfunction

Different assessments needed to evaluate a patient with a neurologic disorder
with lower urinary tract dysfunction are presented in TABLE 10-2.
Management of lower urinary tract dysfunction requires a multidisciplinary
approach involving neurologists, urologists, physical medicine and rehabilitation
specialists, and primary care physicians. The different aims of treatment include
achieving urinary continence, improving quality of life, preventing urinary
tract infections, and preserving upper urinary tract function.27 TABLE 10-3
presents an overview of therapeutic strategies.28
MANAGING STORAGE DYSFUNCTION. Various alternatives are available for

managing urinary storage symptoms, including antimuscarinic agents, β3-
receptor agonists, desmopressin, botulinum toxin, and tibial neuromodulation.
ANTIMUSCARINIC AGENTS. Antimuscarinic agents are the first-line management

for overactive bladder, including urge incontinence. Competitive antagonism of
the muscarinic receptors results in detrusor relaxation and lower intravesical
pressures. The M2 muscarinic receptor is widely distributed throughout the
detrusor, urothelium, and suburothelium; however, it is the M3 receptor that is
TABLE 10-2 Assessment of the Patient With Neurologic Disease Reporting Lower
Urinary Tract Symptomsa
Essentialb Desirable Required in Specific Situations
Bedside History taking, bladder diary Lower urinary tract–specific NA

symptoms and quality-of-life
questionnaires
Noninvasive Urinalysis, bladder scan or in-out Uroflowmetry, blood Urine culture, urine cytology
tests catheterization to measure postvoid biochemistry
residual, ultrasonography
Invasive tests NA NA Video urodynamics, cystoscopy,

pelvic neurophysiology, renal
scintigraphy
a
Modified with permission from Panicker JN, et al, Lancet Neurol.1 © 2015 Elsevier Ltd.
b
In the opinion of the authors.
182 FEBRUARY 2020

functionally most relevant to bladder contractility.29 Since the introduction of
oxybutynin, several newer antimuscarinic agents have been introduced
(TABLE 10-4) and have been shown to be efficacious in patients with neurologic
diseases (CASE 10-1).30 The effects of different agents are comparable, whereas
the extent of side effects varies depending upon the degree of selectivity for
muscarinic receptors across different organs.31 Side effects include dry mouth,
blurred vision for near objects, constipation, and tachycardia; many of these
symptoms are already reported by patients because of their neurologic
conditions. The postvoid residual may increase after starting an antimuscarinic
agent and therefore should be monitored in case of a poor response to treatment
or paradoxical worsening of symptoms.32
Antimuscarinic agents can cross the blood-brain barrier and through their
effects on central muscarinic receptors can result in adverse effects such as
alterations in cognition and consciousness. Using medications with
anticholinergic properties may affect the central effects of acetylcholine in
attention and memory; this is associated with worsening cognitive function, a
decline in physical abilities, increasing risk for falls, and even signs of brain
atrophy on imaging.33–35 Caution is therefore advised when prescribing an
antimuscarinic agent, particularly in susceptible individuals such as the elderly,
and antimuscarinics with potentially less impact on cognition (eg, trospium
chloride or darifenacin) should be considered.36–39
β3 - RECEPTOR AGONISTS . The β3-receptor agonist mirabegron was recently

approved for managing overactive bladder symptoms by the US Food and Drug
Administration (FDA) and European Medicines Agency in 2012. Although devoid
of the adverse effects reported with antimuscarinic agents, side effects affecting
Management of Lower Urinary Tract Symptoms in the Patient With TABLE 10-3
Neurologic Diseasea
Conservative Treatments
◆ Behavioral therapy
◆ Antimuscarinic agents
◆ β3-receptor agonists
◆ Desmopressin
◆ Tibial neuromodulation
◆ OnabotulinumtoxinA injections into the detrusor
Surgical Treatments
◆ Sacral neuromodulation
◆ Bladder augmentation
◆ Sacral deafferentation and anterior root stimulation
◆ Continent/incontinent diversion
a
Modified with permission from Panicker JN, Continuum (Minneap Minn).28 © 2017 American Academy of
Neurology.

the cardiovascular system do occur, including palpitations, raised blood pressure,

and, rarely, atrial fibrillation.40 Studies suggest that mirabegron is efficacious in
patients with MS and spinal cord injuries with tolerable side effect profiles.41,42
DESMOPRESSIN . Desmopressin, a synthetic analogue of arginine vasopressin,

temporarily reduces urine production by promoting fluid reabsorption at the
time of renal excretion. It is useful for the treatment of nocturia in MS, providing
symptom relief for up to 6 hours,43 as well as for managing nocturnal polyuria.
Patients should be monitored for side effects, including hyponatremia or
fluid overload.
BOTULINUM TOXIN . Since the first reports of the use of botulinum toxin injections
into the detrusor in patients with spinal cord injuries,44,45 onabotulinumtoxinA
has become an FDA-approved second-line option for adults (Class IIb, Category
B) for treating neurogenic detrusor overactivity–related incontinence based on
the results of two pivotal phase 3 studies that demonstrated the treatment to be
highly effective, safe, and well tolerated.46,47 The approved dosage is 200 units
of onabotulinumtoxinA delivered through flexible or rigid cystoscopy as
20 to 30 injections into the bladder wall (CASE 10-2). A risk for developing
TABLE 10-4 List of Antimuscarinic Agents Used in the Management of Overactive

Bladder Symptomsa
Antimuscarinic Agentb Preparation Dosage Frequency
Darifenacin Extended release 7.5–15 mg Once daily
Fesoterodinec Extended release 4–8 mg Once daily
Oxybutynin Immediate release 2.5–5 mg 2 or 3 times a day
Extended release 5–20 mg Once daily
Transdermal patch 36 mg, releasing oxybutynin Replace once every 3–4 days
approximately 3.9 mg/24 h
Propiverined Immediate release 15 mg 1 to 3 times a day
Extended release 30 mg Once daily

e
Solifenacin Immediate release 5–10 mg Once daily
Tolterodinef Immediate release 2–4 mg 1 or 2 times a day
Trospium chloride Immediate release 20 mg 2 times a day (before food)
a
Modified with permission from Panicker JN, Continuum (Minneap Minn).28 © 2017 American Academy of Neurology.
b
Side effects include dry mouth, blurred vision for near objects, constipation, and tachycardia.
c
In patients taking potent cytochrome P-450 3A4 inhibitors, the dosage of fesoterodine should not exceed 4 mg/d.
d
Propiverine is not available in the United States.
e
In patients taking potent cytochrome P-450 3A4 inhibitors, the dosage of solifenacin should not exceed 5 mg/d.
f
In patients taking potent cytochrome P-450 3A4 inhibitors, the dosage of tolterodine immediate release should not exceed 4 mg/d.
184 FEBRUARY 2020

A 24-year-old man with a 6-year history of multiple sclerosis with mild CASE 10-1
neurologic disability (Expanded Disability Status Scale [EDSS] score of
3.0) presented to a uro-neurology clinic for evaluation of a 3-year history
of symptoms of urinary urgency, increased daytime frequency (7 to 8
times a day), and nocturia (3 times a night). He experienced weekly
episodes of incontinence associated with urinary urgency. Additionally,
he described urinary hesitancy and an interrupted urinary stream. He also
reported constipation, abdominal bloating, and cramps that he was
managing through alterations in diet.
He had brought in a 72-hour bladder diary that he had been requested
to fill out before this visit, and the findings were consistent with an
overactive bladder. He noted in the diary that he was consuming four
cups of coffee a day.
Further assessment showed that his urine was clear of an infection,
and ultrasonography of his kidneys and bladder was normal and
demonstrated a postvoid residual of 60 mL. Urea and creatinine levels
were normal.
Since he had urinary storage symptoms (overactive bladder symptoms)
and the postvoid residual was low, the risk for upper urinary tract damage
was considered to be low. Therefore, he did not undergo urodynamic
testing. He was advised to reduce coffee and carbonated beverage
intake, and, after the benefits and potential adverse effects of
antimuscarinic agents were explained to him, he elected to begin
solifenacin 5 mg once a day.
At follow-up 3 months later, his incontinence had improved markedly.
However, daytime frequency and nocturia continued to be intrusive. The
postvoid residual was checked and found to be 70 mL. As he was
tolerating solifenacin, the dosage was increased to 10 mg once a day.
At follow-up another 3 months later, his daytime symptoms had
improved considerably. However, he was still waking up 2 to 3 times a
night with the urge to urinate. The option of adding desmopressin was
discussed, and, after checking his baseline sodium level, he was started
on intranasal desmopressin 10 mcg with the plan for periodic monitoring
of his serum sodium levels by his primary care provider.
At follow-up 6 months later, he was satisfied with the degree of
improvement in nocturia and chose to continue with treatment.
This case exemplifies the first-line assessment of patients reporting lower COMMENT
urinary tract dysfunction and the selection of treatment options initially
and at follow-up.

urinary retention exists, and before undergoing treatment, patients should be

counseled about the possibility of requiring to use a catheter. Long-term data
confirm the efficacy and cost-effectiveness of repeat injections.48–50
TIBIAL NEUROMODULATION. Tibial nerve stimulation has been shown

to be a safe and effective treatment for the treatment of overactive bladder
CASE 10-2 A 24-year-old man sustained a fracture of the T9 vertebra in a motorcycle

accident and was diagnosed with an incomplete spinal cord injury
(American Spinal Injury Association [ASIA] Impairment Scale D) with
neurologic level at L1; he was conservatively managed.
On follow-up, he reported that he was experiencing urinary urgency
and incontinence on a daily basis, and a 72-hour bladder diary revealed
five to six episodes of incontinence daily that were associated with
urinary urgency. He required two to three pads per 24 hours, and the pads
were often drenched.
His urine was clear of an infection, and ultrasonography of his kidneys
and bladder was normal. His postvoid residual was consistently in the
range of 150 mL to 200 mL. Urea and creatinine levels were normal. He
underwent video urodynamic testing, which showed detrusor
overactivity and incontinence, detrusor sphincter dyssynergia, and
evidence for grade I vesicoureteric-renal reflux. The continence team
showed him how to perform intermittent self-catheterization, and he was
started on an antimuscarinic agent, tolterodine 4 mg/d.
At follow-up 3 months later, he was catheterizing 7 times per 24 hours,
with catheterization volumes of 150 mL to 200 mL. He attributed the high
catheterization frequency to urinary urgency; however, he was still
becoming incontinent. Moreover, his constipation became worse after
starting tolterodine.
Further treatment options were discussed, and, considering the greater
risk for developing upper urinary tract damage, he proceeded with
botulinum toxin injections. OnabotulinumtoxinA (200 units) was injected
into the detrusor using a flexible cystoscope under local anesthesia. After
14 days, he no longer reported urinary urgency. The video urodynamics
study was repeated and showed his detrusor overactivity and reflux had
resolved. He continued to self-catheterize but was able to reduce the
catheterization frequency to 4 to 5 times per day.
The benefits of the injection lasted for around 10 months, at which time
he began to experience urinary urgency and increased daytime and
nighttime frequency again. Intradetrusor injections of onabotulinumtoxinA
(200 units) were repeated, and he reported a significant improvement in
symptoms thereafter.
COMMENT This case exemplifies how the assessment and management of lower
urinary tract dysfunction differs when patients are deemed to be at higher
risk for developing upper urinary tract damage.
186 FEBRUARY 2020

symptoms.51 Percutaneous tibial nerve stimulation involves stimulating the KEY POINTS
nerve near the medial malleolus using a fine-gauge needle; a course of treatment
● The risk of developing
has been shown to improve bladder storage symptoms and urodynamic upper urinary tract damage
parameters in patients with neurologic diseases.52,53 A typical treatment course is considerably lower in
consists of using a fixed-frequency electrical signal for 30 minutes over the patients with slowly
course of 12 sessions. Percutaneous tibial nerve stimulation is an effective option progressive nontraumatic
neurologic disorders than in
for managing mild to moderate overactive bladder symptoms with few adverse
those with spinal cord injury
effects. Moreover, percutaneous tibial nerve stimulation does not worsen or spina bifida.
voiding difficulties or increase the postvoid residual, unlike other treatments
such as antimuscarinic agents or botulinum toxin.54 However, effects are ● Antimuscarinic agents are
relatively short-lived, and the need to return for maintenance treatments is the first-line management of
urinary incontinence;
influenced by the degree of improvement of lower urinary tract symptoms.55 however, their side effect
Transcutaneous tibial nerve stimulation involves stimulating the nerve near profile and impact on
the medial malleolus through a cutaneous electrode. It may be performed at anticholinergic burden
home and has been shown to be safe and effective in patients with MS and should be considered when
prescribing in patients who
stroke experiencing urgency incontinence.56,57 The advantages of tibial are susceptible.
neuromodulation are that the treatment is noninvasive or minimally invasive
and adverse effects are almost nonexistent. ● β3-Receptor agonists are
a promising new oral
treatment for managing
MANAGING VOIDING DYSFUNCTION. The postvoid residual should be routinely
storage symptoms in
measured during the workup of every patient with neurologic disease reporting patients with neurologic
lower urinary tract symptoms. A significantly elevated postvoid residual may diseases.
exacerbate overactive bladder symptoms and render treatments such as
antimuscarinics and botulinum toxin less effective. Moreover, a high postvoid ● Intradetrusor
onabotulinumtoxinA
residual volume predisposes the patient to recurrent urinary tract infections.58 injections are a highly
The use of intermittent catheterization therefore greatly improves management. effective and minimally
However, the volume considered to be substantial enough to initiate intermittent invasive treatment for
self-catheterization remains undetermined. As the bladder capacity is often storage dysfunctions.
reduced in patients with neurologic diseases, a postvoid residual consistently ● Percutaneous tibial nerve
more than 100 mL is often considered abnormal, warranting treatment if stimulation is a minimally
symptomatic.32 invasive option for managing
A high postvoid residual is managed by intermittent self-catheterization. A patients with mild to
moderate overactive
physical or occupational therapist or urology nurse should be involved in
bladder symptoms and is
teaching the technique. The assessment of a patient for intermittent associated with few adverse
self-catheterization should include a review of neurologic deficits that can be effects.
impediments to self-catheterization, such as poor manual dexterity, truncal
imbalance, tremor, spasticity, impaired visual acuity, or cognitive impairment.59 ● The postvoid residual
should be routinely
Patients with urinary retention should perform catheterization 4 to 6 times per measured during the workup
day; however, the frequency is influenced by several factors, such as bladder of every patient with
capacity, fluid intake, and the degree of urinary retention. The incidence of neurologic disease reporting
symptomatic urinary tract infections is low when intermittent catheterization is lower urinary tract
symptoms.
performed regularly.32,58 In patients for whom intermittent catheterization is not
suitable, a urethral or (preferably) suprapubic indwelling catheter should ● A high postvoid residual is
be considered. important to recognize as it
may contribute to storage
(overactive bladder)
Referral to a Urologist
symptoms and can
A care pathway for managing lower urinary tract dysfunction in patients with predispose to recurrent
progressive nontraumatic neurologic disorders includes evaluating lower urinary urinary tract infections.
tract symptoms, risk assessment for upper urinary tract impairment, and regular
review after instituting treatment. The algorithm in FIGURE 10-2 outlines the

KEY POINTS first-line assessment of patients with

MS reporting lower urinary tract
● Bowel dysfunction is
common in patients with
symptoms.32 In some situations,
neurologic diseases. however, a urologist should be
involved in the care of patients
● Bowel dysfunction not (TABLE 10-5).
only affects patients’
quality of life but may also
lead to gastrointestinal Follow-up for Patients With
emergencies. Lower Urinary Tract Dysfunction
Follow-up of patients with
neurologic diseases who have lower
urinary tract dysfunction should
reflect the severity of lower urinary
tract symptoms and the risk for
developing upper urinary tract
damage.27 Individuals at a greater
risk for upper tract damage should
have more regular follow-up aiming
to achieve an optimal quality of life
and protect the upper urinary tract.
LOWER BOWEL DYSFUNCTION

Functional constipation is common
in the general population60,61 and is
defined as at least two episodes of
any kind of defecation difficulty per
week or fewer than three
spontaneous bowel movements per
FIGURE 10-2 week, according to the Rome IV
Algorithm for the first-line management of criteria, an international definition
lower urinary tract symptoms in patients with
progressive neurologic disorders such as
of gut terminology.62 The
multiple sclerosis. prevalence of constipation increases
CISC = clean intermittent self-catheterization; PVR = with age (up to 50% among
postvoid residual; UTI = urinary tract infection.
octogenarians), significantly affects
Reprinted with permission from Fowler CJ, et al, J Neurol
32
Neurosurg Psychiatry. © 2009 BMJ Publishing Group. quality of life, and causes substantial
morbidity.60,61 Constipation may
occur after reduced dietary fiber
consumption and reduced physical exercise.60,61 It is well known that neurologic
diseases can produce severe gastrointestinal dysfunction, particularly
constipation. This reflects the rich innervation of the bowel by the enteric
nervous system under the extrinsic control of the parasympathetic and
sympathetic systems.
The parasympathetic innervation is provided by the vagus nerve except
for the descending colon, sigmoid, and rectum, which are innervated by the
sacral parasympathetic system. As in the case of the urinary system, the Onuf
nucleus provides somatic innervation to the external rectal sphincter and
pelvic floor. Whereas the role of supratentorial and brainstem structures in
control of lower gastrointestinal function in humans is less well documented
than in control of bladder function, indirect evidence from clinical effects of
lesions suggests involvement of the medial frontal cortex. Animal studies
188 FEBRUARY 2020

indicate that the pelvic organ control center (formerly called the Barrington
nucleus or pontine micturition center) controls the functions of all pelvic
organs, including the rectum. The nucleus retroambiguus in the medulla,
which is involved in expiration, also provides excitatory output to the Onuf
nucleus to prevent incontinence in the setting of increased intraabdominal
pressure.
Frequency and Symptoms of Bowel Dysfunction

Bowel dysfunction affects most patients with a chronic spinal cord injury. Up to
95% report constipation, and fecal incontinence is experienced at least once per
year by 75% and daily by 5%, depending on the level of injury; upper motor
neuron lesions (cervical-thoracic) result in more severe bowel dysfunction
than lower motor neuron lesions (lumbar).60,63,64 Bowel dysfunction is less
studied in other neurologic diseases but is almost as prevalent as in spinal cord
injury.60 About one-third of patients with MS experience constipation, and
one-fourth experience fecal incontinence at least once a week.19,65,66 One-fourth
of stroke survivors have constipation, and 15% experience fecal incontinence.60
In patients with Parkinson disease, constipation occurs in 37% to 80%.67–69
Constipation affects quality of life in patients with Parkinson disease more
than bladder dysfunction does.67 In patients with MSA, constipation occurs
with almost the same frequency as in patients with Parkinson disease70,71;
however, fecal incontinence is more common in MSA than in Parkinson
disease.70,71 In Parkinson disease, both lower and upper gastrointestinal tract
symptoms are observed, the latter including bloating, nausea/vomiting, and
gastroesophageal reflux disease.67 Reduced upper gastrointestinal tract
motility in Parkinson disease also leads to reduced levodopa absorption.72 In
Parkinson disease, constipation may lead to gastrointestinal emergencies,
such as intestinal pseudoobstruction (paralytic ileus), intussusception,
volvulus, stercoral ulcer (ulcer of the colon due to pressure and irritation
resulting from severe, prolonged constipation),73 and, in the most severe
cases, even death. Therefore, management of constipation in patients with
neurologic diseases is crucial.
Red Flags That Should Prompt Referral to a Urologista TABLE 10-5
◆ Presence of hematuria
◆ Recurrent urinary tract infections
◆ Pain suspected to be originating from the urinary tract
◆ Increased risk for upper urinary tract damage or findings of upper tract damage or renal
impairment in imaging or blood tests
◆ Suspicion of concomitant local pathologies (eg, bladder outlet obstruction due to prostate
enlargement in men or stress incontinence in women)
◆ Lower urinary tract symptoms refractory to conservative treatments: consideration of more
invasive treatments such as intradetrusor injections of onabotulinumtoxinA or surgery, or
when suprapubic catheterization appears appropriate
a
Modified with permission from Panicker JN, et al, Lancet Neurol.1 © 2015 Elsevier Ltd.

Geriatric constipation may have a significant degenerative component.

Dementia increases with age (up to 33% among octogenarians), with dementia
with Lewy bodies (typically presenting with dementia and parkinsonism)
comprising up to 10% to 20%. Dementia with Lewy bodies and Parkinson disease
both share Lewy body pathology. Lewy body disorders also cause nonmotor
symptoms, including gastrointestinal tract dysfunction (particularly
constipation) and rapid eye movement (REM) sleep behavior disorder. A
combination of constipation and REM sleep behavior disorder with minimal
neurologic symptoms, together with loss of cardiac norepinephrine uptake
activity, as assessed by cardiac neuroimaging with 123I-metaiodobenzylguanidine
myocardial scintigraphy or central dopamine (dopamine transporter scan), can
be referred to as Lewy body constipation.74 This concept is based on the findings
that Lewy body disease pathology may start in the bowel.75 Epidemiologic studies
in a Japanese immigrant cohort in Hawaii showed a significant association
between constipation and the future risk of developing motor signs (ie,
Parkinson disease) in Lewy body disease.76 The interval between the report of
constipation to the development of motor signs was more than 10 years. Serial
pathology studies by Braak and colleagues77 showed that Parkinson disease
pathology in the brain begins in the dorsal vagal nucleus (which might regulate
bowel function) earlier than in the substantia nigra (which regulates motor
function). Lewy body pathology may develop earlier in peripheral autonomic
structures than in the central nervous system.78
Evidence exists that synuclein aggregates can be identified in visceral organs,
including the salivary glands, and through the gastrointestinal tract at earlier
Braak stages of disease. The frequent reports of constipation as a premotor
symptom in Parkinson disease, together with early involvement of the dorsal
nucleus of the vagus in Braak stage I, have led to the hypothesis that α-synuclein
neuropathology may spread from the enteric nervous system to the central
nervous system via the vagus nerve.79 Whereas some epidemiologic studies
indicating a reduced prevalence of Parkinson disease in patients who underwent
total vagotomy for treatment of peptic ulcers could support this hypothesis,80 the
mechanistic relationship is yet to be confirmed. If this were the case, one or
various neurotoxins from the gut lumen could conceivably initiate the cascade of
events leading to α-synuclein neuropathology and their propagation to the
central nervous system. However, this is still speculative.
Once Lewy body pathology begins in the myenteric plexus, it is assumed that
aggregated α-synuclein has the ability to transmit from neuron to neuron in a
prionlike manner and then spread to the brain through sympathetic (thoracic
and lumbar sympathetic trunk) and parasympathetic (vagal and pelvic)
nerves.80,81 Patients may first visit gastroenterologists or primary care providers
before developing the full clinical manifestations of dementia with Lewy bodies
or Parkinson disease. In summary, in some patients with Parkinson disease,
the pathology may start in the myenteric plexus within the bowel, causing
constipation. This clearly contrasts with patients with MSA, in whom the
pathology may start at the sacral spinal cord innervating the bladder, causing
urinary retention.
Mechanism of Bowel Dysfunction

The bowel is controlled by humoral factors including ghrelin and motilin, both of
which are altered in many neurologic diseases.82 In normal conditions, the
190 FEBRUARY 2020

peripheral enteric nervous system seems to control bowel movements more than
the central nervous system does. Experiments on knockout mice have shown that
the myenteric plexus (Auerbach plexus) and submucosal plexus (Meissner
plexus) have a pivotal role in regulating bowel movements (FIGURE 10-3).83,84
The myenteric plexus contains neurons that innervate the smooth muscle and
local motor interneurons that regulate peristaltic movements. Most of these
neurons utilize acetylcholine (ACh) as their primary neurotransmitter.
Peristaltic movement involves both an ascending excitatory reflex mediated by
cholinergic neurons largely via muscarinic M3 receptors and a descending
inhibitory reflex mediated by nitric oxide (NO) and vasoactive intestinal
polypeptide (VIP) neurons. The peristaltic reflex may be activated by
mechanical distension or by chemical stimuli in the lumen of the gut.
Serotonergic enterochromaffin cells acting via 5-HT3 and 5-HT4 receptors on
intrinsic sensory neurons have a major role in initiating these locally
triggered reflexes.
FIGURE 10-3
Enteric neural circuitry relevant to peristaltic reflex and bowel movement. Following
mucosal stimulation, 5-hydroxytryptamine (5-HT) is released from enterochromaffin cells to
intrinsic primary sensory neurons (with 5-HT3 and 5-HT4 receptors) and extrinsic vagal and
spinal sensory neurons (with 5-HT3 receptors). Sensory neurons release calcitonin
gene-regulated peptide (CGRP), substance P (SP), and acetylcholine (ACh) to interneurons.
Interneurons release ACh and SP orally to excitatory motor neurons, whereas ACh is
released aborally (toward the rectum) to inhibitory motor neurons. Excitatory motor
neurons release ACh and SP to smooth muscle cells, whereas inhibitory motor neurons
release nitric oxide (NO), vasoactive intestinal polypeptide (VIP), pituitary adenylate
cyclase-activating polypeptide (PACAP), and adenosine triphosphate (ATP) to
smooth muscle cells. 5-HT also acts as an excitatory modulator on motor neurons (with
5-HT3 and 5-HT4 receptors), whereas dopamine seems to be an inhibitory modulator on
motor neurons (with D2 receptor [D2-R]). Interstitial cells of Cajal (ICC) interact with
smooth muscle cells for generating rhythmicity (with ACh, VIP, and NO receptors). Gut
motor neurons and ascending and descending interneurons have nicotinic acetylcholine
receptors (nAChR) and neurokinin receptors (NK-R), regulated by sensory neurons
excreting ACh and CGRP/SP.

Peristaltic reflexes can be elicited by surface stroking or circumferential

stretch. Contraction of the longitudinal muscle via ACh is regulated positively by
serotonin (mainly via 5-hydroxytryptamine 4 [5-HT4] receptors) and negatively
by dopamine (via D2 receptors), VIP, and NO. In Parkinson disease, constipation
is most commonly due to neuronal degeneration and the emergence of Lewy
bodies in the myenteric plexus. In particular, dopamine and VIP neurons are
depleted, whereas few reports are available for intestinal ACh and 5-HT neurons
in Parkinson disease.85,86
Extrinsic innervation of the bowel and anus is as follows: (1) parasympathetic
inputs from the dorsal motor nucleus of the vagus to the right colon; (2)
parasympathetic inputs from the sacral parasympathetic nucleus via the pelvic
nerve and ganglia to the left colon and rectal smooth muscle; (3) sympathetic
noradrenergic inhibitory input from the superior and inferior mesenteric ganglia
via the celiac and hypogastric nerves; and (4) somatic inputs to the external
sphincter and pelvic floor via the Onuf nucleus. These extrinsic influences are
thought to be further controlled by inputs from the Barrington nucleus, nucleus
retroambiguus, hypothalamus, striatum, and prefrontal cortex.83,84,87 Inputs
from the Barrington nucleus may coordinate defecation; inputs from the nucleus
FIGURE 10-4
Treatment algorithm for Lewy body constipation.
EMG = electromyography.
a
Bulking agents include psyllium, polyethylene glycol, and polycarbophil.
b
Softening laxatives include lubiprostone, linaclotide, elobixibat, and magnesium.
192 FEBRUARY 2020

retroambiguus to the Onuf nucleus may increase external sphincter and pelvic KEY POINTS
floor muscle tone to prevent incontinence in the setting of increased
● Bowel dysfunction is
intraabdominal pressure during expiration. Inputs from the prefrontal cortex often a combination of slow
and striatum may participate in initiation and inhibitory control of defecation. transit–type constipation
Neurologic diseases such as MS, Parkinson disease, and MSA affect these areas (slowed colonic transit time,
pathologically, but few clinical reports are available. For example, small lesions loss of peristaltic
contractions) and
at the pons/medulla cause anismus,88 ileus,89 and intractable vomiting90 in
anorectal-type constipation
humans88,91; however, the exact role of these areas in impaired bowel function in (weak strain, anismus on
MS, Parkinson disease, and MSA awaits further clarification. defecation, and large
Previous studies of bowel motility and the anal sphincter show similar bowel postdefecation residuals).
dysfunction irrespective of the site of the neural lesion. For example, in spinal
● Bowel dysfunction should
cord injury, the lesion exists in the cervicothoracic spinal cord; in MS, the lesion be managed with a
exists mainly in the spinal cord; in Parkinson disease, the lesion exists mainly in combination of diet,
myenteric plexus; and in MSA, the lesion exists mainly in the sacral spinal cord. exercise, and drugs.
Several abnormalities in gastrointestinal motility have been described in these
disorders. The upper gastrointestinal tract shows slow gastric emptying and loss
of 3 cycles/min on electrogastrography.72,92 The lower gastrointestinal tract
shows both slow transit–type constipation (slowed colonic transit time, loss of
peristaltic contractions [autonomic]) and anorectal-type constipation (weak
strain; anismus, also called paradoxical sphincter contraction on defecation, which
is an involuntary contraction of the anal sphincter muscles that normally relax
considerably during defecation [somatic], as well as large postdefecation
residuals).19,63–70 Reduced bowel sounds may be found,93 and increased
abdominal gas is frequently observed on x-ray or CT scan.
Fecal incontinence has several mechanisms. The most common is secondary
fecal incontinence due to severe constipation (overflow incontinence). Another
mechanism is a weak anal sphincter at rest (or on voluntary squeezing). Low anal
sphincter pressure at rest is mostly due to a lesion affecting the Onuf nucleus or
its projections via the pudendal nerve. Involvement of the Onuf nucleus is a
typical finding in MSA.70 Low anal sphincter pressure on voluntary squeezing
results from lesions at any site of the neuraxis. Another mechanism is increased
rectal pressure; although rare, low rectal compliance (tonic increase in rectal
pressure during slow rectal filling) can be observed in MSA.94 This finding has
also been reported in spinal cord injury and MS.66 As discussed earlier in this
article, these disorders may cause a combination of bladder overactivity during
filling and bladder underactivity during voiding; detrusor hyperactivity with
impaired contraction is common. Increased rectal pressure may also be seen in
MSA,94 which is also characterized by a combination of detrusor hyperactivity
and impaired contraction, as described earlier in this article. Whether increased
rectal pressure coexists with slow colonic transit in these diseases awaits
further studies.
Management of Bowel Dysfunction

Management of constipation in neurologic diseases is the same as of general
constipation; however, in Parkinson disease and dementia with Lewy bodies,
constipation is not always responsive to levodopa, suggesting a complex
underlying mechanism. Add-on therapy may therefore be needed to
ameliorate constipation.
An algorithm for the management of Lewy body constipation is shown in
FIGURE 10-4. This algorithm can be applied to constipation in other neurologic

disorders. The first step is to check for comorbid systemic diseases, particularly
when patients have pain, black or bloody stool, or extremely difficult defecation.
Anticholinergic therapy can produce constipation in patients with Parkinson
disease. In general, levodopa does not cause constipation in patients with de novo
Parkinson disease.95,96
Interventions for bowel dysfunction may include exercise; a bicycle
manometry study showed augmentation of rectal pressure at rest soon after
exercise as compared with that before exercise.97 A change in toileting position
may also help relieve constipation; the Asian lap-up/half-squatting posture
facilitates defecation by widening the rectoanal angle.98
An increase in dietary fiber intake may also be initiated. Dietary fiber, which is
not absorbed, may increase bulk and trigger peristaltic reflexes. However,
adequate increase of water intake is required. Yogurt and probiotics are also
recommended to help alter intestinal microbiota.99 Abdominal massage
facilitates rectal contraction in some patients.100
Drugs used for constipation include bulking agents (eg, psyllium,
polyethylene glycol 3350,101 polycarbophil102) and softening agents
(lubiprostone,103 linaclotide, elobixibat, magnesium). However, when the effects
of bulking and softening agents are insufficient, prokinetic drugs for slow
transit–type constipation are available, including serotonergics (mosapride,104
tegaserod105), cholinergics (nizatidine106), and herbal supplements.107
Treatment for anorectal-type constipation includes suppositories and botulinum
toxin injections to relax the anal sphincter.108 Transanal irrigation is helpful in
most severe cases, including in spinal cord injury and MS.109 However,
instrumental investigations such as anorectal videomanometry should also be
CASE 10-3 A 66-year-old man presented with a 10-year history of constipation and
symptoms of rapid eye movement (REM) sleep behavior disorder. He had
no motor symptoms and could run without difficulty. He reported two
episodes of nocturia per night with no leakage.
On examination, he had anosmia, slight emotional lability, and mild
cognitive impairment. A brain MRI was normal. He was started on a
cognitive training program and prescribed a laxative.
One year later, he was brought to the emergency department because
of intestinal pseudoobstruction. Routine laboratory and colonoscopy
findings were normal. However, neurologic examination revealed mild
rigidity and a slight festinating gait, and he was diagnosed with Parkinson
disease. He was prescribed a dopaminergic drug for his motor disorder
and a prokinetic drug for his bowel dysfunction, which ameliorated his
condition significantly.
COMMENT This case exemplifies how Lewy body diseases may begin with
constipation and REM sleep behavior disorder (this combination has
recently been termed Lewy body constipation). Lewy body constipation
may later be accompanied by motor signs, developing the full clinical
manifestations of Parkinson disease or dementia with Lewy bodies.
194 FEBRUARY 2020

considered in patients who are treatment resistant to determine the KEY POINT
pathophysiology of constipation. CASE 10-3 illustrates the management of
● Collaboration between
constipation in a patient with Parkinson disease. neurologists, urologists, and
gastroenterologists is
CONCLUSION recommended to maximize
Lower urinary tract dysfunction and bowel dysfunction are common in patients the quality of life of patients
with neurologic diseases
with neurologic diseases and have a significant impact on quality of life. A
who have lower urinary tract
structured approach to assessing urinary dysfunction is essential to plan optimal or bowel dysfunction.
management of symptoms. Bowel dysfunction may result in gastrointestinal
emergencies and thus needs appropriate management. Patients with Parkinson
disease may present with constipation and REM sleep behavior disorder without
obvious motor signs (Lewy body constipation), which require specific treatment.
Collaboration with other specialists, including urologists and gastroenterologists,
is highly recommended to maximize patients’ quality of life.
ACKNOWLEDGMENT
Dr Panicker is supported in part by funding from the United Kingdom’s
Department of Health National Institute of Health Research Biomedical Research
Centres funding scheme.
REFERENCES
1 Panicker JN, Fowler CJ, Kessler TM. Lower urinary 8 Smith M, Seth J, Batla A, et al. Nocturia in patients
tract dysfunction in the neurological patient: with Parkinson's disease. Mov Disord Clin Pract
clinical assessment and management. Lancet 2016;3(2):168–172. doi:10.1002/mdc3.12279.
Neurol 2015;14(7):720–732. doi:10.1016/S1474-
9 Sakakibara R, Panicker J, Finazzi-Agro E, et al.
4422(15)00070-8.
A guideline for the management of bladder
2 Andersen JT. Disturbances of bladder and dysfunction in Parkinson's disease and other gait
urethral function in Parkinson's disease. Int Urol disorders. NeurourolUrodyn 2016;5(5):551–663.
Nephrol 1985;17(1):35–41. doi:10.1002/nau.22764.
3 Berger Y, Blaivas JG, DeLaRocha ER, Salinas JM. 10 Sakakibara R, Uchiyama T, Yamanishi T, Kishi M.
Urodynamic findings in Parkinson's disease. J Urol Genitourinary dysfunction in Parkinson's disease.
1987;138(4):836–838. doi:10.1016/s0022-5347(17) Mov Disord 2010;25(1):2–12. doi:10.1002/
43390-8. mds.22519.
4 Magerkurth C, Schnitzer R, Braune S. Symptoms 11 Sakakibara R, Hattori T, Uchiyama T, Yamanishi T.
of autonomic failure in Parkinson's disease: Videourodynamic and sphincter motor unit
prevalence and impact on daily life. Clin Auton potential analyses in Parkinson's disease and
Res 2005;15(2):76–82. doi:10.1007/s10286-005- multiple system atrophy. J Neurol Neurosurg
0253-z. Psychiatry 2001;71(5):600–606. doi:10.1136/
jnnp.71.5.600.
5 Martinez-Martin P, Schapira AH, Stocchi F, et al.
Prevalence of nonmotor symptoms in Parkinson's 12 de Sèze M, Ruffion A, Denys P, et al. The
disease in an international setting; study using neurogenic bladder in multiple sclerosis: review
nonmotor symptoms questionnaire in 545 of the literature and proposal of management
patients. Mov Disord 2007;22(11):1623–1629. guidelines. Mult Scler 2007;13(7):915–928.
doi:10.1002/mds.21586. doi:10.1177/1352458506075651.
6 Balash Y, Peretz C, Leibovich G, et al. Falls in 13 Fowler CJ, Panicker JN, Drake M, et al. A UK
outpatients with Parkinson's disease: frequency, consensus on the management of the bladder in
impact and identifying factors. J Neurol 2005; multiple sclerosis. Postgrad Med J 2009;85(1008):
252(11):1310–1315. doi:10.1007/s00415-005-0855-3. 552–559. doi:10.1136/jnnp.2008.159178.
7 McGrother CW, Jagger C, Clarke M, Castleden 14 Mahajan ST, Patel PB, Marrie RA. Under treatment
CM. Handicaps associated with incontinence: of overactive bladder symptoms in patients with
implications for management. J Epidemiol multiple sclerosis: an ancillary analysis of the
Community Health 1990;44(3):246–248. doi:10. NARCOMS Patient Registry. J Urol 2010;183(4):
1136/jech.44.3.246. 1432–1437. doi:10.1016/j.juro.2009.12.029.

15 Hemmett L, Holmes J, Barnes M, Russell N. What 28 Panicker JN. Urogenital symptoms in neurologic
drives quality of life in multiple sclerosis? QJM patients. Continuum (Minneap Minn) 2017;
2004;97(10):671–676. doi:10.1093/qjmed/hch105. 23(2, Selected Topics in Outpatient Neurology):
533–552. doi:10.1212/CON.0000000000000448.
16 Phé V, Chartier-Kastler E, Panicker JN.
Management of neurogenic bladder in patients 29 Chapple CR, Yamanishi T, Chess-Williams R.
with multiple sclerosis. Nat Rev Urol 2016;13(5): Muscarinic receptor subtypes and management
275–288. doi:10.1038/nrurol.2016.53. of the overactive bladder. Urology 2002;
60(5 suppl 1):82–88; discussion 88–89. doi:10.
17 Panicker JN, Nagaraja D, Kovoor JM, et al. Lower
1016/S0090-4295(02)01803-4.
urinary tract dysfunction in acute disseminated
encephalomyelitis. Mult Scler 2009;15(9): 30 Amarenco G, Sutory M, Zachoval R, et al.
1118–1122. doi:10.1177/1352458509106614. Solifenacin is effective and well tolerated in
patients with neurogenic detrusor overactivity:
18 de Carvalho FL, Gomes CM, Apostolos-Pereira
results from the double-blind, randomized,
SL, et al. Voiding dysfunction in patients with
active- and placebo-controlled SONIC
neuromyelitis optica spectrum disorders.
urodynamic study. Neurourol Urodyn 2017;36(2):
Neurourol Urodyn 2016;35(1):39–43. doi:10.1002/
414–421. doi:10.1002/nau.22945.
nau.22667.
31 Madhuvrata P, Singh M, Hasafa Z, Abdel-Fattah
19 Mutch K, Zhao S, Hamid S, et al. Bladder and
M. Anticholinergic drugs for adult neurogenic
bowel dysfunction affect quality of life. A cross
detrusor overactivity: a systematic review and
sectional study of 60 patients with aquaporin-4
meta-analysis. Eur Urol 2012;62(5):816–830.
antibody positive neuromyelitis optica spectrum
doi:10.1016/j.eururo.2012.02.036.
disorder. Mult Scler Relat Disord 2015;4(6):
614–618. doi:10.1016/j.msard.2015.07.015. 32 Fowler CJ, Panicker JN, Drake M, et al. A UK
consensus on the management of the bladder in
20 Smith MD, Seth JH, Fowler CJ, et al. Urinary
multiple sclerosis. J Neurol Neurosurg Psychiatry
retention for the neurologist. Pract Neurol 2013;
2009;80(5):470–477. doi:10.1136/jnnp.2008.
13(5):288–291. doi:10.1136/practneurol-2012-
159178.
000478.
33 Gray SL, Anderson ML, Dublin S, et al. Cumulative
21 Panicker JN, Game X, Khan S, et al. The possible
use of strong anticholinergics and incident
role of opiates in women with chronic urinary
dementia: a prospective cohort study. JAMA
retention: observations from a prospective
Intern Med 2015;175(3):401–407. doi:10.1001/
clinical study. J Urol 2012;188(2):480–484. doi:10.
jamainternmed.2014.7663.
1016/j.juro.2012.04.011.
34 Risacher SL, McDonald BC, Tallman EF, et al.
22 Datta SN, Chaliha C, Singh A, et al. Sacral
Association between anticholinergic medication
neurostimulation for urinary retention: 10-year
use and cognition, brain metabolism, and brain
experience from one UK centre. BJU Int 2008;
atrophy in cognitively normal older adults. JAMA
101(2):192–196. doi:10.1111/j.1464-410X.2007.07282.x.
Neurol 2016;73(6):721–732. doi:10.1001/
23 Panicker JN, Seth JH, Khan S, et al. Open-label jamaneurol.2016.0580.
study evaluating outpatient urethral sphincter
35 Fox C, Smith T, Maidment I, et al. Effect of
injections of onabotulinumtoxinA to treat women
medications with anti-cholinergic properties on
with urinary retention due to a primary disorder
cognitive function, delirium, physical function
of sphincter relaxation (Fowler's syndrome).
and mortality: a systematic review. Age Ageing
BJU Int 2015;117(5):809–813. doi:10.1111/bju.13342.
2014;43(5):604–615. doi:10.1093/ageing/afu096.
24 Lawrenson R, Wyndaele JJ, Vlachonikolis I, et al.
36 Davis TP, Sanchez-Covarubias L, Tome ME.
Renal failure in patients with neurogenic lower
P-glycoprotein trafficking as a therapeutic target
urinary tract dysfunction. Neuroepidemiology
to optimize CNS drug delivery. Adv Pharmacol
2001;20(2):138–143. doi:10.1159/000054774.
2014;71:25–44. doi:10.1016/bs.apha.2014.06.009.
25 Castel-Lacanal E, Gamé X, Clanet M, et al. Urinary
37 Chancellor MB, Staskin DR, Kay GG, et al. Blood-
complications and risk factors in symptomatic
brain barrier permeation and efflux exclusion of
multiple sclerosis patients. Study of a cohort of
anticholinergics used in the treatment of
328 patients. Neurourol Urodyn 2015;34(1):32–36.
overactive bladder. Drugs Aging 2012;29(4):259–273.
doi:10.1002/nau.22495.
doi:10.2165/11597530-000000000-00000.
26 Fourtassi M, Jacquin-Courtois S, Scheiber-
38 Wagg A, Verdejo C, Molander U. Review of
Nogueira MC, et al. Bladder dysfunction in
cognitive impairment with antimuscarinic agents
hereditary spastic paraplegia: a clinical and
in elderly patients with overactive bladder. Int J
urodynamic evaluation. Spinal Cord 2012;50(7):
Clin Pract 2010;64(9):1279–1286. doi:10.1111/j.1742-
558–562. doi:10.1038/sc.2011.193.
1241.2010.02449.x.
27 Pannek J, Blok B, Castro-Diaz D, et al.
39 Isik AT, Celik T, Bozoglu E, Doruk H. Trospium and
European Association of Urology guidelines on
cognition in patients with late onset Alzheimer
neuro-urology. uroweb.org/wp-content/
disease. J Nutr Health Aging 2009;13(8):672–676.
uploads/21-Neuro-Urology_LR.pdf. Published
doi:10.1007/s12603-009-0144-4.
April 2014. Accessed December 2, 2019.
196 FEBRUARY 2020

40 Chapple CR, Cardozo L, Nitti VW, et al. 51 Peters KM, Carrico DJ, Perez-Marrero RA, et al.
Mirabegron in overactive bladder: a review of Randomized trial of percutaneous tibial nerve
efficacy, safety, and tolerability. Neurourol stimulation versus Sham efficacy in the
Urodyn 2014;33(1):17–30. doi:10.1002/nau.22505. treatment of overactive bladder syndrome:
results from the SUmiT trial. J Urol 2010;183(4):
41 Welk B, Hickling D, McKibbon M, et al. A pilot
1438–1443. doi:10.1016/j.juro.2009.12.036.
randomized-controlled trial of the urodynamic
efficacy of mirabegron for patients with 52 Kabay SC, Kabay S, Yucel M, et al. Acute
neurogenic lower urinary tract dysfunction. urodynamic effects of percutaneous posterior
Neurourol Urodyn 2018;37(8):2810–2817. doi:10. tibial nerve stimulation on neurogenic detrusor
1002/nau.23774. overactivity in patients with Parkinson's disease.
Neurourol Urodyn 2009;28(1):62–67. doi:10.1002/
42 Krhut J, Borovička V, Bilková K, et al. Efficacy and
nau.20593.
safety of mirabegron for the treatment of
neurogenic detrusor overactivity—prospective, 53 Kabay S, Kabay SC, Yucel M, et al. The clinical and
randomized, double-blind, placebo-controlled urodynamic results of a 3-month percutaneous
study. Neurourol Urodyn 2018;37(7):2226–2233. posterior tibial nerve stimulation treatment in
doi:10.1002/nau.23566. patients with multiple sclerosis-related neurogenic
bladder dysfunction. Neurourol Urodyn 2009;
43 Bosma R, Wynia K, Havlikova E, et al. Efficacy of
28(8):964–968. doi:10.1002/nau.20733.
desmopressin in patients with multiple sclerosis
suffering from bladder dysfunction: a meta- 54 Gobbi C, Digesu GA, Khullar V, et al. Percutaneous
analysis. Acta Neurol Scand 2005;112(1):1–5. doi:10. posterior tibial nerve stimulation as an effective
1111/j.1600-0404.2005.00431.x. treatment of refractory lower urinary tract
symptoms in patients with multiple sclerosis:
44 Schurch B, Stöhrer M, Kramer G, et al.
preliminary data from a multicentre, prospective,
Botulinum-A toxin for treating detrusor
open label trial. Mult Scler 2011;17(12):1514–1519.
hyperreflexia in spinal cord injured patients: a
doi:10.1177/1352458511414040.
new alternative to anticholinergic drugs?
Preliminary results. J Urol 2000;164(3 pt 1):692–697. 55 Salatzki J, Liechti MD, Spanudakis E, et al. Factors
doi:10.1097/00005392-200009010-00018. influencing return for maintenance treatment
with percutaneous tibial nerve stimulation for the
45 Schurch B, Schmid DM, Stöhrer M. Treatment of
management of the overactive bladder. BJU Int
neurogenic incontinence with botulinum toxin A.
2019;123(5A):E20–E28. doi:10.1111/bju.14651.
N Engl J Med 2000;342(9):665. doi:10.1056/
NEJM200003023420918. 56 de Sèze M, Raibaut P, Gallien P, et al.
Transcutaneous posterior tibial nerve stimulation
46 Cruz F, Herschorn S, Aliotta P, et al. Efficacy and
for treatment of the overactive bladder syndrome
safety of onabotulinumtoxinA in patients with
in multiple sclerosis: results of a multicenter
urinary incontinence due to neurogenic detrusor
prospective study. Neurourol Urodyn 2011;30(3):
overactivity: a randomised, double-blind,
306–311. doi:10.1002/nau.20958.
placebo-controlled trial. Eur Urol 2011;60(4):
742–750. doi:10.1016/j.eururo.2011.07.002. 57 Monteiro ÉS, de Carvalho LB, Fukujima MM, et al.
Electrical stimulation of the posterior tibialis
47 Ginsberg D, Gousse A, Keppenne V, et al.
nerve improves symptoms of poststroke
Phase 3 efficacy and tolerability study of
neurogenic overactive bladder in men: a
onabotulinumtoxinA for urinary incontinence
randomized controlled trial. Urology 2014;84(3):
from neurogenic detrusor overactivity. J Urol
509–514. doi:10.1016/j.urology.2014.05.031.
2012;187(6):2131–2139. doi:10.1016/j.juro.
2012.01.125. 58 Phé V, Pakzad M, Curtis C, et al. Urinary tract
infections in multiple sclerosis. Mult Scler 2016;
48 Giannantoni A, Mearini E, Del Zingaro M, Porena
22(7):855–861. doi:10.1177/1352458516633903.
M. Six-year follow-up of botulinum toxin A
intradetrusorial injections in patients with 59 Seth JH, Haslam C, Panicker JN. Ensuring patient
refractory neurogenic detrusor overactivity: adherence to clean intermittent self-
clinical and urodynamic results. Eur Urol 2009; catheterization. Patient Prefer Adherence 2014;
55(3):705–711. doi:10.1016/j.eururo.2008.08.048. 8:191–198. doi:10.2147/PPA.S49060.
49 Kennelly M, Dmochowski R, Ethans K, et al. Long- 60 Cotterill N, Madersbacher H, Wyndaele JJ, et al.
term efficacy and safety of onabotulinumtoxinA Neurogenic bowel dysfunction: clinical
in patients with urinary incontinence due to management recommendations of the
neurogenic detrusor overactivity: an interim Neurologic Incontinence Committee of the Fifth
analysis. Urology 2013;81(3):491–497. doi:10.1016/j. International Consultation on Incontinence 2013.
urology.2012.11.010. Neurourol Urodyn 2018;37(1):46–53. doi:10.1002/
nau.23289.
50 National Institute for Health and Care Excellence.
Urinary incontinence in neurological disease: 61 Ghoshal UC. Chronic constipation in Rome IV era:
assessment and management (CG148). nice. the Indian perspective. Indian J Gastroenterol
org.uk/guidance/cg148/resources/urinary- 2017;36(3):163–173. doi:10.1007/s12664-017-0757-1.
incontinence-in-neurological-disease-
assessment-and-management-pdf-35109577553605.
Published August 8, 2012. Accessed
December 2, 2019.

62 Drossman DA, Hasler WL. Rome IV–functional GI 74 Tateno F, Sakakibara R, Kishi M, et al.
disorders: disorders of gut-brain interaction. Constipation and metaiodobenzylguanidine
Gastroenterology 2016;150(6):1257–1261. doi:10. myocardial scintigraphy abnormality. J Am
1053/j.gastro.2016.03.035. Geriatr Soc 2012;60(1):185–187. doi:10.1111/j.1532-
5415.2011.03737.x.
63 Krogh K, Emmanuel A, Perrouin-Verbe B, et al.
International spinal cord injury bowel function 75 Sakakibara R, Doi H, Fukudo S. Lewy body
basic data set (version 2.0). Spinal Cord 2017; constipation. J Anus Rectum Colon 2019;3(1):
55(7):692–698. doi:10.1038/sc.2016.189. 10–17. doi:10.23922/jarc.2018-022.
76 Abbott RD, Petrovitch H, White LR, et al.
64 Trivedi PM, Kumar L, Emmanuel AV. Altered Frequency of bowel movements and the future
colorectal compliance and anorectal physiology risk of Parkinson's disease. Neurology 2001;57(3):
in upper and lower motor neurone spinal injury 456–462. doi:10.1212/wnl.57.3.456.
may explain bowel symptom pattern. Am J
77 Hawkes CH, Del Tredici K, Braak H. A timeline for
Gastroenterol 2016;111(4):552–560. doi:10.1038/
Parkinson’s disease. Parkinsonism Relat Disord
ajg.2016.19.
2010;16(2):79–84. doi:10.1016/j.parkreldis.2009.
65 Nusrat S, Gulick E, Levinthal D, Bielefeldt K. 08.007.
Anorectal dysfunction in multiple sclerosis: a
78 Gelpi E, Navarro-Otano J, Tolosa E, et al. Multiple
systematic review. ISRN Neurol 2012;2012:
organ involvement by alpha-synuclein pathology
376023. doi:10.5402/2012/376023.
in Lewy body disorders. Mov Disord 2014;29(8):
66 Preziosi G, Raptis DA, Raeburn A, et al. Autonomic 1010–1018. doi:10.1002/mds.25776.
rectal dysfunction in patients with multiple
79 Garrido-Gil P, Rodriguez-Perez AI, Dominguez-
sclerosis and bowel symptoms is secondary to
Meijide A, et al. Bidirectional neural interaction
spinal cord disease. Dis Colon Rectum 2014;57(4):
between central dopaminergic and gut lesions in
514–521. doi:10.1097/DCR.0000000000000048.
Parkinson’s disease models. Mol Neurobiol 2018;
67 Sakakibara R, Kishi M, Ogawa E, et al. Bladder, 55(9):7297–7316. doi:10.1007/s12035-018-0937-8.
bowel, and sexual dysfunction in Parkinson's
80 Svensson E, Horváth-Puhó E, Thomsen RW, et al.
disease. Parkinsons Dis 2011;2011:924605.
Vagotomy and subsequent risk of Parkinson's
doi:10.4061/2011/924605.
disease. Ann Neurol 2015;78(4):522–529. doi:10.
68 Wang CP, Sung WH, Wang CC, Tsai PY. Early 1002/ana.24448.
recognition of pelvic floor dyssynergia and
81 Pan-Montojo F, Anichtchik O, Dening Y, et al.
colorectal assessment in Parkinson's disease
Progression of Parkinson's disease pathology is
associated with bowel dysfunction. Colorectal
reproduced by intragastric administration of
Dis 2013;15(3):e130–e137. doi:10.1111/codi.12105.
rotenone in mice. PLoS One 2010;5(1):e8762.
69 Yu T, Wang Y, Wu G, et al. High-resolution doi:10.1371/journal.pone.0008762.
anorectal manometry in Parkinson disease with
82 Sanger GJ, Furness JB. Ghrelin and motilin
defecation disorder: a comparison with
receptors as drug targets for gastrointestinal
functional defecation disorder. J Clin
disorders. Nat Rev Gastroenterol Hepatol 2016;
Gastroenterol 2016;50(7):566–571. doi:10.1097/
13(1):38–48. doi:10.1038/nrgastro.2015.163.
MCG.0000000000000469.
83 Hansen MB. Neurohumoral control of
70 Sakakibara R, Odaka T, Uchiyama T, et al. Colonic
gastrointestinal motility. Physiol Res 2003;
transit time, sphincter EMG, and rectoanal
52(1):1–30.
videomanometry in multiple system atrophy.
Mov Disord 2004;19(8):924–929. doi:10.1002/ 84 Johnson AC, Greenwood-Van Meerveld B.
mds.20165. Critical evaluation of animal models of
gastrointestinal disorders. Handb Exp Pharmacol
71 Yamamoto T, Sakakibara R, Uchiyama T, et al.
2017;239:289–317. doi:10.1007/164_2016_120.
Questionnaire-based assessment of pelvic organ
dysfunction in multiple system atrophy. 85 Cersosimo MG, Benarroch EE. Pathological
Mov Disord 2009;24(7):972–978. doi:10.1002/ correlates of gastrointestinal dysfunction in
mds.22332. Parkinson's disease. Neurobiol Dis 2012;46(3):
559–564. doi:10.1016/j.nbd.2011.10.014. Epub 2011
72 Doi H, Sakakibara R, Sato M, et al. Plasma
Oct 25.
levodopa peak delay and impaired gastric
emptying in Parkinson's disease. J Neurol Sci 86 Cersosimo MG, Benarroch EE. Neural control
2012;319(1–2):86–88. doi:10.1016/j.jns.2012.05.010. of the gastrointestinal tract: implications for
Parkinson disease. Mov Disord 2008;23(8):
73 Tateno F, Sakakibara R, Aiba Y, et al. Stercoral
1065–1075. doi:10.1002/mds.22051.
ulcer and colonic perforation in an individual with
Parkinson's disease with constipation. J Am 87 Weng Y, Qi R, Liu C, et al. Disrupted functional
Geriatr Soc 2016;64(10):e118–e120. doi:10.1111/ connectivity density in irritable bowel syndrome
jgs.14357. patients. Brain Imaging Behav 2017;11(6):1812–1822.
doi:10.1007/s11682-016-9653-z.
198 FEBRUARY 2020

88 Tateno F, Sakakibara R, Kishi M, et al. Brainstem 100 Liu Z, Sakakibara R, Odaka T, et al. Mechanism
stroke and increased anal tone. Low Urin Tract of abdominal massage for difficult defecation in a
Symptoms 2012;4(3):161–163. doi:10.1111/j.1757- patient with myelopathy (HAM/TSP). J Neurol
5672.2012.00143.x. 2005;252(10):1280–1282. doi:10.1007/s00415-
005-0825-9.
89 Ito T, Sakakibara R, Sakakibara Y, et al. Medulla
and gut. Intern Med 2004;43(11):1091. doi:10.2169/ 101 Zangaglia R, Martignoni E, Glorioso M, et al.
internalmedicine.43.1091. Macrogol for the treatment of constipation
in Parkinson's disease. A randomized
90 Sawai S, Sakakibara R, Kanai K, et al. Isolated
placebo-controlled study. Mov Disord 2007;
vomiting due to a unilateral dorsal vagal complex
22(9):1239–1244. doi:10.1002/mds.21243.
lesion. Eur Neurol 2006;56(4):246–248. doi:10.
1159/000096673. 102 Sakakibara R, Yamaguchi T, Uchiyama T, et al.
Calcium polycarbophil improves constipation in
91 Sakakibara R. Cyclic vomiting syndrome: the
primary autonomic failure and multiple system
nervous system has the guts. Clin Auton Res 2018;
atrophy subjects. Mov Disord 2007;22(11):
28(2):167–169. doi:10.1007/s10286-018-0513-3.
1672–1673. doi:10.1002/mds.21250.
92 Sakakibara Y, Asahina M, Suzuki A, et al. Gastric
103 Ondo WG, Kenney C, Sullivan K, et al.
myoelectrical differences between Parkinson's
Placebo-controlled trial of lubiprostone for
disease and multiple system atrophy.
constipation associated with Parkinson disease.
Mov Disord 2009;24(11):1579–1586. doi:10.1002/
Neurology 2012;78(21):1650–1654. doi:10.1212/
mds.22265.
WNL.0b013e3182574f28.
93 Ozawa T, Saji E, Yajima R, et al. Reduced bowel
104 Liu Z, Sakakibara R, Odaka T, et al. Mosapride
sounds in Parkinson's disease and multiple
citrate, a novel 5-HT4 agonist and partial 5-HT3
system atrophy patients. Clin Auton Res 2011;
antagonist, ameliorates constipation in
21(3):181–184. doi:10.1007/s10286-010-0102-6.
parkinsonian patients. Mov Disord 2005;20(6):
94 Sakakibara R, Kishi M, Ogawa E, et al. 680–686. doi:10.1002/mds.20387.
Multiple-system atrophy presenting with low
105 Sullivan KL, Staffetti JF, Hauser RA, et al.
rectal compliance and bowel pain. Mov Disord
Tegaserod (Zelnorm) for the treatment of
2010;25(10):1516–1518. doi:10.1002/mds.23132.
constipation in Parkinson's disease. Mov Disord
95 Tateno F, Sakakibara R, Yokoi Y, et al. Levodopa 2006;21(1):115–116. doi:10.1002/mds.20666.
ameliorated anorectal constipation in de novo
106 Sakakibara R, Doi H, Sato M, et al. Nizatidine
Parkinson's disease: the QL-GAT study.
ameliorates slow transit constipation in
Parkinsonism Relat Disord 2011;17(9):662–666.
Parkinson's disease. J Am Geriatr Soc 2015;
doi:10.1016/j.parkreldis.2011.06.002.
63(2):399–401. doi:10.1111/jgs.13279.
96 Tateno H, Sakakibara R, Shiina S, et al. Transdermal
107 Doi H, Sakakibara R, Sato M, et al. Dietary herb
dopamine agonist ameliorates gastric emptying in
extract rikkunshi-to ameliorates gastroparesis in
Parkinson’s disease. J Am Geriatr Soc 2015;63(11):
Parkinson's disease: a pilot study. Eur Neurol
2416–2418. doi:10.1111/jgs.13800.
2014;71(3–4):193–195. doi:10.1159/000355608.
97 Rao SS, Beaty J, Chamberlain M, et al. Effects of
108 Cadeddu F, Bentivoglio AR, Brandara F, et al.
acute graded exercise on human colonic motility.
Outlet type constipation in Parkinson's disease:
Am J Physiol 1999;276(5):G1221–G1226. doi:10.1152/
results of botulinum toxin treatment. Aliment
ajpgi.1999.276.5.G1221.
Pharmacol Ther 2005;22(10):997–1003. doi:10.1111/
98 Sakakibara R, Tsunoyama K, Hosoi H, et al. j.1365-2036.2005.02669.x.
Influence of body position on defecation in
109 Passananti V, Wilton A, Preziosi G, et al. Long-
humans. Low Urin Tract Symptoms 2010;2(1):
term efficacy and safety of transanal irrigation in
16–21. doi:10.1111/j.1757-5672.2009.00057.x.
multiple sclerosis. Neurogastroenterol Motil
99 Barichella M, Pacchetti C, Bolliri C, et al. 2016;28(9):1349–1355. doi:10.1111/nmo.12833.
Probiotics and prebiotic fiber for constipation
associated with Parkinson disease: an RCT.
Neurology 2016;87(12):1274–1280. doi:10.1212/
WNL.0000000000003127.

REVIEW ARTICLE

Skin Biopsy in Evaluation
C O N T I N UU M AUDIO
INTERVIEW AVAILABLE
ONLINE
of Autonomic Disorders
By Christopher H. Gibbons, MD, MMSc, FAAN; Ningshan Wang, MD, PhD;

Jee Young Kim, MD; Marta Campagnolo, MD; Roy Freeman, MBChB
CITE AS:
200–212.
ABSTRACT
Address correspondence to PURPOSE OF REVIEW: This article provides an up-to-date assessment of the
Dr Christopher Gibbons, Center role of skin biopsy in the evaluation of autonomic disorders. The standard
for Autonomic and Peripheral
Nerve Disorders, Beth Israel
methodology for completing a skin biopsy, the anatomic structures of
Deaconess Medical Center, interest detected within a skin biopsy, and the disease states in which skin
1 Deaconess Rd, Palmer 111, biopsies may provide valuable information are reviewed.
Boston, MA 02215, cgibbons@
bidmc.harvard.edu.
RECENT FINDINGS:Several recent advances in the studies of hereditary
amyloidosis and the various degenerative synucleinopathies have
Dr Gibbons has received
personal compensation for demonstrated that simple skin biopsies can provide valuable pathologic
serving as a scientific advisor for evidence of neurologic disease. In addition to diagnosis of the underlying
Theravance Biopharma and
Lundbeck and as an associate
disorder, skin biopsies provide a quantitative structural measurement of
editor for Autonomic the associated autonomic damage.
Neuroscience: Basic & Clinical,
Grifols, and publishing royalties SUMMARY: Skin biopsies are making great inroads into the study of
from UpToDate, Inc. Dr Gibbons autonomic and peripheral nerve disorders. Complex immunohistochemical
has held stock/stock options in staining protocols are challenging to complete, but the rich data derived
Cutaneous Neurodiagnostics,
LLC, and has given expert from these studies in the diagnosis and monitoring of different disease
medical testimony. Dr Freeman states suggest that the role of skin biopsies in the study of the autonomic
has received personal
compensation and/or stock
nervous system will continue to expand in the years to come.
options for serving on scientific
advisory boards of Abide
Therapeutics; Applied
Therapeutics, Inc; Aptinyx, Inc; INTRODUCTION
S
Astellas Pharma; Biogen;
Biohaven Pharmaceuticals;
kin biopsy is now considered an important diagnostic tool for
Chromocell; Cutaneous neurologists, but this is a relatively recent development. Over the past
Neurodiagnostics, LLC; GW 2 decades, advances in peripheral nerve immunohistochemical
Pharmaceuticals, plc; Ironwood
Pharmaceuticals; Lundbeck; staining have made skin biopsy an important addition to the diagnosis
Mundipharma; NeuroBo of small fiber neuropathy. The quantitation of intraepidermal nerve
Pharmaceuticals; Novartis;
Pfizer, Inc; Regenacy
fibers has provided a pathologic window into previously invisible nerve fiber
Pharmaceuticals; Spinifex subtypes. Reliable and reproducible quantitative methods have emerged and
Pharmaceuticals; Theravance allow for comparison of results between laboratories, increasing the
Continued on page 212
neurobiological understanding of small fiber neuropathies.1
UNLABELED USE OF However, small epidermal sensory fibers encompass only a small proportion of
PRODUCTS/INVESTIGATIONAL the total nerves that can be seen with skin biopsies. Deeper dermal tissue contains
USE DISCLOSURE:
Drs Gibbons, Wang, Kim,
structures that include hair follicles, blood vessels, piloerector muscles, sweat
Campagnolo, and Freeman glands, and sebaceous glands. All these structures are innervated by a variety of
report no disclosures. sensory and autonomic nerve fibers. Advances in immunohistochemical labeling
of nerve fiber subtypes has enabled exploration of the autonomic and sensory
of Neurology. substructures within punch skin biopsies across a spectrum of health and disease.
200 FEBRUARY 2020

This article reviews the neuroanatomy of the skin in healthy individuals, with KEY POINTS
a focused discussion on how specific disease states may alter nerve fiber
● Standard punch biopsies
subtypes. Recently, the number of publications on this topic has grown 3 mm in diameter are used to
exponentially. This article reviews the major advances in the use of skin biopsies obtain sections of tissue,
as a potential biomarker of disease. generally from the distal leg,
distal thigh, and proximal
thigh sites.
SKIN BIOPSY
Although different methodologic approaches to performing a skin biopsy are still ● Although biopsies are
reported, most investigators follow a standard protocol. After local infiltration of frequently used to evaluate
the skin with lidocaine (typically with epinephrine to reduce bleeding), a 3-mm for small fiber neuropathy
punch skin biopsy is obtained (FIGURE 11-1). Standard sites for biopsies in the by quantifying the nerve
fibers within the epidermis,
investigation of peripheral neuropathy include the distal leg 10 cm above the autonomic innervation is all
lateral malleolus, the lateral distal thigh, and the lateral proximal thigh. Selection contained within the deeper
of other sites for skin biopsy may vary by disease state and are discussed in more dermal tissue.
detail later in this article.
Although the blister method was used in the past to obtain skin for analysis of
intraepidermal nerve fibers, it is not discussed further in this article because it
does not allow for acquisition of deeper dermal structures that have
autonomic innervation.
A REVIEW OF CUTANEOUS NEUROANATOMY

A standard punch skin biopsy that is 3 mm in diameter will typically be 3 mm to
5 mm deep. The layers of the skin and the associated dermal structures are
highlighted in FIGURE 11-2. The most superficial layer includes the epidermis,
where unmyelinated nerve fibers reside. These are the fibers that are quantified
in the investigation of small fiber neuropathy. The epidermal layer is separated
from the dermal layer by a basement membrane. The unmyelinated nociceptive
C fibers pierce the basement membrane from a subdermal neural plexus running
just below the basement membrane. The basement membrane often has a wavy
appearance due to the presence of dermal invaginations, otherwise known as
dermal papillae. Capillaries typically reside within the dermal papillae but are not
visible without special staining. The volume of deeper dermal tissue is much
greater than the epidermal tissue and contains bundles of nerve fibers, both
myelinated and unmyelinated. In addition, many dermal structures are present
within the skin. Each of the specific dermal structures and nerve fiber types is
discussed below.
FIGURE 11-1
Skin biopsy procedure using a standard 3-mm punch biopsy tool (A). The biopsy is quite small
(B) and heals by secondary intention.

SKIN BIOPSY IN EVALUATION OF AUTONOMIC DISORDERS
FIGURE 11-2
Skin biopsy anatomy. In this image taken with a confocal microscope and using
immunohistochemical staining with protein gene product 9.5 (red) and vasoactive intestinal
polypeptide (green), the structures of the skin can be visualized. The epidermal layer is the
most superficial layer and is separated from the dermis by the basement membrane
(highlighted on the top left [yellow] to improve visualization). The dermal structures are also
shown and include the sebaceous gland, hair follicle, pilomotor muscle, and sweat gland.
Hair Follicles
Hair follicles are present in biopsy sections from nonglabrous skin, and their
presence and number largely depend on where the biopsy is obtained. Hair
follicles begin at a bulb and extend through the deeper dermal tissue, the
basement membrane, and epithelial layer, finally terminating outside the skin.
The hair follicle itself is anchored to the skin by arrector pili muscles and
sebaceous glands. Hair follicles have many sensory fibers that wrap extensively
around the base of the follicle and extend up the shaft. The innervation to the
hair follicle is predominantly sensory, although sympathetic adrenergic and
sympathetic cholinergic fibers innervate the base of the hair follicle and
regulate growth.
Arrector Pili Muscles

Arrector pili muscles attach through the dermal tissue to the shaft of the hair
follicle and anchor it into the skin. With stimulation and contraction of an
arrector pili muscle, the hair stands on end (piloerection), and cutis anserina
(gooseflesh) is formed. Arrector pili muscles contain a linear pattern of
innervation that is relatively easy to quantify when compared with other dermal
structures. Nerve fibers travel in the plane of the muscle and are easily identified
by microscopy by using a panaxonal marker, such as protein gene product 9.5
202 FEBRUARY 2020

(PGP 9.5).2 Because arrector pili muscles are physically connected to hair KEY POINTS
follicles, their presence in a particular biopsy section will depend largely on the
● Pilomotor nerve fibers
region of the biopsy in hairy skin. predominantly contain
Arrector pili muscles are an important structure in the study of autonomic sympathetic adrenergic
disorders. The pili muscles are predominantly innervated by sympathetic innervation.
adrenergic fibers, thereby allowing for focused study of autonomic disorders.
● Sweat glands contain
The use of selective immunohistochemical stains, such as tyrosine hydroxylase or
sympathetic cholinergic
dopamine β-hydroxylase, enables visualization of sympathetic adrenergic (also known as sudomotor)
innervation.2,3 Quantitation of pilomotor innervation has resulted in the capacity nerve fibers. Quantitation of
to detect structural changes to autonomic innervation across different disease- sweat gland density without
specific states.2,3 In general, the number of nerve fibers running in parallel with reporting the area of sweat
glands measured is a
the length of the muscle is counted in cross section (FIGURE 11-3). The number of common error by
nerve fibers per millimeter is used to define the density of innervation. laboratories and limits the
utility of this technique.
Sweat Glands
Sweat glands are exocrine glands that secrete moisture to the skin via a sweat
duct. Most sweat glands in the skin are eccrine (thermoregulatory) glands, but
apocrine glands are present in the axilla and perianal regions. The type of gland
that appears in the skin depends on the region of skin that is biopsied; almost all
studies refer to eccrine sweat glands. Sweat glands are tubular structures present
within dermal tissue that contain a rich vascular and neural network. Several
challenges to the study of sweat glands exist: they may not be present in every
skin biopsy, they have a complex three-dimensional structure that can be
challenging to quantitate in two-dimensional tissue sections, and they contain a
variety of sensory and autonomic nerve fibers.4
To accurately assess the value of sweat gland nerve fiber density, a
quantitative report of the number of sweat glands measured is required to
prevent overinterpretation of the nerve density in a small piece of a sweat gland.
Despite these challenges, sweat gland innervation has become an important
addition to the study of cutaneous autonomic innervation. Sweat glands contain
FIGURE 11-3
Pilomotor innervation. A, A low-resolution image of a skin biopsy containing a pilomotor
muscle. B, A magnified image of a pilomotor muscle with the diameter of the muscle
measured (red line), and the number of intersecting nerve fibers counted (arrows). The
results are expressed as the number of pilomotor nerve fibers per millimeter.

primarily sympathetic cholinergic (sudomotor) nerve fibers, which can be

visualized by using immunostaining for vasoactive intestinal polypeptide.
However, embryologic remnants of sympathetic adrenergic nerve fibers can also
be detected within sweat glands.5
Efforts to semiquantitatively evaluate sweat glands have been published, but it
is unclear if they provide adequate reliability or reproducibility.6,7 Most recent
studies use a variation of an unbiased stereologic technique to aid in quantitation
of sudomotor density.6,8
Blood Vessels
Capillaries are present through the dermal papillae and are critical to
thermoregulation. To date, limited study of capillaries and their associated
innervation has occurred. Within deeper dermal tissue, blood vessels can be
detected with significant neural innervation and in dense vascular networks that
support dermal structures (sweat glands, hair follicles, and piloerector muscles).
Because of the complexity of cutaneous vascular innervation, the specific
subtypes of nerve fibers that surround blood vessels across health and disease
have not been fully elucidated. Evidence from pathologic and physiologic studies
suggests that vascular innervation may include sensory, sympathetic (cholinergic
and adrenergic), and parasympathetic fibers.9,10
Other Structures
A variety of other dermal nerve fiber subtypes have been studied, including the
subepidermal plexus, the intrapapillary myelinated nerve endings in Meissner
corpuscles, and myelinated nerve bundles. The use of skin biopsy to investigate
cutaneous myelinated nerve fibers has highlighted the potential role of skin
biopsy across a number of disease states, although they may not be traditionally
considered under the umbrella of autonomic disorders. To maximize acquisition
of large fibers, skin biopsies are often taken from glabrous skin to increase the
yield of large fibers within the biopsy. The structures are often evaluated by using
a combination of a panaxonal marker (such as PGP 9.5) with other neuronal
markers to identify specific structures (ie, sodium channel clusters to detect the
nodes of Ranvier).11 Studies in diabetes mellitus, Parkinson disease, or
demyelinating diseases have combined quantitation of autonomic innervation
with morphologic investigations of large myelinated nerve fibers to better define
the disease pathology.11,12
SKIN BIOPSIES TO EVALUATE SPECIFIC AUTONOMIC CONDITIONS

AND DISORDERS
One of the clearest roles for skin biopsy in the evaluation of autonomic disorders
is to quantitate changes to cutaneous autonomic innervation—either to define
a peripheral autonomic neuropathy or to clarify the pathophysiologic process
that is causing specific symptoms. A decrease in sympathetic adrenergic
innervation within piloerector muscles or a decrease in sympathetic cholinergic
innervation within sweat glands can define the subtypes of autonomic nerves
that are impacted by the disease.
For example, in patients with Ross syndrome (presenting clinically with a
combination of segmental anhidrosis, Adie tonic pupil, and areflexia), a severe
reduction exists in the sympathetic cholinergic innervation surrounding sweat
glands in regions of anhidrotic skin, and sympathetic cholinergic innervation is
204 FEBRUARY 2020

absent within blood vessels, hair follicles, and arrector pili muscles in both
anhidrotic and hyperhidrotic skin.13 In contrast, in patients with Holmes-Adie
syndrome, numerous morphologic abnormalities of sympathetic cholinergic
nerves are present, but preserved sympathetic cholinergic nerve fiber density is
seen.13 In a case report in which skin biopsies were obtained from an individual
with cold-induced sweating syndrome type 1 (CISS1), a disorder characterized
by profuse sweating in cold environments with a mutation in cytokine receptor-
like factor 1 (CISS1),14 skin biopsies revealed absent sudomotor cholinergic
innervation and increased sudomotor adrenergic innervation. The results
suggest an embryologic failure of transition of sudomotor fibers from adrenergic
to cholinergic.14 These brief case reports highlight the value of skin biopsy in
defining the structural underpinnings of particular disorders.
The use of skin biopsy has several challenges in the diagnosis of a peripheral
autonomic neuropathy. First, because of the random distribution of sweat
glands and arrector pili muscles within a biopsy, any given tissue section may
or may not have an adequate sample for evaluation. In some cases, these
dermal structures may not be present within the biopsy. Thus, it is critical that
any laboratory reporting autonomic innervation provides a report of the
sample size, with a minimum required standard necessary for interpretation of
the results. Second, dermal structures are typically located deeper in the skin
and are susceptible to crush artifact when the biopsy is taken. A crushed
specimen can appear very similar to a denervated structure, and an
experienced reader is required to differentiate the two. Third, normative
values by age and sex have not been fully established for these tests, and,
therefore, the results must be interpreted with care by the referring physician.
Finally, several different methods have been proposed by various groups with
no clear advantage provided by using one approach over another. Thus, no
consensus has been reached on how to report data in a consistent fashion,
preventing comparison among studies.4,6,15 Despite these limitations, a
number of significant advances have been made in the evaluation of different
autonomic disorders.
Diabetic Autonomic Neuropathy

Many publications have documented the progression of neuropathy in the
setting of diabetes mellitus. Based on pathologic changes seen with sural nerve
biopsies, intraepidermal nerve fiber density, quantified examination scores,
and neurophysiologic testing, a progressive loss of nerve fibers correlates with
the known underlying risk factors.16 Investigators have studied the impact
of diabetes mellitus on autonomic nerve density to demonstrate the validity
of the technique.4,6,17 Studies of autonomic innervation typically reveal a
length-dependent pattern to autonomic nerve fiber damage in diabetes mellitus,
with the distal sites exhibiting the earliest and most severely reduced nerve fiber
densities.4,15,18 The decline in both sudomotor and pilomotor nerve fiber density
parallels overall neuropathy progression and is associated with longer durations
of diabetes mellitus and higher glycosylated hemoglobin levels. The measurement
of autonomic nerve fiber density advances the utility of skin biopsies over
current intraepidermal nerve fiber density measurements and can often be
performed without any additional tissue staining or processing.4,15,18 Similarly,
a reduction in sympathetic adrenergic innervation within pilomotor muscles
correlates with diabetic neuropathy severity.2 Using a human model of

autonomic nerve fiber injury, the authors have demonstrated that autonomic
fibers can regenerate,3 making them an attractive end point in clinical trials of
diabetic neuropathy. However, in more advanced disease, the potential for
neural regeneration is limited even with pancreatic transplantation.19
From a practical perspective, it is not usually necessary to pathologically
confirm a diagnosis of autonomic neuropathy in the setting of diabetes mellitus.
In most cases, the history and examination findings are sufficient for a diagnosis.
In addition, the treatment of the underlying disease is unlikely to change based
on the pathology. However, in situations in which unusual patterns of sweating
occur or if specific questions about neuropathy severity arise, skin biopsy with
evaluation of autonomic innervation may have a potential role.20
Familial Amyloid Polyneuropathy

Hereditary amyloidosis is a progressive disease due to a mutation in the
transthyretin (TTR) gene, resulting in misfolded transthyretin proteins
CASE 11-1 A 45-year-old man presented with progressive pain and loss of sensation
in his feet over the past year. He first felt some lancinating pain in his feet
but began to notice loss of sensation after a mild injury to his toes that he
did not detect. The pain became increasingly severe, and that was what
brought him to medical attention. He had no significant past medical
history, and he was not taking any medications. His family history was
unknown because he was adopted.
His examination revealed diminished sensation to vibration, light
touch, temperature, and pinprick in the feet with some involvement
above the ankles. He had mild weakness of the extensor hallucis longus
(4/5) with absent ankle reflexes and reduced patellar reflexes.
Nerve conduction studies and EMG revealed a moderately severe
sensorimotor axonal neuropathy. Skin biopsies were obtained from the
right distal leg, distal thigh, and proximal thigh. The distal leg site
revealed severe denervation of sensory and autonomic fibers. Apple-
green birefringent deposits were seen by polarized light in the distal leg
and distal thigh site after staining with Congo red (FIGURE 11-4). A diagnosis
of amyloidosis was made, and genetic testing revealed the Val30Met
mutation of the TTR gene.
COMMENT In this patient, the presence of amyloid on skin biopsy led to a definitive
diagnosis of hereditary transthyretin amyloidosis and the possibility of an early
intervention with disease-modifying therapy, such as one of the recently US
Food and Drug Administration (FDA)–approved treatments patisaran,
inotersen, or tafamidis. With the development of novel therapeutic
interventions in patients with hereditary amyloidosis, the need for biomarkers
of disease has emerged. Skin biopsies have served multiple roles in this
process by identifying the presence of amyloid deposits stained by Congo
red and by quantifying the damage to autonomic and sensory nerve fibers
within skin biopsies.
206 FEBRUARY 2020

accumulating as amyloid within multiple organ systems, including the nerves
and the skin. The development of novel therapeutic interventions for hereditary
amyloidosis has raised awareness of the needs for biomarkers of disease and
treatment efficacy.21 Skin biopsy has become an important diagnostic tool in this
disease for several reasons. First, Congo red has long been used to visualize
amyloid under polarized light from a variety of different organs and is a simple
means to pathologically confirm a diagnosis when positive.22 The sensitivity and
specificity of skin biopsy in the pathologic diagnosis of polyneuropathy
accompanying hereditary transthyretin amyloidosis has not yet been established,
although if positive, this will confirm a diagnosis of amyloidosis.22 A recent study
of 70 individuals with TTR-A97S mutations revealed that amyloid could not be
detected in asymptomatic carriers, but it could be detected in 25% of those with
mild disease, in approximately 60% of those with moderate disease, and more
than 80% of those with severe disease, suggesting that the role of skin biopsy in
the diagnosis of transthyretin amyloidosis may expand.8 One of the challenges
FIGURE 11-4
Cutaneous amyloid deposition in the patient in CASE 11-1. In these two images, amyloid
deposits can be seen as apple-green under polarized light. Larger deposits are shown with
the red arrowheads, and smaller amyloid deposits are pointed out by the white arrowheads.
The presence of amyloid on skin biopsy confirms a pathologic diagnosis of amyloidosis.

to the broad application of these findings is the mutation-specific variance in

tissue deposition. Future studies across a broader array of TTR mutation types
are necessary to understand the role of skin biopsy in the diagnosis of
transthyretin amyloidosis.
In this same study of 70 patients with TTR-A97S mutations, it was determined
that intraepidermal nerve fiber density and the density of sympathetic
cholinergic nerve fibers surrounding sweat glands were both reduced in TTR
mutation carriers, even before clinical evidence of disease.8 A study by the
same investigators of 28 patients with TTR-A97S mutations detected significant
reduction in sudomotor (sweat gland) nerve fiber density with a selective
vulnerability of sympathetic cholinergic fibers (stained with vasoactive
intestinal polypeptide) compared with other types of nerve fibers.23 The degree
of denervation correlated with autonomic symptoms, autonomic function
testing, and overall disability.23 These findings support the role of skin biopsy
as a marker of early neuropathy involvement and marker of disease severity
using immunohistochemical nerve stains as well as a diagnostic marker of
CASE 11-2 A 68-year-old man reported disturbingly vivid dreams to his physician,
and his spouse reported that he kicked her in his sleep so often that she
began sleeping in an adjacent bed. This began approximately 6 months
earlier after he was started on a low dose of a selective serotonin
reuptake inhibitor (SSRI). He had become mildly depressed after retiring
from his job of 40 years. He drank several cups of coffee every morning to
keep his bowel movements regular, and he reported that recently he had
trouble smelling his coffee. He had no other prior medical history except
elevated cholesterol, for which he took simvastatin, and low-dose
citalopram for the depression.
His neurologic examination was normal; he had no evidence of a
masked face, cogwheeling, tremor, or hyperreflexia, and he had a normal
blink frequency and gait.
As part of a research protocol, skin biopsies obtained from the right
distal thigh and posterior cervical region were stained with protein gene
product 9.5 (PGP 9.5) and for phosphorylated α-synuclein. The nerve
fiber density was normal at both sites. Phosphorylated α-synuclein was
detected within nerve fibers surrounding blood vessels, sweat glands,
and arrector pili muscles (FIGURE 11-5).
With the presence of phosphorylated α-synuclein detected by skin
biopsy, a diagnosis of a synucleinopathy was pathologically confirmed;
however, the specific form of synucleinopathy could not be determined
based on the biopsy results. Confirmation of the type of synucleinopathy
would be dependent on follow-up clinical history, examination findings,
and any ancillary neurophysiologic testing. At this point, based on the
clinical history and examination (ie, absence of autonomic features and
abnormal olfaction), multiple system atrophy and pure autonomic failure
were less likely than the possibility that his symptoms were an early
manifestation of one of the Lewy body disorders (ie, Parkinson disease or
dementia with Lewy bodies).
208 FEBRUARY 2020

disease using Congo red. Again, the caveat that mutation-specific differences
occur must be considered when interpreting the results of skin biopsies
(CASE 11-1).
Synucleinopathies
The synucleinopathies are neurodegenerative diseases characterized by the presence
of phosphorylated α-synuclein within nerves and glia. The synucleinopathies
include Parkinson disease, multiple system atrophy, dementia with Lewy bodies,
and pure autonomic failure. Traditionally, these disorders have been defined
by a combination of history and examination findings and supported by ancillary
diagnostic testing, including neuroimaging and autonomic testing.24 However,
despite these advances, the rate of incorrect diagnosis, even among movement
disorder specialists, is often high particularly in early disease.25 The search for a
definitive biomarker of the synucleinopathies has been of great interest as
patients, physicians, and pharmaceutical companies seek opportunities to
improve the diagnosis of these conditions.26
FIGURE 11-5
Phosphorylated α-synuclein in the patient in CASE 11-2. A pilomotor muscle is seen stained with
protein gene product 9.5 (PGP 9.5) on the left (green). The same image in the middle is
costained for phosphorylated α-synuclein (P-SYN, red), and the merged image is shown on the
right, with overlapping regions seen in gold that confirm the presence of phosphorylated
α-synuclein within pilomotor nerve fibers.
In this case, skin biopsy was helpful in ascertaining that the patient had a COMMENT
synucleinopathy, although diagnosis of the particular type of
synucleinopathy required corroboration with history and examination
findings. Recent studies have demonstrated that skin biopsies may play a
larger role in the future in the diagnosis of the synucleinopathies by detecting
the presence of phosphorylated α-synuclein. In addition, the quantitation of
synuclein within the skin and autonomic innervation may provide pathologic
evidence of disease severity that may prove useful in clinical trials that seek
to alter the natural history of the disease.

KEY POINTS An increasing number of publications have highlighted the ability to detect
phosphorylated α-synuclein within peripheral nerve fibers of individuals with
● In patients with hereditary
amyloidosis, skin biopsy can
any of the synucleinopathies.27–32 Many of the publications have focused on
provide quantitative Parkinson disease, and initially studies reported abnormal α-synuclein deposition
assessment of neuropathy in 10% of cases.33 Over the past decade, many technical advances have improved
severity, but it can also the rates of positive findings across all synucleinopathies.27,28,32,34–37 A recent
provide pathologic
publication of 43 patients with a variety of synucleinopathies used interlaboratory
confirmation of disease by
detection of the presence and intralaboratory comparisons to define reproducibility and reliability of
of amyloid through Congo the testing.38 Results are typically positive in more than 90% of individuals
red staining. with clinical evidence of disease38 and greater than 50% positive in individuals
with prodromal disease (rapid eye movement [REM] sleep behavior disorder)
● Skin biopsies are used in
research studies to measure (CASE 11-2).39
phosphorylated α-synuclein In addition to synuclein staining, investigations have evaluated the density of
to aid in confirming a sudomotor nerve fibers in patients with these neurodegenerative diseases.28,34,37,40,41
diagnosis of an Peripheral autonomic innervation may hold clues about differences between the
α-synucleinopathy such as
Parkinson disease, multiple
synucleinopathies. The autonomic nervous system involvement in patients with
system atrophy, pure multiple system atrophy is believed to be preganglionic, whereas patients with
autonomic failure, or Lewy Parkinson disease have peripheral postganglionic nerve damage.7,30 Future studies
body dementia. are required to determine the potential role of peripheral autonomic nerve fiber
density analysis in patients with various synucleinopathies.
CONCLUSION
The addition of skin biopsies to existing measures of autonomic function
can provide a valuable addition to structural assessment of the autonomic
nervous system. Autonomic nerve fibers can be sampled both regionally and
chronologically to monitor disease progression and response to treatment.
Skin biopsies are simple to obtain, although they require advanced laboratory
processing for immunohistochemical staining. Despite the recent advances,
many diseases of the autonomic nervous system lack detailed descriptions
of the autonomic innervation derived from skin biopsies. In addition,
standardization of techniques across different laboratories is necessary for
results to be comparable. Normative control data are needed to adequately
describe the range of expression in healthy individuals. As these data become
available, the utility of skin biopsy for evaluation of autonomic structures
will lead to novel understanding of pathophysiology and enhance the
development of treatments for diseases of the autonomic nervous system.
REFERENCES
1 Lauria G, Hsieh ST, Johansson O, et al. European 2 Nolano M, Provitera V, Caporaso G, et al.
Federation of Neurological Societies/Peripheral Quantification of pilomotor nerves: a new tool
Nerve Society Guideline on the use of skin biopsy to evaluate autonomic involvement in diabetes.
in the diagnosis of small fiber neuropathy. Report Neurology 2010;75(12):1089–1097. doi:10.1212/
of a joint task force of the European Federation WNL.0b013e3181f39cf4.
of Neurological Societies and the Peripheral
3 Gibbons CH, Wang N, Freeman R. Capsaicin
Nerve Society. Eur J Neurol 2010;17(7):903–909.
induces degeneration of cutaneous autonomic
doi:10.1111/j.1468-1331.2010.03023.x.
nerve fibers. Ann Neurol 2010;68(6):888–898.
doi:10.1002/ana.22126.
210 FEBRUARY 2020

4 Gibbons CH, Illigens BM, Wang N, Freeman R. 17 Ebenezer GJ, O'Donnell R, Hauer P, et al. Impaired
Quantification of sweat gland innervation: a neurovascular repair in subjects with diabetes
clinical-pathologic correlation. Neurology 2009; following experimental intracutaneous axotomy.
72(17):1479–1486. doi:10.1212/WNL. Brain 2011;134(pt 6):1853–1863. doi:10.1093/brain/
0b013e3181a2e8b8. awr086.
5 Wang N, Gibbons CH, Freeman R. Novel 18 Luo KR, Chao CC, Hsieh PC, et al. Effect of
immunohistochemical techniques using glycemic control on sudomotor denervation in
discrete signal amplification systems for human type 2 diabetes. Diabetes Care 2012;35(3):
cutaneous peripheral nerve fiber imaging. 612–616. doi:10.2337/dc11-1607.
J Histochem Cytochem 2011;59(4):382–390.
19 Havrdova T, Boucek P, Saudek F, et al. Severe
doi:10.1369/0022155410396931.
epidermal nerve fiber loss in diabetic neuropathy
6 Gibbons CH, Illigens BM, Wang N, Freeman R. is not reversed by long-term normoglycemia
Quantification of sudomotor innervation: a after simultaneous pancreas and kidney
comparison of three methods. Muscle Nerve transplantation. Am J Transplant 2016;16(7):
2010;42(1):112–119. doi:10.1002/mus.21626. 2196–2201. doi:10.1111/ajt.13715.
7 Dabby R, Djaldetti R, Shahmurov M, et al. Skin 20 Gibbons CH, Freeman R. Treatment-induced
biopsy for assessment of autonomic denervation neuropathy of diabetes: an acute, iatrogenic
in Parkinson's disease. J Neural Transm (Vienna) complication of diabetes. Brain 2015;138(pt 1):
2006;113(9):1169–1176. doi:10.1007/s00702-005- 43–52. doi:10.1093/brain/awu307.
0431-0.
21 Coelho T, Maia LF, Martins da Silva A, et al.
8 Chao CC, Hsueh HW, Kan HW, et al. Skin nerve Tafamidis for transthyretin familial amyloid
pathology: biomarkers of premanifest and polyneuropathy: a randomized, controlled trial.
manifest amyloid neuropathy. Ann Neurol 2019; Neurology 2012;79(8):785–792. doi:10.1212/
85(4):560–573. doi:10.1002/ana.25433. WNL.0b013e3182661eb1.
9 Ramien M, Ruocco I, Cuello AC, et al. 22 Ebenezer GJ, Liu Y, Judge DP, et al. Cutaneous
Parasympathetic nerve fibers invade the upper nerve biomarkers in transthyretin familial amyloid
dermis following sensory denervation of the rat polyneuropathy. Ann Neurol 2017;82(1):44–56.
lower lip skin. J Comp Neurol 2004;469(1):83–95. doi:10.1002/ana.24972.
doi:10.1002/cne.10998.
23 Chao CC, Huang CM, Chiang HH, et al. Sudomotor
10 Ruocco I, Cuello AC, Parent A, Ribeiro-da-Silva A. innervation in transthyretin amyloid neuropathy:
Skin blood vessels are simultaneously innervated pathology and functional correlates. Ann Neurol
by sensory, sympathetic, and parasympathetic 2015;78:272–283. doi:10.1002/ana.24438.
fibers. J Comp Neurol 2002;448(4):323–336.
24 Postuma RB, Berg D, Stern M, et al. MDS clinical
doi:10.1002/cne.10241.
diagnostic criteria for Parkinson's disease. Mov Disord
11 Peltier AC, Myers MI, Artibee KJ, et al. Evaluation 2015;30(12):1591–1601. doi:10.1002/mds.26424.
of dermal myelinated nerve fibers in diabetes
25 Adler CH, Beach TG, Hentz JG, et al. Low
mellitus. J Peripher Nerv Syst 2013;18(2):162–167.
clinical diagnostic accuracy of early vs advanced
doi:10.1111/jns5.12027.
Parkinson disease: clinicopathologic study.
12 Nolano M, Provitera V, Manganelli F, et al. Loss of Neurology 2014;83(5):406–412. doi:10.1212/
cutaneous large and small fibers in naive and WNL.0000000000000641.
l-dopa-treated PD patients. Neurology 2017;89(8):
26 Malek N, Swallow D, Grosset KA, et al. Alpha-
776–784. doi:10.1212/WNL.0000000000004274.
synuclein in peripheral tissues and body fluids as
13 Nolano M, Provitera V, Perretti A, et al. Ross a biomarker for Parkinson's disease—a systematic
syndrome: a rare or a misknown disorder of review. Acta Neurol Scand 2014;130(2):59–72.
thermoregulation? A skin innervation study on doi:10.1111/ane.12247.
12 subjects. Brain 2006;129(pt 8):2119–2131.
27 Gibbons CH, Wang N, Freeman R. Cutaneous
doi:10.1093/brain/awl175.
alpha-synuclein from paraffin embedded
14 Di Leo R, Nolano M, Boman H, et al. Central and autopsy specimens in Parkinson’s disease.
peripheral autonomic failure in cold-induced J Parkinsons Dis 2017;7(3):503–509.
sweating syndrome type 1. Neurology 2010;75(17): doi:10.3233/JPD-171088.
1567–1569. doi:10.1212/WNL.0b013e3181f96237.
28 Gibbons CH, Garcia J, Wang N, et al. The
15 Luo KR, Chao CC, Chen YT, et al. Quantitation diagnostic discrimination of cutaneous
of sudomotor innervation in skin biopsies of α-synuclein deposition in Parkinson disease.
patients with diabetic neuropathy. J Neuropathol Neurology 2016;87(5):505–512. doi:10.1212/
Exp Neurol 2011;70(10):930–938. doi:10.1097/ WNL.0000000000002919.
NEN.0b013e318230b0f4.
29 Navarro-Otano J, Casanova-Mollà J, Morales M,
16 Gibbons CH, Freeman R, Tecilazich F, et al. The et al. Cutaneous autonomic denervation in
evolving natural history of neurophysiologic Parkinson’s disease. J Neural Transm (Vienna)
function in patients with well-controlled 2015;122(8):1149–1155. doi:10.1007/s00702-014-
diabetes. J Peripher Nerv Syst 2013;18(2):153–161. 1355-3.
doi:10.1111/jns5.12021.

30 Zange L, Noack C, Hahn K, et al. Phosphorylated 36 Donadio V, Incensi A, Rizzo G, et al. Spine
α-synuclein in skin nerve fibres differentiates topographical distribution of skin α-synuclein
Parkinson's disease from multiple system deposits in idiopathic Parkinson disease.
atrophy. Brain 2015;138(pt 8):2310–2321. J Neuropathol Exp Neurol 2017;76(5):384–389.
doi:10.1093/brain/awv138. doi:10.1093/jnen/nlx021.
31 Donadio V, Incensi A, Cortelli P, et al. Skin 37 Donadio V, Incensi A, Piccinini C, et al. Skin nerve
sympathetic fiber α-synuclein deposits: a misfolded α-synuclein in pure autonomic failure
potential biomarker for pure autonomic failure. and Parkinson disease. Ann Neurol 2016;79(2):
Neurology 2013;80(8):725–732. doi:10.1212/ 306–316. doi:10.1002/ana.24567.
WNL.0b013e3182825127.
38 Donadio V, Doppler K, Incensi A, et al. Abnormal
32 Donadio V. Skin nerve α-synuclein deposits in α-synuclein deposits in skin nerves: intra- and
Parkinson's disease and other synucleinopathies: inter-laboratory reproducibility. Eur J Neurol
a review [published online]. Clin Auton Res 2018. 2019;26(10):1245–1251. doi:10.1111/ene.13939.
doi:10.1007/s10286-018-0581-4.
39 Doppler K, Jentschke HM, Schulmeyer L, et al.
33 Miki Y, Tomiyama M, Ueno T, et al. Clinical Dermal phospho-alpha-synuclein deposits
availability of skin biopsy in the diagnosis of confirm REM sleep behaviour disorder as
Parkinson's disease. Neurosci Lett 2010;469(3): prodromal Parkinson’s disease. Acta
357–359. doi:10.1016/j.neulet.2009.12.027. Neuropathol 2017;133(4):535–545. doi:10.1007/
s00401-017-1684-z.
34 Donadio V, Incensi A, Del Sorbo F, et al. Skin
nerve phosphorylated α-synuclein deposits in 40 Donadio V, Incensi A, Rizzo G, et al. A new
Parkinson disease with orthostatic hypotension. potential biomarker for dementia with Lewy
J Neuropathol Exp Neurol 2018;77(10):942–949. bodies: skin nerve α-synuclein deposits.
doi:10.1093/jnen/nly074. Neurology 2017;89(4):318–326. doi:10.1212/
WNL.0000000000004146.
35 Antelmi E, Donadio V, Incensi A, et al. Skin
nerve phosphorylated α-synuclein deposits in 41 Wang N, Gibbons CH, Lafo J, Freeman R.
idiopathic REM sleep behavior disorder. α-Synuclein in cutaneous autonomic nerves.
Neurology 2017;88(22):2128–2131. doi:10.1212/ Neurology 2013;81(18):1604–1610. doi:10.1212/
WNL.0000000000003989. WNL.0b013e3182a9f449.
DISCLOSURE
Continued from page 200
Biopharma; Toray Medical Co, Ltd; and Vertex

Pharmaceuticals. Dr Freeman has received personal
compensation for serving as editor-in-chief of
Autonomic Neuroscience: Basic & Clinical. Drs Wang,
Kim, and Campagnolo report no disclosures.
212 FEBRUARY 2020

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(credits are automatically calculated).

POSTREADING TEST
ARTICLE 1: PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE AUTONOMIC

NERVOUS SYSTEM
1 Sympathetic ganglion neurons to which of the following effector

organs are primarily cholinergic?
A adrenal medulla
B blood vessels
C eye
D gastrointestinal tract
E sweat glands
2 Which of the following manifestations of autonomic neuropathy

reflects sympathetic failure?
A constipation
B erectile dysfunction
C impaired upper gastrointestinal motility
D orthostatic hypotension
E urinary incontinence
3 Which of the following brainstem structures innervates ganglia in the

gastrointestinal tract to control motility and secretion?
A dorsal motor nucleus of the vagus

B midbrain periaqueductal gray
C nucleus ambiguus
D nucleus raphe pallidus
E reticular formation
4 A 50-year-old man with type 2 diabetes mellitus complicated by

neuropathy is seen in the emergency department with headache and
blurred vision developing after he took an over-the counter
decongestant containing pseudoephedrine. Review of systems reveals
constipation and erectile dysfunction. His blood pressure is 198/102.
Examination is otherwise significant for absent ankle jerks and sensory
loss to all modalities in the feet. Which of the following is the most
likely explanation for his new symptoms?
A allergy to pseudoephedrine
B infarct of the rostral ventrolateral medulla
C loss of baroreceptor afferent input
D parasympathetic failure
E upregulation of vascular α1 receptors
216 FEBRUARY 2020

ARTICLE 2: AUTONOMIC HISTORY, EXAMINATION, AND LABORATORY
EVALUATION
5 In patients with neurogenic orthostatic hypotension, the change in

vital signs from supine or sitting to standing differs from that in
patients with orthostatic hypotension caused by dehydration in which
of the following ways?
A the decrease in blood pressure is the same, but it takes longer to

occur
B there is an associated heart rate decrement of more than
20 beats/min
C there is an associated heart rate increment of less than
10 beats/min
D there is an associated increase in diastolic blood pressure
E there is a smaller drop in systolic blood pressure
6 A 60-year-old woman with a 10-year history of type 2 diabetes mellitus

presents with 6 months of symptoms of feeling hot, lightheaded, and
severely fatigued on hot days. She also reports severe flushing of her
entire body and headaches when in hot environments. On examination,
her skin feels rough throughout (face, torso, and extremities) when
gently stroked. Failure of which of the following systems is responsible
for her symptoms and examination findings?
A parasympathetic and sympathetic cholinergic

B parasympathetic cholinergic
C sympathetic adrenergic
D sympathetic cholinergic
E sympathetic noradrenergic
7 A 65-year-old man presents with episodic, severe hypertension with

systolic blood pressures of up to 220 mm Hg. His past medical history is
significant for benign prostatic hypertrophy, early-stage throat cancer
diagnosed and treated a decade ago, hypercholesterolemia, measles as a
child, and cluster headaches. Which of the following diagnoses may be
pertinent to his labile hypertension?
A benign prostatic hypertrophy

B cluster headaches
C hypercholesterolemia
D measles
E throat cancer

POSTREADING TEST
ARTICLE 3: AUTOIMMUNE AUTONOMIC DISORDERS
8 A 48-year-old woman presents with a 5-week history of emesis,

dehydration, constipation, urinary retention, weight loss, dry eyes, and
fatigue. Examination reveals orthostatic hypotension. Pupillometry
reveals premature pupillary redilation, and the quantitative sudomotor
axon reflex test (QSART) results are reduced at all sites. Which of the
following diagnoses is most likely in this patient?
A autoimmune autonomic ganglionopathy

B Lambert-Eaton myasthenic syndrome
C multiple system atrophy
D peripheral autonomic neuropathy
E Sjögren syndrome
9 In a patient with subacute-onset autonomic symptoms, which of the

following features would better support a diagnosis of immune-mediated
sensory and autonomic neuropathy rather than autoimmune autonomic
ganglionopathy?
A gastrointestinal dysmotility
B neuropathic pain
C orthostatic hypotension
D pupillary abnormalities
E urinary retention
10 A 52-year-old man had profuse diarrhea and 20-kg (44-lb) weight loss
over a 4-month period followed by confusion, myoclonus, exaggerated
startle, tremor, personality change, and psychosis. The neurologic
syndrome progressed over 6 months. Antibodies against which of the
following targets is most likely to be found in this patient?
A acetylcholine (ACh) receptor

B contactin-associated proteinlike 2 (CASPR2)
C dipeptidyl-peptidase–like protein 6 (DPPX)
D leucine-rich glioma inactivated protein 1 (LGI1)
E N-methyl-D-aspartate (NMDA)
218 FEBRUARY 2020

ARTICLE 4: AUTONOMIC PERIPHERAL NEUROPATHY
11 A patient presents with several weeks of worsening severe distal pain

of all extremities, lightheadedness with standing, diarrhea, nausea,
early satiety, weight loss, urinary retention, and gustatory sweating.
Which of the following is the most likely clinical scenario preceding
symptom onset?
A an 18-year-old with type 1 diabetes mellitus who recently moved

away from home to attend college and is now missing occasional
insulin doses
B a 22-year-old with type 1 diabetes mellitus who, after recently
getting a job with better insurance benefits, is no longer having to
severely ration insulin after doing so for a year
C a 55-year-old with type 2 diabetes mellitus who recently was able
to discontinue metformin after losing a significant amount of
weight with strict diabetic diet and exercise
D a 65-year-old with closely followed prediabetes who was just
started on low-dose metformin for a slight bump in hemoglobin
A1c percentage
E a 70-year-old diagnosed with type 2 diabetes mellitus 20 years
ago with no recent changes in stable oral management
12 A 45-year old-man presents for a second opinion for 8 months of

progressive sensory and autonomic symptoms, including paresthesia
and numbness of his distal extremities, orthostatic lightheadedness,
diminished sweating, nausea, early satiety, bloating, constipation
alternating with diarrhea, urinary retention, and erectile dysfunction.
Early in his course he was given a diagnosis of bilateral carpal tunnel
syndrome. Examination reveals distal hair loss and dry skin. He has
distal lower extremity weakness and muscle atrophy on motor
examination. Vibration is absent at the toes and moderately diminished
at the ankles and pinprick is diminished in a stocking-glove distribution.
Ankle reflexes are absent. Gait is slightly wide based and cautious. His
brother has similar symptoms, and his father died at age 60 of renal failure.
Gene sequencing is most likely to detect which of the following mutations?
A Ala117Val
B Asp178Asn
C Glu6Val
D Pro102Leu
E Val30Met

POSTREADING TEST
13 Elevation of which of the following antibodies is associated with EMG

findings of peripheral nerve hyperexcitability, myokymia, and clinical
autonomic dysfunction?
A anticyclic citrullinated peptide

B antineuronal nuclear antibody type 1 (ANNA-1)
C contactin-associated proteinlike 2 (CASPR2)
D myelin protein zero
E Purkinje cell antibody type 2 (PCA-2)
ARTICLE 5: SYNUCLEINOPATHIES
14 A 60-year-old man presents with lightheadedness. He has a 2-year

history of supine hypertension, urinary urgency, erectile dysfunction,
and heat intolerance. Over the past 9 months, he had developed
lightheadedness upon standing, a tremor in his hands, and falls. On
examination, he has severe orthostatic hypotension, increased tone in
the neck and all extremities, bilateral arm tremor with posture
holding, postural instability, and shuffling steps. Which of the
following diagnoses is most likely in this patient?
A dementia with Lewy bodies

B multiple system atrophy
C Parkinson disease
D progressive supranuclear palsy
E pure autonomic failure
15 Which of the following sleep disturbances is classically associated

with synucleinopathies and may precede the autonomic and motor
features?
A central sleep apnea

B narcolepsy
C obstructive sleep apnea
D periodic limb movement disorder
E rapid eye movement (REM) sleep behavior disorder
16 Which of the following factors is most likely the major contributor to

sialorrhea in Parkinson disease?
A anatomic abnormalities
B dopaminergic medications
C esophageal dysfunction
D overproduction of saliva
E reduced swallowing frequency
220 FEBRUARY 2020

17 Which of the following manifestations of autonomic system
involvement in Parkinson disease typically occurs the earliest and may
precede motor symptoms by over 20 years?
A constipation
B heat intolerance
C orthostatic hypotension
D sexual dysfunction
E urinary urgency
ARTICLE 6: POSTURAL TACHYCARDIA SYNDROME AND NEURALLY

MEDIATED SYNCOPE
18 A 19-year-old woman with a history of migraines presents with 1 year

of lightheadedness, vision dimming, palpitations, and tremulousness
with prolonged standing. She is in her junior year of college and
reports that she is struggling academically because of a constant
sensation of “brain fog.” She used to play intramural volleyball but
recently stopped playing because her symptoms worsened during
games. Examination reveals an increase in her heart rate of
45 beats/min within 10 minutes of standing. Which of the following
findings is most likely to be seen on examination?
A cardiac murmur
B decrease in systolic blood pressure after 5 minutes of standing
C erythema of extremities after 5 minutes of standing
D hyperreflexia
E joint hypermobility
19 Which of the following tests should be part of the initial evaluation in

all patients suspected of having postural tachycardia syndrome?
A 12-lead ECG
B Holter monitor
C scintigraphic transit study
D tilt-table testing
E transthoracic echocardiogram

POSTREADING TEST
20 A 17-year-old woman presents with 6 months of lightheadedness and

presyncope with prolonged standing associated with worsening
insomnia, generalized fatigue, nausea, and abdominal pain. Her
symptoms worsen with hot showers and any physical activity. She has
attempted to deal with her symptoms by staying in bed for as long as
possible for days at a time, but her symptoms continue to worsen. She
has missed over a month of school because of her symptoms. Which
of the following is the most appropriate treatment strategy?
A high-intensity interval training

B knee-high compression stockings
C scheduled caffeine intake
D supplemental magnesium
E water bolus therapy
21 Which of the following characteristics should be considered a red flag

and warrants further workup in a patient with a spell of loss of
consciousness?
A eye opening during the event

B loss of consciousness during exertion
C postevent fatigue
D prodrome of diaphoresis, pallor, and lightheadedness
E several myoclonic jerks after loss of consciousness
ARTICLE 7: SWEATING DISORDERS
22 An 18-year-old woman is referred for evaluation after her basketball

teammates noticed that during training, one side of her face flushed
and sweated while the other remained pale and dry. Her pupils are
symmetric and reactive to light, and stretch reflexes are normal. A
thermoregulatory sweat test shows anhidrosis of the right face and
neck. Which of the following diagnostic tests is warranted?
A chest radiograph
B EMG
C head CT
D head-up tilt-table test
E heart rate variability to deep breathing and Valsalva
23 Which of the following treatments is recommended for initial

management of focal primary hyperhidrosis?
A anticholinergic medications
B anxiolytics
C intradermal botulinum toxin injections
D tap water iontophoresis
E topical antiperspirants
222 FEBRUARY 2020

24 Which of the following medications is a common cause of generalized
hyperhidrosis?
A benztropine
B glycopyrrolate
C ipratropium bromide
D oxybutynin
E sertraline
25 A patient with a T3 spinal cord injury has episodes of hypertension,

bradycardia, facial flushing, and profuse sweating above the level of
the lesion and pale, cold skin and piloerection below the level of the lesion.
Which of the following precipitants of the episodes is most likely?
A anxiety
B constipation
C crying
D eating
E hiccups
ARTICLE 8: AUTONOMIC HYPERACTIVITY
26 The presence of which of the following features may be useful in

distinguishing paroxysmal sympathetic hyperactivity due to primary
neurologic disease from paroxysmal sympathetic hyperactivity due to
sepsis?
A excess oral secretions

B hyperthermia over 39.2°C (102.5°F)
C rapid-onset tachycardia
D severe muscle rigidity
E tachypnea involving use of the accessory muscles
27 Paroxysmal sympathetic hyperactivity is most likely to develop in

which of the following patients following a motor vehicle accident?
A a 17-year-old with a Glasgow Coma Scale score of 5 and fevers

that began on day 3 of hospital admission
B an 18-year-old with a Glasgow Coma Scale score of 14 and
tachypnea that began on day 10 of hospital admission
C a 30-year-old with a Glasgow Coma Scale score of 14 and
hypoxemia that was noted on admission
D an 80-year-old with a Glasgow Coma Scale score of 6 and
increased nasal congestion that began on day 4 of hospital
admission
E an 85-year-old with a Glasgow Coma Scale score of 13 and fevers
that began after discharge to acute rehab

POSTREADING TEST
28 A 55-year-old woman presents with rapid ascending paralysis

following a gastrointestinal viral illness. EMG shows
electrodiagnostic evidence of a severe demyelinating
polyradiculoneuropathy. She reports severe low back pain and is
started on acetaminophen and hydrocodone every 4 hours as needed
for pain. Several days later, she develops marked abdominal
distention with evidence for adynamic ileus on abdominal x-ray. She
also has labile heart rate and blood pressure. Narcotics are held
without improvement. Which of the following medications is the
most appropriate next step in the management of this patient?
A naloxone
B naltrexone
C nebivolol
D neostigmine
E nifedipine
29 A 45-year-old man has been quadriplegic after a C5 spinal cord injury

due to a diving accident that occurred 6 months ago. He is brought to
the emergency department from his long-term acute care facility
because of more frequent episodes of severe hypertension associated
with pronounced facial flushing, headache, sweating, and nasal
congestion. Which of the following tests is the most appropriate next
step in the evaluation of this patient?
A arterial Doppler of the upper extremities

B CT scan of the head
C echocardiogram
D skin examination
E tilt-table testing
ARTICLE 9: MANAGEMENT OF ORTHOSTATIC HYPOTENSION
30 The definition of orthostatic hypotension requires a reduction in

blood pressure of at least which of the following magnitudes within
the first 3 minutes of standing or head-up tilt on a tilt table?
A 10 mm Hg systolic or 5 mm Hg diastolic
B 20 mm Hg systolic or 10 mm Hg diastolic
C 20 mm Hg systolic or 15 mm Hg diastolic
D 30 mm Hg systolic or 10 mm Hg diastolic
E 30 mm Hg systolic or 15 mm Hg diastolic
224 FEBRUARY 2020

31 A 66-year-old woman with orthostatic lightheadedness has a supine
blood pressure of 135/90 mm Hg with a heart rate of 86 beats/min.
Upon standing, her blood pressure falls to 95/76 mm Hg with a heart
rate of 112 beats/min. Which of the following causes of her symptoms
is most likely?
A amyloidosis
B diabetes mellitus
C hypovolemia
D pure autonomic failure
E vestibular disorder
32 A 62-year-old man with a history of depression presents with

progressive orthostatic and postprandial intolerance, erectile
dysfunction, and generalized loss of sweating over the past 2 years.
His medications and supplements include venlafaxine and ginseng. He
drinks four cups of coffee daily. His blood pressure in the supine
position is 139/92 mm Hg with a heart rate of 72 beats/min. His blood
pressure after 3 minutes of standing up is 89/52 mm Hg with a heart
rate of 83 beats/min, at which time patient reports feeling moderately
lightheaded. ECG is normal. Laboratory studies reveal a mild
normocytic, normochromic anemia with normal iron, vitamin B12,
and folic acid levels. Which of the following interventions is most
appropriate to recommend to improve this patient’s orthostasis?
A begin erythropoietin
B reduce coffee intake
C start sildenafil
D stop ginseng supplementation
E switch from venlafaxine to amitriptyline
33 Which of the following recommendations for aerobic exercise is most

appropriate for a patient with neurogenic orthostatic intolerance?
A avoidance of exercise
B dancing
C running
D swimming
E tennis

POSTREADING TEST
ARTICLE 10: LOWER URINARY TRACT AND BOWEL DYSFUNCTION IN

NEUROLOGIC DISEASE
34 The presence of nocturia in patients with Parkinson disease is

associated with an increased risk of which of the following
complications?
A aspiration
B behavioral disturbances
C erectile dysfunction
D falls
E truncal rigidity
35 A 33-year-old woman with a 5-year history of multiple sclerosis has

had worsening bladder symptoms for 6 months, including daytime
and nighttime urinary frequency. After cutting down her caffeine
intake, her daytime symptoms improved; however, she has persistent
nocturia, getting up 4 times a night to urinate, which is contributing to
significant daytime fatigue. Review of systems is positive for chronic
constipation. A basic metabolic panel, urinalysis, and renal and
bladder ultrasound are all normal. Which of the following
interventions should be started in this patient?
A botulinum toxin
B citalopram
C desmopressin
D intermittent self-catheterization
E oxybutynin
36 A 68-year-old man with newly diagnosed Parkinson disease presents

for follow-up 3 months after treatment with carbidopa/levodopa was
initiated. He reports improvement in his resting tremor and rigidity to
the point that he was able to resume daily exercise, but he has had no
improvement in his chronic constipation. Which of the following
treatment options should be recommended next?
A bisacodyl
B lactulose
C psyllium
D sennosides
E tegaserod
226 FEBRUARY 2020

ARTICLE 11: SKIN BIOPSY IN EVALUATION OF AUTONOMIC DISORDERS
37 The utility of skin biopsy in the diagnosis of peripheral autonomic

neuropathies may be limited by which of the following factors?
A dermal structure susceptibility to crush artifact

B homogenous distribution of dermal structures
C lack of staining uptake by dermal structures
D large surface area of biopsy required for adequate testing
E three-dimensional structure of large nerve fibers
38 Skin biopsy in an asymptomatic carrier of the transthyretin (TTR)-

A97S gene mutation that causes familial amyloid polyneuropathy
would likely show which of the following findings?
A apple-green birefringent deposits by polarized light after

staining with Congo red
B increased density of intraepidermal nerve fiber density
C increased density of sympathetic adrenergic fibers within
piloerector muscles
D reduced density of sudomotor sympathetic cholinergic nerve
fibers
E reduced density of sympathetic adrenergic fibers in the base of
hair follicles
39 A 39-year-old man presents with increased sweating on his left leg and
right chest. Examination demonstrates tonic, poorly reactive pupils,
absent muscle stretch reflexes, and an absence of sweating on one side of
his body. Skin biopsy reveals severely reduced sympathetic cholinergic
innervation underlying anhidrotic skin and loss of cutaneous blood flow
regulation in both anhidrotic and hyperhidrotic skin. Which of the
following disorders does this patient most likely have?
A autoimmune autonomic ganglionopathy

B familial amyloid polyneuropathy
C Holmes-Adie syndrome
D neurosyphilis
E Ross syndrome
40 Staining of skin biopsy specimens with which of the following

compounds is most likely to be diagnostic in a patient with vivid,
frightening dreams and dream-enactment behavior?
A Congo red
B phosphorylated α-synuclein
C protein gene product 9.5
D tyrosine hydroxylase
E vasoactive intestinal polypeptide

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment
and CME Test—Preferred
Responses
By Allison L. Weathers, MD, FAAN; Allyson R. Zazulia, MD
AUTONOMIC 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 Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (www.mainport.org) to record learning
and outcomes. Canadian participants can claim a maximum of 20 hours
(credits are automatically calculated).
ARTICLE 1: PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE AUTONOMIC

NERVOUS SYSTEM
1 The preferred response is E (sweat glands). Most postganglionic sympathetic

neurons are adrenergic (ie, use primarily norepinephrine). A notable exception
to this rule is the sympathetic innervation of sweat glands, in which the
neurotransmitter at both preganglionic and postganglionic synapses is
228 FEBRUARY 2020

acetylcholine. For more information, refer to pages 13–14 of the Continuum
article “Physiology and Pathophysiology of the Autonomic Nervous System.”
2 The preferred response is D (orthostatic hypotension). Orthostatic hypotension

is a manifestation of sympathetic failure, whereas the other symptoms of
autonomic neuropathy listed reflect parasympathetic failure. Impaired upper
gastrointestinal motility reflects vagal failure, constipation reflects enteric
nervous system failure, and erectile dysfunction and urinary incontinence reflect
sacral parasympathetic failure. For more information, refer to pages 13–15 of
the Continuum article “Physiology and Pathophysiology of the Autonomic
Nervous System.”
3 The preferred response is A (dorsal motor nucleus of the vagus). Each of the
listed structures has a prominent role in autonomic function. Vagal preganglionic
neurons located in the dorsal motor nucleus of the vagus provide cholinergic
input to the ganglia of the enteric nervous system. Midbrain periaqueductal gray
mediates the micturition reflex and has a role in coordinated autonomic,
somatomotor, and pain modulatory responses to stress. Neurons of the nucleus
ambiguus provide vagal output to cardiac ganglion neurons controlling the sinus
node. Neurons of the nucleus raphe pallidus mediate sympathoexcitatory
responses to external stressors and exposure to cold. Premotor
sympathoexcitatory neurons in the reticular formation of the rostral
ventrolateral medulla control regulate peripheral resistance in response to
baroreflex inputs. For more information, refer to page 22 of the Continuum
article “Physiology and Pathophysiology of the Autonomic Nervous System.”
4 The preferred response is E (upregulation of vascular α1 receptors). This patient

with diabetic autonomic neuropathy developed hypertension in response to
pseudoephedrine, most likely reflecting denervation supersensitivity. In the
setting of peripheral denervation, loss of tonic modulation of adrenergic
receptor kinetics results in upregulation of adrenergic receptors, accounting for
the exaggerated vasoconstrictor response/hypertension to a low-dose
sympathomimetic agent. For more information, refer to page 22 of the
Continuum article “Physiology and Pathophysiology of the Autonomic Nervous
System.”
ARTICLE 2: AUTONOMIC HISTORY, EXAMINATION, AND LABORATORY

EVALUATION
5 The preferred response is C (there is an associated heart rate increment of less

than 10 beats/min). In the dehydrated state, when intravascular volume is
decreased and the autonomic nervous system is functioning normally,
orthostatic hypotension is accompanied by reflex tachycardia. This reflex
tachycardia is often deficient in autonomic failure. For more information, refer to

POSTREADING TEST—PREFERRED RESPONSES
page 35 of the Continuum article “Autonomic History, Examination, and

Laboratory Evaluation.”
6 The preferred response is D (sympathetic cholinergic). Failure of the

sympathetic cholinergic system results in hypohidrosis or anhidrosis. This
prevents thermoregulatory sweating and results in patients becoming
symptomatic in hot environments and with exercise. This occurs as
acetylcholine is the primary neurochemical messenger at eccrine neuroeffector
junctions. Cutaneous flushing may occur as a secondary mechanism for heat
dissipation. Patients with impairment in thermoregulatory sweating are at risk for
heat exhaustion and heatstroke. The sympathetic cholinergic impairment that
occurs in diabetic autonomic neuropathy may occur in a distal, radicular, or
global pattern. For more information, refer to page 31 of the Continuum article
“Autonomic History, Examination, and Laboratory Evaluation.”
7 The preferred response is E (throat cancer). This patient likely had radiation to
his neck to treat his early-stage throat cancer, which may result in damage to the
carotid baroreceptors and impaired reflex control of central sympathetic
outflow. This question is a critical aspect of the history of patients who present
with episodic hypertension, as they may view their cancer and its treatment as
remote and unrelated and may not volunteer the information. Patients should
also be asked about the use of stimulant medications, especially dietary
supplements and over-the-counter medications, as they may also not think this
is pertinent to their current presentation. For more information, refer to
page 31 of the Continuum article “Autonomic History, Examination, and
Laboratory Evaluation.”
ARTICLE 3: AUTOIMMUNE AUTONOMIC DISORDERS
8 The preferred response is A (autoimmune autonomic ganglionopathy).

Autoimmune autonomic ganglionopathy is a syndrome of panautonomic failure
caused by antibodies to ganglionic nicotinic acetylcholine receptors. The clinical
syndrome commonly follows an acute or subacute course and is characterized
by diffuse cholinergic and adrenergic impairment, postural hypotension,
gastrointestinal dysmotility, urinary retention, and pupillary dysfunction.
Autonomic symptoms may be seen with all of the other options, but the
prominent cholinergic failure and absence of parkinsonian or cerebellar signs and
sensory symptoms help to differentiate autoimmune autonomic ganglionopathy
from the other disorders. For more information, refer to pages 46–47 of the
Continuum article “Autoimmune Autonomic Disorders.”
9 The preferred response is B (neuropathic pain). Sensory symptoms including

neuropathic pain and objective evidence of small or large fiber sensory
230 FEBRUARY 2020

involvement in a patient with autonomic symptoms suggest a diagnosis of
immune-mediated sensory and autonomic neuropathy. Antibody-mediated
autonomic ganglionopathy is more likely in patients with prominent cholinergic
symptoms, urinary retention, and pupillary abnormalities. Orthostatic
hypotension and gastrointestinal dysmotility may be seen in both disorders. For
more information, refer to pages 48, 50 of the Continuum article “Autoimmune
Autonomic Disorders.”
10 The preferred response is C (dipeptidyl-peptidase–like protein 6 [DPPX]). This

patient with cognitive deficits and symptoms of central nervous system
hyperexcitability preceded by severe symptoms of gastrointestinal dysmotility
most likely has DPPX antibody–associated encephalitis. DPPX is a regulatory
protein of the Kv4.2 potassium channels that are expressed by neurons in the
central nervous system and myenteric plexus. For more information, refer to
pages 52–53 of the Continuum article “Autoimmune Autonomic Disorders.”
ARTICLE 4: AUTONOMIC PERIPHERAL NEUROPATHY
11 The preferred response is B (a 22-year-old with type 1 diabetes mellitus who,

after recently getting a job with better insurance benefits, is no longer having to
severely ration insulin after doing so for a year). The patient is presenting with
severe pain and autonomic dysfunction of subacute onset consistent with a
diagnosis of treatment-induced neuropathy of diabetes mellitus. The typical
clinical scenario is symptom onset in association with rapidly achieved glycemic
control in patients with a high pretreatment hemoglobin A1c. Out of the options
provided, the patient with type 1 diabetes mellitus who was unable to afford
adequate insulin dosing and suddenly restarted full-dose insulin is most at risk for
developing this complication. For more information, refer to page 61 of the
Continuum article, “Autonomic Peripheral Neuropathy.”
12 The preferred response is E (Val30Met). This patient’s constellation of

symptoms and examination findings, their time course, and his positive family
history are suggestive of a hereditary autonomic neuropathy. Out of the options
provided, Val30Met occurring on the TTR gene is the most commonly observed
mutation in hereditary amyloidosis. This hereditary neuropathy has an autosomal
dominant inheritance pattern and usually presents in the third to fifth decade
with a subacute to chronic onset. Autonomic and sensory symptoms are both
significant. The other options provided are not associated with hereditary
autonomic neuropathies. For more information, refer to page 64 of the
Continuum article, “Autonomic Peripheral Neuropathy.”
13 The preferred response is C (contactin-associated proteinlike 2 [CASPR2]).

Elevations in CASPR2, a protein associated with the voltage-gated potassium

channel complex, are commonly encountered in patients with Morvan

syndrome, a syndrome manifested by autonomic dysfunction, sensory
symptoms, neuromytonia, and neuropsychiatric features, with peripheral nerve
hyperexcitability seen on electrodiagnostic testing. For more information, refer
to page 65 of the Continuum article, “Autonomic Peripheral Neuropathy.”
ARTICLE 5: SYNUCLEINOPATHIES
14 The preferred response is B (multiple system atrophy). Multiple system atrophy is

characterized by autonomic failure, which typically occurs early and is severe, and
motor symptoms (parkinsonism or ataxia). Although autonomic failure is
commonly found in dementia with Lewy bodies and Parkinson disease, it is
typically less severe in these conditions. Similarly, although motor signs may be
seen in a subset of patients with pure autonomic failure, they are typically less
prominent. Autonomic failure is not a feature of progressive supranuclear palsy.
For more information, refer to pages 79–80 of the Continuum article
“Synucleinopathies.”
15 The preferred response is E (rapid eye movement [REM] sleep behavior

disorder). REM sleep behavior disorder is a parasomnia characterized by vivid,
often frightening dreams associated with simple or complex motor behaviors as
patients appear to “act out their dreams.” The polysomnographic features of
REM sleep behavior disorder include increased electromyographic tone with or
without dream enactment behavior during REM sleep. Clinically suspected and
polysomnography-proven REM sleep behavior disorder occurs with
disproportionally greater frequency in patients with multiple system atrophy,
Parkinson disease, and dementia with Lewy bodies (all synucleinopathies)
compared to other neurodegenerative disorders and may precede the
autonomic and motor manifestations of the disease. For more information, refer
to page 72 of the Continuum article “Synucleinopathies.”
16 The preferred response is E (reduced swallowing frequency). Sialorrhea is a

common nonmotor symptom of Parkinson disease that is believed to be
primarily due to impaired intraoral salivary clearance secondary to reduced
swallowing frequency. Poor muscle control of the tongue and upper esophageal
dysmotility may contribute to the impaired clearance. Several studies have
demonstrated that patients with Parkinson disease who drool actually produce
less saliva than normal controls, and this may be due to dopamine deficiency.
Dopaminergic medications, therefore, may be beneficial for some patients. For
more information, refer to pages 85–86 of the Continuum article “Synucleinopathies.”
17 The preferred response is A (constipation). Autonomic symptoms occur commonly

in patients with Parkinson disease. Constipation, in particular, often occurs early
232 FEBRUARY 2020

and may be the presenting symptom of disease due to early and extensive
α-synuclein involvement of the enteric nervous system. All the other autonomic
symptoms listed may become problematic later in the disease course. For more
information, refer to pages 85–86 of the Continuum article “Synucleinopathies.”
ARTICLE 6: POSTURAL TACHYCARDIA SYNDROME AND NEURALLY

MEDIATED SYNCOPE
18 The preferred answer is E (joint hypermobility). The patient’s presentation is

consistent with postural tachycardia syndrome (POTS). POTS is associated with
disorders of the connective tissue matrix (most frequently Ehlers-Danlos
syndrome hypermobility type); therefore, many patients with POTS will have
some evidence of joint hypermobility on examination. Patients may develop
peripheral coldness and cyanosis with prolonged standing rather than erythema.
The remainder of the cardiac examination and the neurologic examination are
usually normal. For more information, refer to page 95 of the Continuum article
“Postural Tachycardia Syndrome and Neurally Mediated Syncope.”
19 The preferred answer is A (12-lead ECG). All patients with suspected postural
tachycardia syndrome (POTS) should have a complete neurologic and cardiac
examination, orthostatic vitals (with prolonged standing up to 10 minutes), and a
12-lead ECG. Holter monitor and ambulatory event loop recordings and
transthoracic echocardiograms are not indicated as part of the workup of all
patients suspected of having POTS. When performed, Holter monitor testing will
usually reveal only sinus rhythm or sinus tachycardia, and echocardiogram is
most often normal. Patients with POTS often have gastrointestinal symptoms,
and scintigraphic testing may be abnormal with evidence for either rapid or
delayed transit. However, this study is not part of the standard workup of
patients with POTS. Tilt-table testing is also not indicated in the workup of all
patients. For more information, refer to page 101 of the Continuum article
“Postural Tachycardia Syndrome and Neurally Mediated Syncope.”
20 The preferred answer is E (water bolus therapy). The patient’s presentation is

consistent with postural tachycardia syndrome (POTS). Nonpharmacologic
therapies are the mainstay of the treatment of POTS, with pharmacologic
therapies being reserved for second-line treatment. In water bolus therapy,
patients rapidly drink about 500 mL of cold water immediately before planned
upright activity (up to 3 times a day). Patients with POTS should have an overall
fluid intake of approximately 2 L of noncaffeinated beverages a day. Caffeine
should be used very sparingly as it may result in diuresis and worsen
hypovolemia. Patients may benefit from sodium supplementation, not
magnesium. Thigh-high or waist-high compression stockings are recommended
for patients with POTS, not knee-high stockings; however, these are often not
well tolerated, and patients may need to substitute compression shorts or
abdominal binders. Graduated exercise is recommended, with nonupright

exercises such as a recumbent bike or swimming, at least to start. High-intensity

interval training would not be well tolerated and should not be advised as an
initial exercise program. For more information, refer to pages 101–102 of the
Continuum article “Postural Tachycardia Syndrome and Neurally Mediated
Syncope.”
21 The preferred answer is B (loss of consciousness during exertion). While

postexertional syncope is usually a benign reflex syncope, syncope during
exertion suggests a more serious cardiac etiology, such as ventricular
arrhythmia, atrioventricular block, hypertrophic obstructive cardiomyopathy,
aortic stenosis, or subclavian steal syndrome. Eye opening during the event is
typical of syncope. Forcible eye closure is seen in psychogenic pseudosyncope.
A prodrome and postevent fatigue are usually seen in patients with syncope.
Lack of a prodrome should raise concern for a cardiac etiology, such as an
arrhythmia. Myoclonic jerks may be seen in the unresponsive phase of syncope,
especially in patients who are kept upright. These are often multifocal and
arrhythmic, lasting less than 15 seconds (fewer than 10 jerks per event). For more
information, refer to page 109 of the Continuum article “Postural Tachycardia
Syndrome and Neurally Mediated Syncope.”
ARTICLE 7: SWEATING DISORDERS
22 The preferred response is A (chest radiograph). This patient has hemifacial

flushing and hyperhidrosis consistent with harlequin syndrome, which is due to
contralateral sympathetic denervation leading to anhidrosis. Although most
cases of harlequin syndrome are idiopathic, investigation should include
imaging of the cervicothoracic region in the area of the thoracic sympathetic
chain to evaluate for an underlying lesion such as local malignancy. For more
information, refer to page 125 of the Continuum article “Sweating Disorders.”
23 The preferred response is E (topical antiperspirants). Topical treatments are

recommended for initial management of focal primary hyperhidrosis, with
topical antiperspirants containing 6% to 25% aluminum chloride in alcohol
applied nightly over affected areas. When topical treatments are ineffective,
other interventions, including tap water iontophoresis, oral medications, and
intradermal botulinum toxin injections, may be instituted. Anxiolytics may be
useful when anxiety triggers hyperhidrosis. For more information, refer to
pages 121–123 of the Continuum article “Sweating Disorders.”
24 The preferred response is E (sertraline). Common offenders of

medication-induced hyperhidrosis include antidepressants, especially selective
serotonin reuptake inhibitors (SSRIs) such as sertraline, opioids, and
prostaglandin inhibitors. The other listed medications are antimuscarinics and
234 FEBRUARY 2020

may cause hypohidrosis. For more information, refer to page 120 of the
Continuum article “Sweating Disorders.”
25 The preferred response is B (constipation). Patients with spinal cord injury,

especially when above T6, may experience autonomic dysreflexia manifested
by hypertension, bradycardia, flushing, and hyperhidrosis above the level of the
lesion and hypohidrosis below the level of the lesion. Episodes are due to
stimulation of sympathetic afferents below the lesion resulting in exaggerated
sympathetic discharges resulting from disconnection from supraspinal
regulation. Thus, bowel or bladder distension and skin or visceral irritation are
the most likely precipitants. For more information, refer to pages 124–125 of the
Continuum article “Sweating Disorders.”
ARTICLE 8: AUTONOMIC HYPERACTIVITY
26 The preferred answer is D (severe muscle rigidity). While mild hypertonicity may
be present in patients with sympathetic hyperactivity from any cause, severe
muscle rigidity is usually not seen in patients with sepsis-associated
sympathetic hyperactivity. Hyperthermia, tachycardia, and tachypnea are
present in paroxysmal sympathetic hyperactivity from neurologic and
non-neurologic etiologies. Excess oral secretions do not occur with paroxysmal
sympathetic hyperactivity from either neurologic or non-neurologic causes but
can be seen in autonomic dysreflexia associated with spinal cord injury due to
an exaggerated compensatory increase in parasympathetic activation above
the level of the cord lesion. For more information, refer to page 143 of the
Continuum article “Autonomic Hyperactivity.”
27 The preferred answer is A (a 17-year-old with a Glasgow Coma Scale score of 5

and fevers that began on day 3 of hospital admission). Paroxysmal sympathetic
hyperactivity is more likely to occur in pediatric patients, especially
adolescents, with low Glasgow Coma Scale scores. It can present early in the
hospital course following traumatic brain injury, and the earliest sign may be
fevers within the first week of admission. Delayed fever in an older patient with
a high Glasgow Coma Scale score should prompt workup for another etiology
such as infection or venous thromboembolism. Delayed tachypnea should
also prompt workup for a systemic etiology. Nasal congestion is a sign of
parasympathetic hyperactivity and is not an early sign of paroxysmal
sympathetic hyperactivity. Hypoxemia is also not a sign of paroxysmal
sympathetic hyperactivity, and early hypoxemia requires urgent workup for a
pulmonary etiology, especially immediately following a motor vehicle accident.
For more information, refer to page 144 of the Continuum article “Autonomic
Hyperactivity.”

28 The preferred answer is B (naltrexone). The most likely diagnosis in this patient
is Guillain-Barré syndrome. Opioids should be avoided to the extent possible in
patients with Guillain-Barré syndrome as they can cause or worsen ileus. In
patients who develop adynamic ileus while on opioids, naltrexone may be
beneficial. Naloxone is a much shorter-acting opioid antagonist used for opioid
overdoses. Nebivolol is a beta-blocker, and nifedipine is a calcium channel
blocker; neither will treat adynamic ileus. Neostigmine, a cholinesterase inhibitor,
has been used in the management of ileus but may cause severe bradycardia
in patients with Guillain-Barré syndrome with dysautonomia and therefore is
not the most appropriate medication in this patient. For more information,
refer to page 149 of the Continuum article “Autonomic Hyperactivity.”
29 The preferred answer is D (skin examination). This patient’s presentation is

consistent with autonomic dysreflexia in the setting of spinal cord injury, a
condition that may occur as a subacute to chronic sequela of injury in patients
with complete lesions to the cervical or upper thoracic spinal cord. Episodes
are triggered by processes below the level of the cord lesion, such as bladder
and bowel distension, stimulation from nursing care below the lesion, and
pressure sores. Therefore, in this patient, the most appropriate next step out of
the options provided is a thorough skin examination to look for pressure sores.
Other appropriate studies include rectal examination and bladder scanning. For
more information, refer to page 148 of the Continuum article “Autonomic
Hyperactivity.”
ARTICLE 9: MANAGEMENT OF ORTHOSTATIC HYPOTENSION
30 The preferred response is B (20 mm Hg systolic or 10 mm Hg diastolic).

According to a consensus statement endorsed by the American Autonomic
Society, the European Federation of Autonomic Societies, the Autonomic
Research Group of the World Federation of Neurology, and the Autonomic
Disorders section of the American Academy of Neurology, orthostatic
hypotension is defined as a sustained reduction of systolic blood pressure of at
least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 minutes of
standing or head-up tilt to at least 60 degrees on a tilt table. According to the
statement, a caveat is that in patients with supine hypertension, a reduction in
systolic blood pressure of 30 mm Hg may be more appropriate because the
magnitude of the orthostatic blood pressure fall is dependent on the baseline
blood pressure. For more information, refer to page 154 of the Continuum
article “Management of Orthostatic Hypotension.”
31 The preferred response is C (hypovolemia). In patients with orthostatic

hypotension, it is important to determine whether the cause is neurogenic
(secondary to a lesion of sympathetic neurons) or non-neurogenic (due to
medical causes). A heart rate increase of at least 0.5 beat/min for each mm Hg
236 FEBRUARY 2020

fall in systolic blood pressure (ie, change in heart rate [ΔHR]/change in systolic
blood pressure [ΔSBP] ratio ≥0.5 beats per minute/mm Hg) has very high
sensitivity and specificity to diagnose non-neurogenic orthostatic hypotension.
This patient’s blood pressure fell 40/14 mm Hg, and her ΔHR/ΔSBP ratio of
0.65 beats per minute/mm Hg is consistent with a non-neurogenic etiology for
her orthostasis, such as hypovolemia, antihypertensive medications, varicose
veins, physical deconditioning, heart failure, or adrenal insufficiency.
Amyloidosis, diabetes mellitus, and pure autonomic failure are all causes of
neurogenic orthostatic hypotension. For more information, refer to pages 157–159
of the Continuum article “Management of Orthostatic Hypotension.”
32 The preferred response is A (begin erythropoietin). The first steps in the

management of patients with neurogenic orthostatic hypotension are to
correct aggravating factors, including stopping or adjusting doses of
medications that reduce intravascular volume, trigger vasodilatation, or block
norepinephrine release at the sympathetic-vascular junction, and to treat
anemia. This patient is not taking any medications or supplements known to
worsen orthostatic hypotension; venlafaxine, ginseng, and caffeine are better
known for inducing hypertension. Anemia of chronic disease is common in
patients with neurogenic orthostatic hypotension, including a mild normocytic,
normochromic anemia in pure autonomic failure, as this patient has.
Recombinant erythropoietin raises the red cell mass and packed cell volume,
which may increase the ability to maintain adequate cerebral oxygenation when
blood pressure falls in orthostatic hypotension. It has been demonstrated to
improve symptoms in this condition and is an appropriate recommendation for
the patient described. For more information, refer to page 159 of the Continuum
article “Management of Orthostatic Hypotension.”
33 The preferred response is D (swimming). Exercise is important in patients with

neurogenic orthostatic intolerance since avoidance of physical activity may
result in deconditioning, which worsens orthostatic hypotension. Exercise in a
recumbent or seated position (stationary bicycle, rowing machine, swimming) is
recommended, and exercising in a pool has the added benefit that the hydrostatic
pressure of water counteracts the gravity-induced fall in blood pressure and
improves orthostatic tolerance. Patients must exit the pool carefully, though,
because the sudden decrease of hydrostatic pressure can trigger venous pooling
and worsen symptoms of orthostatic hypotension. For more information, refer to
page 161 of the Continuum article “Management of Orthostatic Hypotension.”
ARTICLE 10: LOWER URINARY TRACT AND BOWEL DYSFUNCTION IN

NEUROLOGIC DISEASE
34 The preferred response is D (falls). Nocturia occurs with a high prevalence in

patients with Parkinson disease and is the most common of the nonmotor
symptoms. Its presence is associated with an increased risk of falls as well as

early institutionalization and increased health-related costs. No clear direct

association has been identified with the other choices provided. For more
information, refer to page 180 of the Continuum article, “Lower Urinary Tract
and Bowel Dysfunction in Neurologic Disease.”
35 The preferred response is C (desmopressin). Desmopressin is effective in the

treatment of nocturia and nocturnal polyuria as it reduces urine production,
resulting in up to 6 hours of symptomatic management. Its mechanism of action
is the promotion of fluid reabsorption at the point of renal excretion. Patients
need to be monitored for hyponatremia and fluid overload. As this patient has a
normal sodium level and her symptoms are predominantly nocturnal,
desmopressin is a reasonable first-line choice in this case. Botulinum toxin is a
second-line option for treating neurogenic detrusor overactivity–related
urinary incontinence. Citalopram may worsen urinary symptoms, especially in
patients who are predisposed. Intermittent self-catheterization is not
indicated in this case. Oxybutynin is an antimuscarinic agent, the side effects of
which include dry mouth, blurred vision, and constipation, symptoms that may
already be present in patients with multiple sclerosis. For more information,
refer to page 184 of the Continuum article, “Lower Urinary Tract and Bowel
Dysfunction in Neurologic Disease.”
36 The preferred response is C (psyllium). Constipation is a commonly reported

symptom in patients with Parkinson disease and may precede the motor
symptoms and signs by many years. While constipation may improve with
treatment with levodopa, additional management is often needed.
Nonpharmacologic interventions, such as exercise and toileting strategies, are
first-line interventions, followed by dietary fiber and probiotics. Psyllium is a
bulking fiber and therefore would be the recommended intervention out of the
options provided. Bisacodyl, sennosides, and lactulose are laxative agents and
are not recommended. Tegaserod is a prokinetic agent and is second-line
therapy after dietary supplementation and nonpharmacologic interventions
fail. For more information, refer to page 194 of the Continuum article, “Lower
Urinary Tract and Bowel Dysfunction in Neurologic Disease.”
ARTICLE 11: SKIN BIOPSY IN EVALUATION OF AUTONOMIC DISORDERS
37 The preferred answer is A (dermal structure susceptibility to crush artifact).

Because dermal structures are usually located deeper in the skin, they are
susceptible to crush artifact at the time the biopsy is obtained. Crushed biopsy
tissue can appear similar in appearance to that of a denervated structure,
leading to false-positive results. Dermal structures, including sweat glands and
piloerector muscles, are distributed randomly, not homogeneously and,
therefore, may not be present in sufficient quantities in a biopsy for evaluation.
For more information, refer to page 205 of the Continuum article “Skin Biopsy in
Evaluation of Autonomic Disorders.”
238 FEBRUARY 2020

38 The preferred response is D (reduced density of sudomotor sympathetic
cholinergic nerve fibers). Transthyretin (TTR)-A97S gene mutation carriers have
been shown in recent studies to have reduced density of sudomotor
sympathetic cholinergic nerve fibers and decreased intraepidermal nerve fiber
density. Asymptomatic carriers have not been found to have apple-green
birefringent deposits after staining with Congo red, as can be seen in patients
with symptomatic hereditary amyloidosis. For more information, refer to
pages 207–208 of the Continuum article “Skin Biopsy in Evaluation of
39 The preferred response is E (Ross syndrome). Ross syndrome is a progressive

autonomic disease that causes tonic pupils, areflexia, and anhidrosis. Skin
biopsy in Ross syndrome shows severe reduction in the sympathetic
cholinergic innervation surrounding sweat glands in regions of anhidrotic skin
and an absence of sympathetic cholinergic innervation within blood vessels,
hair follicles, and arrector pilorum muscles in both anhidrotic and hyperhidrotic
skin. Ross syndrome can be differentiated from Holmes-Adie syndrome by
the lack of anhidrosis and preserved sympathetic cholinergic nerve fiber
density on skin biopsy in Holmes-Adie syndrome. For more information, refer
to pages 204–205 of the Continuum article “Skin Biopsy in Evaluation of
40 The preferred response is B (phosphorylated α-synuclein). Vivid, frightening

dreams and dream-enactment behavior suggest rapid eye movement (REM)
sleep behavioral disorder. Abnormal phosphorylated α-synuclein deposition
can be seen on skin biopsy in more than half of patients with REM sleep
behavioral disorder, suggesting an underlying prodromal state of a
synucleinopathy such as Parkinson disease, Lewy body disease, or multiple
system atrophy. For more information, refer to page 210 of the Continuum
article “Skin Biopsy in Evaluation of Autonomic Disorders.”

ERRATUM
In the October 2019 issue of Continuum

(Neuro-ophthalmology, Vol. 25, No. 5), the following

errors occurred:
In TABLE 8-1 of “Approach to Diplopia” by

Christopher C. Glisson, DO, MS, FAAN (Continuum:
Lifelong Learning in Neurology 2019:25:1368), two
entries were listed incorrectly. The action of the
medial rectus was incorrectly listed as “abduction”;
the action should be listed as “adduction.” The action
of the lateral rectus was listed as “adduction”; the
action should be listed as “abduction.”
See the corrected table below.
Glisson CG. Approach to diplopia. Continuum (Minneap Minn) 2019;

25(5, Neuro-ophthalmology):1362–1375. doi:10.1212/CON.0000000000000786
The editors regret these errors.
TABLE 8-1 Innervations and Actions of the Ocular Motor System
Cranial Nerve Muscle Action
III (Superior branch) Superior rectus Elevation, intorsion, adduction
III (Inferior branch) Medial rectus Adduction
Inferior rectus Depression, extorsion, adduction
Inferior oblique Extorsion, elevation, abduction
IV Superior oblique Intorsion, depression, abduction
VI Lateral rectus Abduction
240 FEBRUARY 2020

LIST OF ABBREVIATIONS
Autonomic Disorders HSAN Hereditary sensory and autonomic neuropathy

ICU Intensive care unit
IgE Immunoglobulin E
IV Intravenous
5-HT 5-Hydroxytryptamine
IVIg Intravenous immunoglobulin
ACh Acetylcholine
LEMS Lambert-Eaton myasthenic syndrome
ADEM Acute disseminated encephalomyelitis
LGI1 Leucine-rich glioma inactivated protein 1
AL Immunoglobulin light chain
MIBG Metaiodobenzylguanidine
ANNA-1 Antineuronal nuclear antibody type 1
MoCA Montreal Cognitive Assessment
ASIA American Spinal Injury Association
MRA Magnetic resonance angiography
BiPAP Bilevel positive airway pressure
MRI Magnetic resonance imaging
CASPR2 Contactin-associated proteinlike 2
mRNA Messenger ribonucleic acid
CDC Centers for Disease Control and Prevention
MS Multiple sclerosis
CIDP Chronic inflammatory demyelinating
polyradiculoneuropathy MSA Multiple system atrophy
CNS Central nervous system MSA-C Multiple system atrophy with predominant
cerebellar ataxia
CPAP Continuous positive airway pressure
MSA-P Multiple system atrophy with predominant
CRMP-5 Collapsin response mediator protein-5 parkinsonism
CSF Cerebrospinal fluid NMDA -methyl-D-aspartate
N-methyl-
CT Computed tomography NMO Neuromyelitis optica
∆HR Change in heart rate PCA-2 Purkinje cell antibody type 2
∆SBP Change in systolic blood pressure PET Positron emission tomography
DLB Dementia with Lewy bodies PGP 9.5 Protein gene product 9.5
DPPX Dipeptidyl-peptidase–like protein 6 POTS Postural tachycardia syndrome
ECG Electrocardiogram PRES Posterior reversible encephalopathy syndrome
EDSS Expanded Disability Status Scale QSART Quantitative sudomotor axon reflex test
EEG Electroencephalography REM Rapid eye movement
EMG Electromyography RNA Ribonucleic acid
FDA US Food and Drug Administration SNRI Serotonin norepinephrine reuptake inhibitor
FDG Fludeoxyglucose SPECT Single-photon emission computed tomography
GABA γ-Aminobutyric
-Aminobutyric acid SSRI Selective serotonin reuptake inhibitor
GBS Guillain-Barré syndrome TBI Traumatic brain injury
GRE Gradient recalled echo TSH Thyroid-stimulating hormone
© 2020 American Academy of Neurology.

Autonomic Disorders
Article 1: Physiology and Pathophysiology
of the Autonomic Nervous System
Eduardo E. Benarroch, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1
Autonomic Disorders):12–24.
ABSTRACT
PURPOSE OF THE REVIEW:
This article reviews the anatomic, functional, and neurochemical organization of the
sympathetic and parasympathetic outputs; the effects on target organs; the central mechanisms
controlling autonomic function; and the pathophysiologic basis for core symptoms of autonomic
failure.
RECENT FINDINGS:
Functional neuroimaging studies have elucidated the areas involved in central control of
autonomic function in humans. Optogenetic and other novel approaches in animal experiments
have provided new insights into the role of these areas in autonomic control across behavioral
states, including stress and the sleep-wake cycle.
SUMMARY:
Control of the function of the sympathetic, parasympathetic, and enteric nervous system
functions depends on complex interactions at all levels of the neuraxis. Peripheral sympathetic
outputs are critical for maintenance of blood pressure, thermoregulation, and response to
stress. Parasympathetic reflexes control lacrimation, salivation, pupil response to light,
beat-to-beat control of the heart rate, gastrointestinal motility, micturition, and erectile
function. The insular cortex, anterior and midcingulate cortex, and amygdala generate
autonomic responses to behaviorally relevant stimuli. Several nuclei of the hypothalamus
generate coordinated patterns of autonomic responses to internal or social stressors. Several
brainstem nuclei participate in integrated control of autonomic function in relationship to
respiration and the sleep-wake cycle. Disorders affecting the central or peripheral autonomic
pathways, or both, manifest with autonomic failure (including orthostatic hypotension,
anhidrosis, gastrointestinal dysmotility, and neurogenic bladder or erectile dysfunction) or
autonomic hyperactivity, primary hypertension, tachycardia, and hyperhidrosis.
KEY POINTS
• The sympathetic nervous system mediates patterns of responses critical for maintenance of blood pressure,
local regulation of blood flow, thermoregulation, and response to exercise and stress.

• Autonomic dysreflexia results from interruption of supraspinal pathways coordinating the activity of
preganglionic sympathetic neurons.
• Norepinephrine elicits vascular and visceral smooth muscle contraction via α1 receptors, presynaptic
inhibition of neurotransmitter release via α2 receptors, cardiac stimulation via β1 receptors, and vasodilation
and smooth muscle relaxation via β2 and β3 receptors.
• The parasympathetic nervous system is critical for lacrimation, salivation, pupil reaction to light,
beat-to-beat control of the heart rate, gastrointestinal motility and secretion, micturition, and erectile
function.
• Parasympathetic neurons releasing acetylcholine activate smooth muscle contraction, exocrine gland
secretion, and vasodilation via M3 receptors and inhibit cardiac function via M2 receptors; neurons releasing
nitric oxide and vasoactive intestinal polypeptide elicit vasodilation and smooth muscle relaxation.
• The insula is the primary viscerosensory cortex and contributes to conscious bodily sensation.
• The anterior midcingulate cortex and the anterior insular cortex are part of the so-called salience network
and are activated during tasks associated with increased sympathetic activity.
• The central nucleus of the amygdala triggers autonomic, endocrine, and motor response to emotionally
salient stimuli.
• The hypothalamus initiates specific patterns of autonomic responses to internal or external stressors via
projection from the paraventricular and dorsomedial nuclei and orexin/hypocretin neurons.
• The periaqueductal gray coordinates autonomic, somatomotor, and pain modulatory responses to stress.
• The parabrachial nucleus is involved in arousal, respiratory control, and modulation of cardiovascular and
gastrointestinal reflexes.
• The nucleus of the solitary tract is the first relay station for medullary cardiovascular, respiratory, and
gastrointestinal reflexes.
• Sympathoexcitatory neurons of the rostral ventrolateral medulla, including the C1 group, mediate the
baroreflex and responses to hypoxia and other internal stressors.
• Neurons of the rostral ventromedial medulla and nucleus raphe pallidus mediate sympathoexcitatory
responses to external stressors and exposure to cold.
• Arterial blood pressure is primarily regulated by the sympathetic noradrenergic input to skeletal muscle and
mesenteric blood vessels, mediated by α1 receptors and driven by premotor neurons in the rostral
ventrolateral medulla.
• The baroreceptor reflex is the principal mechanism for short-term, moment-to-moment control of blood
pressure, buffering acute fluctuations in response to orthostatic changes or stress.
• Baroreflex-triggered sympathetic vasoconstriction mediated by α1 receptors and skeletal muscle and
splanchnic vessels is critical to prevent orthostatic hypotension, which may be a manifestation of disorders
affecting every step of the efferent baroreflex sympathoexcitatory pathway.
• Baroreflex afferent failure manifests with fluctuating hypertension and hypotension.
• Impaired heart rate response to deep breathing is a reliable index of cardiovagal failure.
• The sympathetic output to the sweat glands and skin blood vessels is critical for thermoregulation.
• Peripheral autonomic denervation results in exaggerated responsiveness of target organs to cholinergic or
adrenergic agonists (denervation supersensitivity).
Article 2: Autonomic History,

Examination, and Laboratory Evaluation
William P. Cheshire Jr, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1

ABSTRACT
PURPOSE OF REVIEW:
Autonomic disorders offer a fascinating view of the complexity of the nervous system. Their
impact on human health ranges from benign to severe. Deciphering autonomic symptoms and
signs draws on the cognitive skills and personal interest in the plight of patients that first
attracted many physicians to the field of neurology. This article provides tools to sharpen those
skills.
RECENT FINDINGS:
Autonomic neuroscience and accumulated clinical knowledge have led to the categorization of
autonomic disorders into specific syndromes that can be identified on the basis of clinical
phenotypes and physiologic responses to standardized stimuli in the autonomic laboratory. A
key development has been the ability to distinguish neurogenic orthostatic hypotension from
other causes of hypotension. Quantification of sudomotor responses has proven valuable in the
diagnosis of thermoregulatory disorders and small fiber neuropathies such as those related to
diabetes mellitus. Increasing attention has focused on autonomic failure as a defining feature of
neurodegenerative α-synucleinopathies, especially multiple system atrophy. As awareness of
autonomic disorders has increased, the once obscure term dysautonomia has entered into
common parlance.
SUMMARY:
With appropriate knowledge and experience, neurologists can diagnose autonomic dysfunction
accurately and with confidence. The opportunity to play an important role in caring for patients
with autonomic disorders is worth the effort.
KEY POINTS
• Autonomic disorders are common and diverse in character and can present with sustained or episodic
hypofunction or hyperfunction of sympathetic or parasympathetic systems.
• A thoughtful autonomic history is the most important component of the evaluation of the patient with
autonomic symptoms. The art of the history consists in taking a jumble of clues and formulating a coherent
set of questions and conclusions.
• Key aspects of the autonomic history are timing of onset, temporal course, associated illness or context,
modifying factors, and use of medications and dietary supplements.
• The impact of autonomic symptoms on daily functioning and quality of life is important. Standing activities
may be limited, and tolerance of heat or cold may be impaired. Social and job-related function may also
be impaired.
• Dysautonomias are syndromic and cluster into recognizable patterns of presentation that help to organize
the history and examination.
• Sympathetic noradrenergic failure causes neurogenic orthostatic hypotension, which is often worse in the
morning, in hot environments, after exercise, or after meals.
• Sympathetic noradrenergic hyperactivity causes hypertension, tachycardia, palpitations, pupillary
dilatation, and piloerection.
• Sympathetic adrenergic failure occurs in adrenal failure and presents with fatigue. Sympathetic adrenergic
hyperactivity causes palpitations, dilated pupils, facial pallor, palmar sweating, and decreased intestinal
motility.
• Sympathetic cholinergic failure causes hypohidrosis or anhidrosis. When severe or widespread, patients may
be at risk for heat-related illness, including heatstroke. Anticholinergic medications or carbonic anhydrase
inhibitors can contribute to anhidrosis.
• Sympathetic cholinergic hyperactivity causes increased sweating. Opioids, selective serotonin reuptake
inhibitors, and serotonin norepinephrine reuptake inhibitors may contribute to sweating. Consider serotonin
syndrome in the patient who has increased the dose of a serotonergic agent.

• Orthostatic hypotension is a sustained reduction in systolic blood pressure of >20 mm Hg within 3 minutes of
standing, with or without symptoms. Orthostatic hypotension cannot be diagnosed by symptoms alone but
requires measurement of blood pressure.
• Postural tachycardia syndrome is a sustained increase in heart rate during standing or head-up tilt
≥30 beats/min above baseline, or, for patients younger than 20 years of age, ≥40 beats/min above baseline.
The tachycardia must not be in response to orthostatic hypotension.
• About one-third of orthostatic hypotension is neurogenic, as recognized by impaired blood pressure
responses to the Valsalva maneuver and by deficient reflex tachycardia. Blood pressure drops in neurogenic
orthostatic hypotension can also be more profound than orthostatic hypotension that does not have a
neurogenic basis.
• Harlequin syndrome consists of strikingly unilateral facial flushing provoked by heat stress. The opposite side
of the face, which remains pale, is abnormal and lacks sympathetic vasomotor innervation.
• Physicians who perform autonomic testing should be knowledgeable about the autonomic nervous system
and its disorders.
• The quantitative sudomotor axon reflex test evaluates distal postganglionic sudomotor neurons innervating
eccrine glands. This test is a sensitive method for detecting small fiber peripheral neuropathies, but the
results can be confounded by medications that inhibit sweating. Such medications should be withheld in
advance of testing when it is safe to do so.
• A sensitive test of cardiovagal function is the variation in heart rate with sinusoidal deep breathing, which
assesses respiratory sinus arrhythmia. Another method is the Valsalva ratio, which is the maximum heart rate
divided by the minimum heart rate in response to straining.
• The Valsalva maneuver consists of four phases. Phases I and III are mechanical and occur at the beginning and
end of straining. Baroreflex-sympathoneural (noradrenergic cardiovascular) function is assessed by how
quickly and completely the blood pressure recovers during phases II and IV and overshoots in phase IV in
response to the drop in blood pressure early in phase II that occurs in response to straining.
• Not all tilt-table tests are the same, but the duration and conditions of the test are adjusted to the goals of
the test. A duration of 5 minutes is sufficient to establish neurogenic orthostatic hypotension. Longer
durations of tilt are needed when assessing orthostatic intolerance and syncope.
• Personal health devices that display autonomic data such as heart rate and blood pressure are increasingly
available to patients. Such data have become part of the autonomic evaluation. The numbers can be useful,
but they can also be misinterpreted.
• Dysautonomia is not a specific diagnosis but rather a broad category. No one universal treatment exists for
“dysautonomia.” Treatment decisions must be directed to the patient’s specific diagnosis and condition.
Article 3: Autoimmune Autonomic

Disorders
Steven Vernino, MD, PhD, FAAS, FAAN. Continuum (Minneap Minn). February 2020; 26
(1 Autonomic Disorders):44–57.
ABSTRACT
PURPOSE OF REVIEW:
Autonomic disorders sometimes occur in the context of systemic autoimmune disease or as a
direct consequence of autoimmunity against the nervous system. This article provides an
overview of autonomic disorders with potential autoimmune etiology.

RECENT FINDINGS:
Recent evidence highlights a close association between the autonomic nervous system and
inflammation. The autonomic nervous system regulates immune function, and autonomic
manifestations may occur in a number of systemic autoimmune diseases. In a few instances,
autoimmunity directly influences autonomic function. Autoimmune autonomic ganglionopathy is
the prototypic antibody-mediated autonomic disorder. Over time, a better understanding of the
clinical spectrum of autoimmune autonomic ganglionopathy, the significance of ganglionic
nicotinic acetylcholine receptor antibodies, other immune-mediated autonomic neuropathies,
and autonomic manifestations of other systemic or neurologic autoimmune disorders has
emerged.
SUMMARY:
Autoimmune autonomic disorders may be challenging, but correct identification of these
conditions is important. In some cases, potential exists for effective immunomodulatory
treatment.
KEY POINTS
• The autonomic nervous system regulates inflammation through a cholinergic anti-inflammatory reflex.
• Some cases of autoimmune autonomic failure are associated with antibodies against the ganglionic nicotinic
• Synaptic transmission in all autonomic ganglia requires acetylcholine and the ganglionic nicotinic
• Autoimmune autonomic ganglionopathy is an antibody-mediated disorder caused by antibodies to the
ganglionic nicotinic acetylcholine receptor.
• Features of autoimmune autonomic ganglionopathy include prominent cholinergic failure, orthostatic
hypotension, and abnormal pupillary light responses.
• Paresthesia (but not pain) occurs in autoimmune autonomic ganglionopathy without objective evidence of
sensory neuropathy.
• Low levels of ganglionic nicotinic acetylcholine receptor (<0.2 nmol/L) antibody are nonspecific and should
not be considered diagnostic of an autoimmune autonomic disorder.
• Immunotherapy may be beneficial for autoimmune autonomic ganglionopathy.
• Intermediate levels of ganglionic nicotinic acetylcholine receptor antibodies may be associated with chronic
cases of autoimmune autonomic ganglionopathy or with limited forms of autonomic failure such as isolated
gastrointestinal dysmotility.
• Chronic idiopathic anhidrosis is suspected to be an autoimmune disorder but is not associated with ganglionic
nicotinic acetylcholine receptor antibodies.
• Acute autonomic and sensory neuropathy differs from autoimmune autonomic ganglionopathy in clinical
features and response to treatment and is not associated with ganglionic nicotinic acetylcholine receptor
antibodies.
• The clinical features of acute immune-mediated sensory and autonomic neuropathy are varied but often
include neuropathic pain, orthostatic hypotension, and gastrointestinal dysmotility.
• Paraneoplastic autonomic neuropathy is most commonly associated with small cell lung carcinoma and
anti-Hu antibodies.
• Severe gastrointestinal dysmotility with gastroparesis is the most common presentation of paraneoplastic
autonomic/enteric neuropathy.
• Other clinical syndromes such as limbic encephalitis may coexist with paraneoplastic autonomic neuropathy.
• Patients with Lambert-Eaton myasthenic syndrome commonly report dry mouth, constipation, and sexual
dysfunction.
• Various autonomic disturbances can be seen in patients with Guillain-Barré syndrome independent of the
severity of muscle weakness.

• Autonomic hyperactivity (hypertension, tachycardia, hypersalivation) can be seen in disorders associated
with voltage-gated potassium channel complex antibodies (leucine-rich glioma inactivated protein 1 [LGI1]
and contactin-associated proteinlike 2 [CASPR2]).
• Central autonomic dysfunction may be seen in patients with N-methyl-D-aspartate (NMDA) receptor
antibody encephalitis.
• Encephalitis associated with severe gastrointestinal dysmotility has been associated with dipeptidyl-
peptidase–like protein 6 (DPPX) antibodies.
• Autonomic dysfunction may be seen in patients with Sjögren syndrome.
• Autonomic symptoms in Sjögren syndrome are mostly cholinergic. In addition to sicca symptoms, orthostatic
intolerance with tachycardia and gastrointestinal symptoms are seen.
• Various degrees of autonomic dysfunction have been reported in systemic lupus erythematosus, rheumatoid
arthritis, and scleroderma and may represent effects of deconditioning and chronic systemic inflammation
rather than autonomic neuropathy.
• An autoimmune basis for postural tachycardia syndrome has been proposed but not yet proven.
• Various autoantibodies have been found in patients with postural tachycardia syndrome.
Article 4: Autonomic Peripheral

Neuropathy
Roy Freeman, MBChB. Continuum (Minneap Minn). February 2020; 26 (1 Autonomic
Disorders):58–71.
ABSTRACT
PURPOSE OF REVIEW:
This article provides a summary of the autonomic neuropathies, including neuropathies
associated with diabetes mellitus, neuropathies due to amyloid deposition, immune-mediated
autonomic neuropathies (including those associated with a paraneoplastic syndrome), inherited
autonomic neuropathies, and toxic autonomic neuropathies. The presenting features, diagnostic
investigations, and natural history of these neuropathies are discussed.
RECENT FINDINGS:
Recent findings in autonomic peripheral neuropathy include data on the epidemiology and
atypical presentations of diabetic autonomic neuropathy, treatment-induced neuropathy of
diabetes mellitus, the presentation of immune-mediated neuropathies, and advances in
hereditary neuropathy associated with amyloidosis and other hereditary neuropathies.
SUMMARY:
Knowledge and recognition of the clinical features of the autonomic neuropathies, combined
with appropriate laboratory and electrophysiologic testing, will facilitate accurate diagnosis and
management.
KEY POINTS
• A generalized autonomic neuropathy typically occurs in the setting of a generalized diabetic polyneuropathy
but may occur in isolation.
• Treatment-induced neuropathy of diabetes mellitus should be considered when a patient with diabetes
mellitus presents with the sudden onset of pain and autonomic dysfunction. This is a reversible diabetic
peripheral neuropathy.

• Prominent autonomic features do not occur in chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP), and when patients present with such features, alternative diagnoses should be considered. The
peripheral neuropathy associated with hereditary amyloidosis is sometimes misdiagnosed as CIDP,
particularly in nonendemic areas.
• The peripheral neuropathy associated with hereditary transthyretin amyloidosis has a heterogeneous
presentation, even within families in endemic areas.
• When autonomic features occur in combination with peripheral nerve excitability and neuropsychiatric
features such insomnia, agitation, hallucinations, and memory loss, antibodies to the voltage-gated
potassium channel complex protein should be considered.
• Among the hereditary sensory and autonomic neuropathies (HSANs), autonomic manifestations are most
prominent in HSAN III (also known as Riley-Day syndrome or familial dysautonomia). HSAN III is caused by
homozygous mutations in the ELP1 gene.
• Chemotherapeutic agents are the most common cause of a toxic autonomic neuropathy. Predisposing
factors to a chemotherapy-induced peripheral neuropathy include genetic factors and an underlying clinical
or subclinical peripheral neuropathy.
Article 5: Synucleinopathies
Elizabeth A. Coon, MD; Wolfgang Singer, MD. Continuum (Minneap Minn). February
2020; 26 (1 Autonomic Disorders):72–92.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the α-synucleinopathies pure autonomic failure, multiple system atrophy,
dementia with Lewy bodies, and Parkinson disease with respect to autonomic failure.
RECENT FINDINGS:
The pattern and severity of autonomic involvement in the synucleinopathies is related to
differences in cellular deposition and neuronal populations affected by α-synuclein aggregation,
which influences the degree and manifestation of autonomic failure. Clinical and laboratory
autonomic features distinguish the different synucleinopathies based on pattern and severity.
These features also determine which patients are at risk for evolution from pure autonomic
failure to the synucleinopathies with prominent motor involvement, such as multiple system
atrophy, dementia with Lewy bodies, or Parkinson disease.
SUMMARY:
Autonomic failure is a key feature of the synucleinopathies, with varying type and degree of
dysfunction from predominantly peripheral involvement in the Lewy body disorders to central
involvement in multiple system atrophy.
KEY POINTS
• α-Synuclein aggregation in central and peripheral autonomic structures may lead to autonomic
manifestations of orthostatic hypotension, urogenital dysfunction, gastrointestinal dysmotility, or
thermoregulatory dysfunction.
• Rapid eye movement sleep behavior disorder is a unifying feature of the synucleinopathies and may precede
autonomic or motor features in the various diseases.
• Pure autonomic failure is a sporadic, gradually progressive neurodegenerative disorder characterized by
orthostatic hypotension with a tendency for syncope.

• Supine hypertension is found in approximately half of all patients with pure autonomic failure; it may be
severe and often complicates treatment of orthostatic hypotension.
• The diagnosis of pure autonomic failure is based on detection of orthostatic hypotension, usually with clinical
history or evaluation consistent with widespread autonomic failure.
• Evaluation in pure autonomic failure reveals peripheral involvement with decreased uptake on cardiac
functional imaging and low levels of supine norepinephrine that have minimal to no increase upon standing.
• A subset of patients with pure autonomic failure phenoconvert to a synucleinopathy with motor or cognitive
impairment, or both. Greater severity and earlier autonomic symptoms with central autonomic failure on
autonomic testing predicts conversion to multiple system atrophy (MSA).
• MSA is characterized by autonomic failure with motor symptoms of predominant parkinsonism (MSA-P) or
predominant cerebellar ataxia (MSA-C), although parkinsonism and ataxia often overlap later in disease.
• Autonomic dysfunction in MSA tends to occur early and be severe, with orthostatic hypotension that may
have concomitant supine hypertension and genitourinary failure characterized by sexual dysfunction and
urinary retention leading to incontinence.
• Autonomic function testing in MSA generally shows orthostatic hypotension with central autonomic
dysfunction characterized by a large degree of anhidrosis on thermoregulatory sweat test with relatively
preserved quantitative sudomotor axon reflex test volumes.
• Characteristic brain MRI findings in MSA include the putaminal rim sign, which is more commonly seen in
MSA-P, and the hot cross bun sign, which is more commonly seen in MSA-C.
• Treatment for MSA involves a multidisciplinary team managing autonomic failure, motor features, sleep, and
respiratory dysfunction.
• The neuropathologic hallmark of MSA is oligodendroglial cytoplasmic inclusions, which are frequently found
in the substantia nigra, basal ganglia, brainstem, cerebellum, and spinal cord.
• The diagnosis of dementia with Lewy bodies (DLB) is based on the presence of dementia, often with early
prominent deficits in attention, executive function, and visuoperceptual ability along with core clinical
features that include fluctuating cognition, visual hallucinations, rapid eye movement sleep behavior
disorder, and parkinsonism. Syncope and severe autonomic dysfunction are supportive clinical features.
• The degree of autonomic failure in DLB is less severe than MSA but more prominent than typically seen in
Parkinson disease.
• Constipation, neurogenic bladder, and orthostasis are common nonmotor symptoms in Parkinson disease
reflecting autonomic dysfunction.
• Orthostatic hypotension is found in 30% to 50% of all patients with Parkinson disease, and treatment with
dopaminergic medications may contribute to blood pressure drop.
• Thermoregulatory dysfunction in Parkinson disease may manifest as heat or cold intolerance, intermittent
hyperhidrosis episodes, and hypohidrosis.
• The Lewy body disorders typically have early and more extensive peripheral α-synuclein involvement,
although central involvement of autonomic structures likely contributes to orthostatic hypotension in DLB.
Article 6: Postural Tachycardia Syndrome

and Neurally Mediated Syncope
Jeremy K. Cutsforth-Gregory, MD. Continuum (Minneap Minn). February 2020; 26 (1
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the diagnosis and management of the most common disorders of orthostatic
intolerance: postural tachycardia syndrome (POTS) and neurally mediated syncope.

RECENT FINDINGS:
POTS is a heterogeneous syndrome caused by several pathophysiologic mechanisms that may
coexist (limited autonomic neuropathy, hyperadrenergic state, hypovolemia, venous pooling,
joint hypermobility, deconditioning). Neurally mediated syncope occurs despite intact
autonomic reflexes. Management of orthostatic intolerance aims to increase functional
capacity, including standing time, performance of daily activities, and exercise tolerance.
Nonpharmacologic strategies (fluid and salt loading, physical countermaneuvers, compression
garments, exercise training) are fundamental for patients with POTS, occasionally
complemented by medications to raise blood pressure or slow heart rate. Neurally mediated
syncope is best managed by recognition and avoidance of triggers.
SUMMARY:
Significant negative effects on quality of life occur in patients with POTS and in patients with
recurrent neurally mediated syncope, which can be mitigated through targeted evaluation and
thoughtful management.
KEY POINTS
• The normal response to standing, via activation of the baroreflex, is a small fall in systolic blood pressure, a
small rise in diastolic blood pressure, and a small rise in heart rate.
• Orthostatic intolerance is the inability to tolerate upright posture because of symptoms of cerebral
hypoperfusion or sympathetic activation, or both, which are relieved with recumbency.
• Postural tachycardia syndrome (POTS) is the most prevalent form of orthostatic intolerance.
• POTS is defined as a symptomatic and sustained heart rate increment of 30 beats/min or more within
10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is
often 120 beats/min or higher. For individuals 12 to 19 years of age, the required increment is at least
40 beats/min.
• The main POTS mechanisms are impaired sympathetically mediated vasoconstriction in the lower limbs
(neuropathic POTS), excessive cardiac sympathoexcitatory responses (hyperadrenergic POTS), volume
dysregulation, joint hypermobility, and physical deconditioning.
• A postinfectious autoimmune process is likely in many patients with POTS, as evidenced by an antecedent
illness of presumed viral etiology in approximately one-half and organ-specific autoantibodies in up to
one-third.
• Hyperadrenergic POTS is characterized by episodes of tachycardia, sweating, and hypertension that can be
triggered by upright posture, physical activity, and emotional stimuli, and episodes may even occur during
sleep.
• Most patients with POTS have some degree of hypovolemia, with low plasma and total blood volumes
resulting in reduced cardiac preload upon standing.
• A sizable minority of patients with POTS have hypermobile joints consistent with an underlying disorder of
the connective tissue matrix, most commonly Ehlers-Danlos syndrome hypermobility type.
• Many patients with POTS have additional chronic conditions, including inappropriate sinus tachycardia,
migraine and other headaches, visceral hypersensitivity, gastrointestinal dysmotility, chronic fatigue,
insomnia, and fibromyalgia.
• The syndrome of inappropriate sinus tachycardia is defined as a sinus heart rate higher than 100 beats/min at
rest, with a mean 24-hour heart rate higher than 90 beats/min, accompanied by bothersome palpitations.
• Patients with suspected POTS should undergo comprehensive cardiac and neurologic examinations, supine
and standing heart rate and blood pressure measurement, and a 12-lead ECG.
• The primary objective of POTS management is to improve patients’ functional capacity (ie, increase the time
that they can stand, perform daily activities, and exercise).
• Physical counterpressure maneuvers for patients with POTS aim to counteract venous pooling and include
crossing the legs, bending forward at the waist, rising on toes, slow marching in place, and squatting.

• Compression garments for patients with POTS should cover the abdomen and thighs.
• Patients with POTS should engage in a graduated exercise program that includes both endurance and
resistance training.
• Medications should be considered for treatment of POTS only after nonpharmacologic strategies have been
implemented.
• Beta-blockers are probably most beneficial for patients with hyperadrenergic POTS.
• Pyridostigmine reduces orthostatic tachycardia and improves chronic symptoms of POTS without
aggravating supine hypertension.
• Syncope is a transient loss of consciousness and postural muscle tone due to global cerebral hypoperfusion,
with relatively abrupt onset and spontaneous, complete, and relatively prompt recovery.
• Syncope can occur at any age, with the first peak usually occurring in the teen or young adult years and a
second peak near 80 years of age. Syncope at younger age is usually the neurally mediated type.
• The typical episode of neurally mediated syncope can be divided into prodrome and unresponsive phases.
The prodrome can be of variable duration, generally less than 1 minute, and is recognized or later recalled by
only two-thirds of patients.
• When syncope occurs abruptly without any prodrome, the clinician should be suspicious for ventricular arrhythmia.
• Prolonged unresponsiveness in alleged syncope should raise concern for epilepsy, vertebrobasilar
insufficiency, subarachnoid hemorrhage, traumatic brain injury, hypoglycemia, drug or medication
intoxication, or psychogenic pseudosyncope.
• Convulsive syncope can be distinguished from an epileptic seizure by the number of myoclonic jerks: fewer
than 10 in syncope, more than 20 in seizures.
• Neurally mediated syncope is associated with one or both of two hemodynamic patterns. The vasodepressor
pattern is an abrupt fall in blood pressure that occurs beyond the time cutoff (3 minutes) for orthostatic
hypotension; the cardioinhibitory pattern is a pronounced bradycardia of fewer than 40 beats/min or
asystole of more than 3 seconds.
• Vasovagal syncope may be a protective reflex response to excessive sympathetic activity, to which the heart
is particularly prone.
• Prodromal symptoms typically occur when mean blood pressure falls below 60 mm Hg. Unresponsiveness
occurs below 50 mm Hg at heart level, corresponding to 30 mm Hg cerebral arterial pressure.
• In contrast to postexertional syncope, which is a benign reflex syncope, syncope during exertion points
toward ventricular arrhythmias, atrioventricular block, hypertrophic obstructive cardiomyopathy, aortic
stenosis, or subclavian steal syndrome.
• Patients with psychogenic pseudosyncope often deny any prodrome, report longer periods of apparent loss
of consciousness (up to several minutes), and may be suggestible. A definite diagnosis of psychogenic
pseudosyncope is made by recording normal blood pressure, heart rate, and EEG during an episode.
• Tilt-table test results must be interpreted with caution, as both false negatives and false positives are common.
• Neurally mediated syncope, especially vasovagal and the various situational syncopes, is most effectively
managed by recognition and avoidance of triggers.
Article 7: Sweating Disorders

Elizabeth A. Coon, MD; William P. Cheshire Jr, MD, FAAN. Continuum (Minneap Minn).
February 2020; 26 (1 Autonomic Disorders):116–137.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews disorders of sweating, including hyperhidrosis and anhidrosis due to central
or peripheral autonomic nervous system causes.

RECENT FINDINGS:
Disorders of thermoregulation and sweating may manifest with hyperhidrosis or hypohidrosis/
anhidrosis. Primary disorders of hyperhidrosis may significantly impact quality of life yet tend
to be benign. Many sweating disorders present with compensatory hyperhidrosis due to areas of
anhidrosis. Anhidrosis may occur due to either central or peripheral damage to the autonomic
nervous system. The thermoregulatory control of sweating involves central pathways from
the hypothalamus to the brainstem and then spinal cord as well as projections to peripheral
structures, including the sympathetic chain ganglia, peripheral nerves, and eccrine sweat
glands. Disruption at any point of this pathway may lead to impaired sweating. Characterization
of sweating dysfunction helps localize different autonomic disorders to guide diagnosis and may
allow for evaluation of treatment effect.
SUMMARY:
Sweating dysfunction manifests in myriad ways, including essential hyperhidrosis, complete
anhidrosis with heat intolerance, and compensatory hyperhidrosis due to anhidrosis, and often
indicates involvement of underlying central or peripheral autonomic dysfunction.
KEY POINTS
• Warm-sensitive neurons in the preoptic nucleus of the hypothalamus respond to subtle changes in core
temperature to invoke a sympathetic nervous system response of generalized sweating, vasodilation, and
hyperpnea triggering radiant and evaporative heat loss.
• Innervation of sweat glands is predominantly by unmyelinated C fibers to cholinergic M3-type receptors.
• The highest density of sweat glands involved in thermoregulation is on the forehead, followed by the upper
limbs and then the trunk and lower limbs, whereas acral (hands and feet) sweating is chiefly triggered by
emotional stimuli.
• Hyperhidrosis is defined as excessive sweating beyond the need to maintain core temperature; it tends to be
more socially limiting than medically worrisome.
• Medications frequently cause hyperhidrosis, with common offenders including selective serotonin reuptake
inhibitors, opioids, and prostaglandin inhibitors.
• Shapiro syndrome is characterized by episodic hypothermia and hyperhidrosis with abnormalities of midline
structures, such as agenesis of the corpus callosum.
• Paroxysmal sympathetic hyperactivity after acquired brain injury is characterized by paroxysmal sympathetic
overreactivity leading to diaphoresis, fever, flushing, shivering, hypertension, tachypnea, tachycardia, and,
occasionally, motor involvement.
• Primary focal hyperhidrosis frequently involves palms and soles and may significantly interfere with quality
of life.
• Treatment options for primary focal hyperhidrosis include topical agents, systemic medications,
iontophoresis, or endoscopic thoracic sympathotomy.
• Cold-induced sweating syndrome is a genetic disorder characterized by profuse truncal sweating when
exposed to cold with paradoxical anhidrosis when exposed to heat.
• Autonomic dysreflexia may occur in patients with spinal cord injuries with lesions above T6 and is
characterized by hypertension with concomitant bradycardia and facial flushing with profuse sweating
above the level of the spinal cord lesion.
• Treatment for autonomic dysreflexia involves fast-acting antihypertensives with urgent identification of the
trigger, such as bowel or bladder distension or skin irritation.
• Harlequin syndrome is characterized by hemifacial flushing and hyperhidrosis contralateral to sympathetic
denervation and may include Horner syndrome when oculosympathetic fibers are involved.
• Patients with multiple system atrophy typically have a high degree of anhidrosis, which is predominantly due
to a central/preganglionic lesion.

• Patients with Parkinson disease typically have mild distal anhidrosis that is peripheral in origin, whereas
patients with dementia with Lewy bodies also show a peripheral pattern of sweat loss that is to a greater
degree than in patients with Parkinson disease.
• Patients with autoimmune autonomic ganglionopathy may manifest a high degree of anhidrosis, which tends
to increase distally; the degree of autonomic failure may correlate with the antibody titer.
• Familial dysautonomia is characterized by episodes of orthostatic hypotension or hypertension in addition to
profuse sweating related to underlying neuropathy and central sudomotor pathway hyperexcitability.
• Diabetic autonomic neuropathy is the most common cause of autonomic neuropathy and may manifest as
length-dependent sweat loss and focal areas of anhidrosis or lead to global anhidrosis when severe.
• Chronic idiopathic anhidrosis is characterized by heat intolerance and widespread anhidrosis in the absence
of accompanying autonomic failure; the pattern of anhidrosis may be preganglionic or postganglionic.
Article 8: Autonomic Hyperactivity

Alejandro A. Rabinstein, MD, FAAN. Continuum (Minneap Minn). February 2020; 26 (1
ABSTRACT
PURPOSE OF REVIEW:
Autonomic hyperactivity is a relatively common consequence of severe acute brain injury and
can also be seen with spinal cord and peripheral nerve disorders. This article reviews basic
pathophysiologic concepts regarding autonomic hyperactivity, its various forms of clinical
presentation, and practical management considerations.
RECENT FINDINGS:
Paroxysmal sympathetic hyperactivity is most common after traumatic brain injury but can also
occur after other forms of severe acute diffuse or multifocal brain injury. Formal criteria for the
diagnosis and severity grading of paroxysmal sympathetic hyperactivity have now been proposed.
A growing body of literature is beginning to elucidate the mechanisms underlying this disorder, but
treatment remains based on observational data. Our mechanistic understanding of other distinct
forms of autonomic hyperactivity, such as autonomic dysreflexia after traumatic spinal cord injury
and dysautonomia after Guillain-Barré syndrome, remains rudimentary, yet clinical experience
shows that their appropriate management can minimize the risk of serious complications.
SUMMARY:
Syndromes of autonomic hyperactivity can result from injury at all levels of the neuraxis. Much
more research is needed to refine our understanding of these disorders and guide optimal
management decisions.
KEY POINTS
• Recognition of autonomic hyperactivity is important because it can provoke dangerous complications.
• Injury at multiple levels of the neuraxis can cause autonomic hyperactivity.
• Damage causing disconnection of sympathetic centers from descending inhibitory pathways and
maladaptive changes in the spinal cord can result in excessive sympathetic responses.
• Sympathetic signs predominate in most patients with central autonomic hyperactivity.
• Autonomic hyperactivity may cause exaggerated responses to various medications and therefore puts
patients at risk of serious iatrogenic complications.
• Careful attention can reliably distinguish paroxysmal sympathetic hyperactivity caused by brain injury from
adrenergic manifestations of sepsis, pulmonary embolism, or seizures.

• Paroxysmal sympathetic hyperactivity can be seen in up to one-third of patients with severe traumatic brain
injury.
• Standardized criteria have been proposed for the diagnosis and severity assessment of paroxysmal
sympathetic hyperactivity.
• Young age and coma are associated with higher risk of paroxysmal sympathetic hyperactivity.
• Deep brain lesions affecting connecting tracts, as seen with diffuse axonal injury, are commonly seen in
patients with paroxysmal sympathetic hyperactivity.
• Management of paroxysmal sympathetic hyperactivity includes minimizing stimulation and using abortive
(eg, morphine) and preventive (eg, gabapentin and propranolol) medications.
• Paroxysmal sympathetic hyperactivity can negatively affect the outcome of traumatic brain injury.
• Although primarily a complication of traumatic brain injury, paroxysmal sympathetic hyperactivity can occur
after other forms of acute brain injury, most notably global anoxia-ischemia.
• Autonomic dysreflexia occurs after severe spinal cord injury at the cervical or upper thoracic (T5 and above)
levels.
• Episodes of autonomic dysreflexia are often triggered by urinary retention, fecal impaction, or nursing care.
• Sudden hypertension is the most common and most serious manifestation of autonomic dysreflexia.
• Close attention to potential triggers is the key element in the management of autonomic dysreflexia.
• The clinical presentation of dysautonomia in Guillain-Barré syndrome is unpredictable and potentially
life-threatening.
• Rapid fluctuations in blood pressure and heart rate, urinary retention, and adynamic ileus are the most
prevalent expressions of dysautonomia in Guillain-Barré syndrome.
• Dysautonomic signs in patients with Guillain-Barré syndrome are best managed conservatively to prevent
iatrogenic complications.
Article 9: Management of Orthostatic

Hypotension
Jose-Alberto Palma, MD, PhD; Horacio Kaufmann, MD, FAAN. Continuum (Minneap
Minn). February 2020; 26 (1 Autonomic Disorders):154–177.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the management of orthostatic hypotension with emphasis on neurogenic
RECENT FINDINGS:
Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic
neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie,
non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and
heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line
treatment in the past, it is associated with adverse events including renal and cardiac failure and
increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic
hypotension is caused by central or peripheral dysfunction has therapeutic implications.
Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/
precursors such as droxidopa, whereas patients with central autonomic dysfunction respond
better to norepinephrine reuptake inhibitors.

SUMMARY:
Management of orthostatic hypotension is aimed at improving quality of life and reducing
symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to
success. Pharmacologic options include volume expansion with fludrocortisone and
sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors.
Neurogenic supine hypertension complicates management of orthostatic hypotension and is
primarily ameliorated by avoiding the supine position and sleeping with the head of the bed
elevated.
KEY POINTS
• Diagnosing orthostatic hypotension requires blood pressure measurements. The presence of orthostatic
intolerance is not sufficient or necessary to diagnose orthostatic hypotension.
• Orthostatic hypotension is very common in the elderly, usually due to drug effects, volume depletion, or
cardiovascular deconditioning.
• Neurogenic orthostatic hypotension is a feature of neurologic disorders affecting sympathetic pathways,
including diabetes mellitus, neurodegenerative synucleinopathies, and amyloid neuropathies.
• Exercise, meals (postprandial hypotension), prolonged bed rest (physical deconditioning), and hot and humid
environments typically worsen symptoms of neurogenic orthostatic hypotension.
• Patients with cognitive impairment may not accurately identify symptoms of orthostatic hypotension,
despite low blood pressure when standing.
• A heart rate increase of at least 0.5 beats/min for each 1 mm Hg fall in systolic blood pressure (ΔHR/ΔSBP
ratio ≥0.5 beats per minute/mm Hg) is sensitive and specific to diagnose non-neurogenic orthostatic
hypotension.
• Treatment of orthostatic hypotension should be geared to the patients’ symptoms and their impact on daily
function rather than a target blood pressure.
• The initial treatment of orthostatic hypotension focuses on nonpharmacologic measures first: removing
offending medications, increasing salt and fluid intake, using compression garments, and instituting physical
maneuvers and exercise.
• Drugs that reduce intravascular volume (eg, diuretics) or induce vasodilatation (eg, α-adrenergic blockers,
nitrates, phosphodiesterase-5 inhibitors, tricyclic antidepressants, centrally acting α-adrenergic agonists)
exacerbate orthostatic hypotension and worsen symptoms; thus, they should be reduced or discontinued.
• In patients with orthostatic hypotension, anemia should be investigated and treated.
• Because carbohydrate-rich meals trigger insulin, a potent vasodilator, patients with neurogenic orthostatic
hypotension should reduce carbohydrate content, eat smaller and more frequent meals, and choose low
glycemic index carbohydrates.
• Bolus water drinking produces a marked, albeit short-lived, increase in blood pressure in patients with
neurogenic orthostatic hypotension.
• Waist-high compression stockings are effective to increase blood pressure in patients with neurogenic
orthostatic hypotension, although compliance is very low. Elastic abdominal binders are a good alternative.
• Sleeping with the head of the bed raised 30 to 45 degrees reduces nocturnal hypertension, thus decreasing
natriuresis, which, in turn, prevents volume depletion overnight and improves orthostatic tolerance the next
morning.
• When medications for neurogenic orthostatic hypotension are used, patients should be taught to avoid the
flat position, sleep with the head of the bed raised 30 to 45 degrees, and measure their own blood pressure.
• Determining the site of the autonomic lesion (central versus peripheral) in patients with neurogenic
orthostatic hypotension has important therapeutic implications. Patients with central autonomic dysfunction
(ie, decentralization) have a more pronounced pressor response to norepinephrine reuptake inhibitors,
whereas patients with peripheral autonomic dysfunction (ie, denervation) have a more pronounced pressor
response to norepinephrine enhancers and agonists.

• For patients who still remain symptomatic despite nonpharmacologic measures, stepwise pharmacologic
treatment begins with low-dose fludrocortisone (0.1 mg/d), particularly in patients with volume depletion.
• Frequently used fludrocortisone dosages range from 0.05 mg/d to 0.2 mg/d. There is little benefit in
increasing fludrocortisone to dosages higher than 0.2 mg/d. Common short-term side effects include
hypokalemia; long-term side effects include left ventricular hypertrophy and renal failure.
• In patients with anemia of chronic disease and orthostatic hypotension, subcutaneous recombinant human
erythropoietin increases blood pressure and improves orthostatic tolerance.
• When starting droxidopa, a careful titration is required to identify the best dose for each patient and prevent
excessive supine hypertension.
• Treatment with norepinephrine reuptake inhibition is emerging as a potentially effective option for patients
with neurogenic orthostatic hypotension, particularly those with autonomic dysfunction from damage to the
central nervous system (eg, decentralization).
• Pyridostigmine alone has little effect to increase blood pressure. It appears to have synergistic effects when
combined with midodrine or atomoxetine.
• Neurogenic supine hypertension is best treated with postural measures, ie, avoiding the flat position and
sleeping with the head of the bed raised 30 to 45 degrees with the help of an electric bed or mattress. In
patients with refractory supine hypertension and high risk of organ damage, short-acting antihypertensives at
bedtime might be considered.
Article 10: Lower Urinary Tract and Bowel

Dysfunction in Neurologic Disease
Jalesh N. Panicker, MD, DM, FRCP; Ryuji Sakakibara, MD, PhD, FAAN. Continuum
(Minneap Minn). February 2020; 26 (1 Autonomic Disorders):178–199.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the clinical presentation, investigations, and treatment
options for lower urinary tract and bowel dysfunction in patients with neurologic diseases.
RECENT FINDINGS:
The site of the neurologic lesion influences the pattern of lower urinary tract dysfunction.
Antimuscarinic agents are first-line management for urinary incontinence; however, the side
effect profile should be considered when prescribing them. β3-Receptor agonists are a
promising alternative oral medication. Botulinum toxin injections into the detrusor have
revolutionized the management of neurogenic detrusor overactivity.
Bowel dysfunction commonly presents as constipation and fecal incontinence. Gastrointestinal
emergencies may arise, including intestinal pseudoobstruction, intussusception, volvulus, and
stercoral ulcer (ulcer of the colon due to pressure and irritation resulting from severe, prolonged
constipation). Bowel function tests in neurologic patients often show a combination of slow
transit and anorectal dysfunction. Management for slow transit constipation includes bulking
agents, softening agents, yogurt/probiotics, and prokinetic agents. Suppositories, botulinum
toxin injections, and transanal irrigation are options for managing anorectal constipation.
SUMMARY:
Functions of the lower urinary tract and bowel are commonly affected in neurologic disease.
Neurologists play an important role in assessing lower urinary tract and bowel symptoms in their
patients and planning treatment strategies, often in collaboration with specialist teams.

KEY POINTS
• The site of the neurologic lesion influences the pattern of lower urinary tract dysfunction. Symptoms of an
overactive bladder (urinary urgency, increased daytime frequency, nocturia, and, often, incontinence) are
the most common presentation.
• The risk of developing upper urinary tract damage is considerably lower in patients with slowly progressive
nontraumatic neurologic disorders than in those with spinal cord injury or spina bifida.
• Antimuscarinic agents are the first-line management of urinary incontinence; however, their side effect
profile and impact on anticholinergic burden should be considered when prescribing in patients who are
susceptible.
• β3-Receptor agonists are a promising new oral treatment for managing storage symptoms in patients with
neurologic diseases.
• Intradetrusor onabotulinumtoxinA injections are a highly effective and minimally invasive treatment for
storage dysfunctions.
• Percutaneous tibial nerve stimulation is a minimally invasive option for managing patients with mild to
moderate overactive bladder symptoms and is associated with few adverse effects.
• The postvoid residual should be routinely measured during the workup of every patient with neurologic
disease reporting lower urinary tract symptoms.
• A high postvoid residual is important to recognize as it may contribute to storage (overactive bladder)
symptoms and can predispose to recurrent urinary tract infections.
• Bowel dysfunction is common in patients with neurologic diseases.
• Bowel dysfunction not only affects patients’ quality of life but may also lead to gastrointestinal emergencies.
• Bowel dysfunction is often a combination of slow transit–type constipation (slowed colonic transit time, loss
of peristaltic contractions) and anorectal-type constipation (weak strain, anismus on defecation, and large
postdefecation residuals).
• Bowel dysfunction should be managed with a combination of diet, exercise, and drugs.
• Collaboration between neurologists, urologists, and gastroenterologists is recommended to maximize the
quality of life of patients with neurologic diseases who have lower urinary tract or bowel dysfunction.
Article 11: Skin Biopsy in Evaluation of

Autonomic Disorders
Christopher H. Gibbons, MD, MMSc, FAAN; Ningshan Wang, MD, PhD; Jee Young Kim,
MD; Marta Campagnolo, MD; Roy Freeman, MBChB. Continuum (Minneap Minn).
February 2020; 26 (1 Autonomic Disorders):200–212.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an up-to-date assessment of the role of skin biopsy in the evaluation of
autonomic disorders. The standard methodology for completing a skin biopsy, the anatomic
structures of interest detected within a skin biopsy, and the disease states in which skin biopsies
may provide valuable information are reviewed.
RECENT FINDINGS:
Several recent advances in the studies of hereditary amyloidosis and the various degenerative
synucleinopathies have demonstrated that simple skin biopsies can provide valuable pathologic
evidence of neurologic disease. In addition to diagnosis of the underlying disorder, skin biopsies
provide a quantitative structural measurement of the associated autonomic damage.

SUMMARY:
Skin biopsies are making great inroads into the study of autonomic and peripheral nerve
disorders. Complex immunohistochemical staining protocols are challenging to complete, but
the rich data derived from these studies in the diagnosis and monitoring of different disease
states suggest that the role of skin biopsies in the study of the autonomic nervous system will
continue to expand in the years to come.
KEY POINTS
• Standard punch biopsies 3 mm in diameter are used to obtain sections of tissue, generally from the distal leg,
distal thigh, and proximal thigh sites.
• Although biopsies are frequently used to evaluate for small fiber neuropathy by quantifying the nerve fibers
within the epidermis, autonomic innervation is all contained within the deeper dermal tissue.
• Pilomotor nerve fibers predominantly contain sympathetic adrenergic innervation.
• Sweat glands contain sympathetic cholinergic (also known as sudomotor) nerve fibers. Quantitation of sweat
gland density without reporting the area of sweat glands measured is a common error by laboratories and
limits the utility of this technique.
• In patients with hereditary amyloidosis, skin biopsy can provide quantitative assessment of neuropathy
severity, but it can also provide pathologic confirmation of disease by detection of the presence of amyloid
through Congo red staining.
• Skin biopsies are used in research studies to measure phosphorylated α-synuclein to aid in confirming a
diagnosis of an α-synucleinopathy such as Parkinson disease, multiple system atrophy, pure autonomic
failure, or Lewy body dementia.

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Issue Overview

Autonomic Disorders, Volume 26, Number 1, February 2020

Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay

Upon completion of this Continuum: Lifelong Learning in Neurology Autonomic Disorders

issue, participants will be able to:

 Describe the anatomic and functional organization of the sympathetic and

parasympathetic systems, the central mechanisms of autonomic controls, and the

pathophysiologic basis of the manifestations of autonomic failure

 Describe the clinical features and management of autoimmune autonomic disorders,

including autoimmune autonomic ganglionopathy and immune-mediated autonomic

history of the autonomic peripheral neuropathies

of the α-synucleinopathy disorders of pure autonomic failure, multiple system atrophy,

dementia with Lewy bodies, and Parkinson disease

disorders due to central and peripheral autonomic nervous system causes

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

disease and principles for their safe management

 Diagnose orthostatic hypotension and implement nonpharmacologic and pharmacologic

strategies for its management

patients with neurologic disorders

 Discuss the role of skin biopsy in the evaluation of autonomic disorders

following core competencies:

 Practice-Based Learning and Improvement

 Interpersonal and Communication Skills

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

Eduardo E. Benarroch, MD, FAAN, Guest Editor

Unlabeled Use of Products/Investigational Use Disclosure: Dr Benarroch reports no disclosure.

Relationship Disclosure: Dr Campagnolo reports no disclosure.

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William P. Cheshire Jr, MD, FAAN

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Relationship Disclosure: Dr Cutsforth-Gregory receives publishing royalties from Mayo Clinic

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Roy Freeman, MBChB

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Christopher H. Gibbons, MD, MMSc, FAAN

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Jee Young Kim, MD

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Jose-Alberto Palma, MD, PhD

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Unlabeled Use of Products/Investigational Use Disclosure: Dr Panicker reports no disclosure.

Alejandro A. Rabinstein, MD, FAAN

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Ryuji Sakakibara, MD, PhD, FAAN

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Steven Vernino, MD, PhD, FAAS, FAAN

Ningshan Wang, MD, PhD

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Self-Assessment and CME Test Writers

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Relationship Disclosure: Dr Zazulia reports no disclosure.

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Methods of Participation and Instructions for Use

Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay

as important as, if not more important than, the material itself.

The goals of Continuum include disseminating up-to-date information to the practicing

information, and comprehensive continuing medical education (CME) and self-assessment

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issue topic accompanies issues when applicable.

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