Sleep Neurology A Comprehensive Guide to Basic and

Clinical Aspects, 1st Edition

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Foreword

Long ago, when I started learning about Sleep Medicine, the only clinical text avail-
able was Christian Guilleminault’s landmark book Sleeping and Waking Disorders:
Indications and Techniques. Wow, has that limited publication availability ever
changed over the ensuing years! Currently there so many more books it is some-
times overwhelming for someone seeking good texts. Available formats include
encyclopedic approaches, broad coverage–limited depth approaches, update books,
small scope–high depth of subject, and board review–focused publications, just to
name a few. Now, when I see a new book I ask, “Is this one useful?” and “For what
audiences?” As a career educator, I also look for applicability for both learners and
teachers as well. I believe the answer for Sleep Neurology: A Comprehensive Guide
to Basic and Clinical Aspects, edited by Lourdes M. DelRosso and Raffaele Ferri,
is a clear yes; it is useful to the sleep medicine field.
Those looking for a solid coverage with updated information about relevant clin-
ical aspects of the field of Sleep Medicine as related to Neurology, but less material
than wading through an encyclopedia, will find a good clinical focus and solid cov-
erage of major underlying facts and findings. As an added bonus, many of the
authors are experienced faculty, having focused their career on teaching, both at
their academic institutions as well as for the American Academy of Sleep Medicine
committees, courses, and publications. That combination results in a recipe for suc-
cess with their subject coverage.
Cross discipline students, residents and fellows, sleep fellows, mid-level practi-
tioners from neurology-based programs, neurologists, and sleep medicine practitio-
ners who want to learn more about sleep and neurology interrelation, and those
looking for solid coverage of the indexed subjects, especially relevant for teaching,
are all likely beneficiaries.
The book’s overall organizational format is well designed to be helpful to the
reader. The chapters typically provide an efficient focus for the presented topic with
an abstract, keywords, and/or an introduction to indicate the scope. The chapter
organization includes integrating the neurological topic with the relevant sleep med-
icine topic(s) making it useful whether the reader is looking for specific areas of
sleep or neurology focus, or for providing a framework for the integration of the
fuller topic scope of that chapter. References are provided liberally for readers
wanting greater depth in specific areas but who do not wish to get bogged down in

v
vi Foreword

excessive detail while reading. The coverage of neurology topics related to sleep
appears to have been well thought out.
I believe the reader will likely find their time well spent as they read this book
and that it will be a useful addition to the educational literature on Neurology and
Sleep Medicine.

Andrew L. Chesson Jr, MD

Dean Emeritus, School of Medicine
Professor Emeritus Neurology and Division of Sleep Medicine
LSU Health Sciences Center – Shreveport
Shreveport, LA, USA
Preface

Sleep science has undergone incredible development during the last decades, prob-
ably more pronounced than other areas of science. This rapidly evolving field is still
demonstrating a fast growth which will probably continue in future years. As a
result of this astonishing increase in knowledge and pieces of information coming
from a wide range of studies, experts dealing with sleep disorders may find it diffi-
cult to integrate this amount of information in their clinical practice.
It is with great hope we present Sleep Neurology: A Comprehensive Guide to
Basic and Clinical Aspects as a useful aid to sleep clinicians, researchers, and the
neurology and medical community in general. With this book, we want to present
easy access to a comprehensive view of the neurologic basis of sleep disorders. We
have gathered together experts from all over the world to contribute to this book,
with a goal to connect the neurophysiology of sleep with sleep disorders seen in
common neurologic conditions. We want the information to be relevant to the
understanding of sleep processes, practical to highlight important clinical informa-
tion, and concise to summarize all the key facts in sleep and neurology. The review
of the list of pertinent citations and references at the end of each chapter provides
the opportunity to expand the knowledge beyond the current volume. The group of
authors are experts in their field and represent colleagues from various regions of
the world, including Europe and North and South America. The contributors bring
various perspectives and expertise to this volume.
In this first edition, we organize the material into two main parts. The first part
covers the neurobiology of normal sleep and sleep functions. We start with a general
description of sleep and wakefulness, discussing the circadian and homeostatic con-
trol of sleep, expanding into the neurophysiology of dreams, memory consolidation,
and sleep deprivation. The second part is dedicated to the understanding of sleep
symptomatology in various neurologic conditions. Here, we discuss sleep changes
in patients with dementia, seizures, headaches, and stroke among other common
neurologic disorders. Illustrations and tables are added to emphasize important key
points discussed in each chapter.
As said above, the knowledge about the science of sleep has grown exponentially
in the last decade and research has shown the association between sleep disorders
and many other medical conditions. Sleep disorders can contribute to comorbidities
and, vice versa, medical/neurological conditions can present with specific sleep dis-
orders. As knowledge of the importance of sleep grows, we see it imperative to

vii
viii Preface

bring forth this book as a reference source of useful information for both clinicians
and researchers.
We want to thank all the authors for their expert knowledge and valuable contri-
bution to this book. We also want to thank Mariah Gumpert and Gregory Sutorius of
Springer for their administrative assistance.

San Francisco, CA, USA Lourdes M. DelRosso

Troina, Enna, Italy Raffaele Ferri
Contents

Part I Neurobiology of Sleep and Wakefulness

1 Neurobiology of Wakefulness��������������������������������������������������������������������   3
Lourdes M. DelRosso and Marisa Pedemonte
2 Neurobiology of Sleep�������������������������������������������������������������������������������� 15
Ibrahim J. Raphael and Marisa Pedemonte
3 Neurobiology of the Control of Sleep ������������������������������������������������������ 31
Lourdes M. DelRosso, Joanna E. Wrede, Carey T. Lockhart,
and Daniel P. Cardinali
4 The Neurological Consequences of Sleep Deprivation �������������������������� 45
Lynn Keenan and Karl Van Gundy
5 Neurobiology of Dreams���������������������������������������������������������������������������� 57
Carlo Cipolli and Luigi De Gennaro
6 Neurobiology of Memory and Sleep �������������������������������������������������������� 81
Michael Blechner
7 Neurobiology of Insomnia ������������������������������������������������������������������������ 91
Célyne H. Bastien, Thierry Provencher, Jessica Lebel,
and Roxanne Bolduc-Landry
8 Narcolepsy and Central Nervous System Hypersomnias���������������������� 111
Fabio Pizza and Giuseppe Plazzi
9 Neurobiology of Parasomnias ������������������������������������������������������������������ 121
Tommaso Baldini, Giuseppe Loddo, Raffaele Ferri, and
Federica Provini
10 Neurobiology of Sleep-Related Movements�������������������������������������������� 147
Michela Figorilli, Monica Puligheddu, Patrizia Congiu, Stefan
Clemens, and Raffaele Ferri

ix
x Contents

Part II Sleep in Neurologic Conditions

11 Sleep in Seizure Disorders������������������������������������������������������������������������ 169
Silvia Miano
12 Sleep in Headaches������������������������������������������������������������������������������������ 195
Oliviero Bruni
13 Sleep in Cerebral Palsy������������������������������������������������������������������������������ 215
Michelle Sobremonte-King
14 Sleep and Cerebrovascular Disease���������������������������������������������������������� 231
Claude Nguyen
15 Sleep in Amyotrophic Lateral Sclerosis �������������������������������������������������� 243
Swapan Dholakia and Saiprakash B. Venkateshiah
16 Sleep After Traumatic Brain Injury�������������������������������������������������������� 255
Patrizia Congiu, Monica Puligheddu, Michela Figorilli, Stefania
Mondello, and Raffaele Ferri
17 Disorders of Sleep and Wakefulness in Parkinson’s Disease and Other
Movement Disorders���������������������������������������������������������������������������������� 269
John C. Carter and Vishesh K. Kapur
18 Sleep in Elderly Adults and in Subjects with Dementia ������������������������ 289
Helmut Frohnhofen and Dirk M. Hermann

Index�������������������������������������������������������������������������������������������������������������������� 301
List of Contributors

Tommaso Baldini, MD Department of Biomedical and Neuromotor Sciences,

University of Bologna, Bellaria Hospital, Bologna, Italy
Célyne H. Bastien, PhD School of Psychology, Laval University, Quebec,
QC, Canada
Michael Blechner, MD Department of Pediatric Pulmonary and Sleep Medicine,
St. Joseph’s Children’s Hospital, Paterson, NJ, USA
Roxanne Bolduc-Landry, BA School of Psychology, Laval University, Quebec,
QC, Canada
Oliviero Bruni, MD Department of Developmental and Social Psychology,
S. Andrea Hospital – Sapienza University, Rome, Italy
Daniel P. Cardinali, MD, PhD Faculty of Medical Sciences, University of Buenos
Aires, CONICET, Buenos Aires, Argentina
Pontifical Catholic University of Argentina, Buenos Aires, Argentina
John C. Carter, MD Department of Medicine, Division of Pulmonary, Critical
Care, and Sleep Medicin, Case Western Reserve University School of Medicine and
MetroHealth Medical Center, Cleveland, OH, USA
Andrew L. Chesson Jr, MD Neurology and Division of Sleep Medicine, School
of Medicine, LSU Health Sciences Center – Shreveport, Shreveport, LA, USA
Carlo Cipolli, PhD Department of Specialty, Diagnostic and Experimental
Medicine, University of Bologna, Bologna, Italy
Stefan Clemens, PhD Department of Physiology, Brody School of Medicine, East
Carolina University, Greenville, NC, USA
Patrizia Congiu, MD, PhD Neurophysiology Unit, Sleep Disorder Centre,
Department of Medical Sciences and Public Health, University of Cagliari,
Cagliari, Italy
Lourdes M. DelRosso, MD, MSEd Department of Pediatrics, University of
Washington/Seattle Children’s Hospital, Seattle, WA, USA

xi
xii List of Contributors

Swapan Dholakia, MD Department of Neurology, Atlanta VA Medical Center,

Emory University School of Medicine, Decatur, GA, USA
Raffaele Ferri, MD Sleep Research Centre, Oasi Research Institute - IRCCS,
Troina, Italy
Michela Figorilli, MD Neurophysiology Unit, Sleep Disorder Centre, Department
of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Helmut Frohnhofen, MD Department of Internal Medicine and Geriatrics, Alfried
Krupp Krankenhaus, Essen, Germany
Luigi De Gennaro, PhD Department of Psychology, University of Rome Sapienza,
Rome, Italy
Karl Van Gundy, MD, FCCP Departments of Pulmonary, Critical Care, and
Sleep Medicine, UCSF Fresno, Fresno, CA, USA
Division of Internal Medicine, Community Regional Medical Center,
Fresno, CA, USA
Dirk M. Hermann, MD Department of Neurology, Universitätsklinikum Essen,
Essen, Germany
Vishesh K. Kapur, MD, MPH Department of Medicine, Division of Pulmonary,
Critical Care and Sleep Medicine, University of Washington, Harborview Medical
Center, Seattle, WA, USA
Lynn Keenan, MD, FAASM Department of Internal Medicine, UCSF Fresno,
Fresno, CA, USA
Jessica Lebel, MS School of Psychology, Laval University, Quebec, QC, Canada
Carey T. Lockhart, MD Department of Pediatric Sleep Medicine and Neurology,
University of Washington, Seattle Children’s Hospital, Seattle, WA, USA
Giuseppe Loddo, MD Department of Biomedical and Neuromotor Sciences,
University of Bologna, Bellaria Hospital, Bologna, Italy
Silvia Miano, MD, PhD Neurocenter of Southern Switzerland, Civic Hospital,
Lugano, Switzerland
Stefania Mondello, MD, MPH, PhD Department of Biomedical and Dental
Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
Claude Nguyen, MD, MSEd Division of Stroke and Neurocritical Care, California
Pacific Medical Center, Sutter Health, San Francisco, CA, USA
Marisa Pedemonte, MD, PhD Department of Physiology, School of Medicine,
CLAEH University, Prado and Salt Lake, Punta del Este, Maldonado, Uruguay
Fabio Pizza, MD, PhD DIBINEM, Department of Biomedical and Neuromotor
Sciences, University of Bologna, Bologna, Italy
IRCCS, Institute of Neurological Sciences of Bologna, UOC Neurological Clinic,
Bellaria Hospital, Bologna, Italy
List of Contributors xiii

Giuseppe Plazzi, MD DIBINEM, Department of Biomedical and Neuromotor

Sciences, University of Bologna, Bologna, Italy
IRCCS, Institute of Neurological Sciences of Bologna, UOC Neurological Clinic,
Bellaria Hospital, Bologna, Italy
Thierry Provencher, BA School of Psychology, Laval University, Quebec,
QC, Canada
Federica Provini, MD, PhD Department of Biomedical and Neuromotor Sciences,
University of Bologna, Bologna, Italy
IRCCS Institute of Neurological Sciences, Bologna, Italy
Monica Puligheddu, MD, PhD Neurophysiology Unit, Sleep Disorder Centre,
Department of Medical Sciences and Public Health, University of Cagliari,
Caligari, Italy
Ibrahim J. Raphael, MD Department of Pulmonary, Sleep, and Critical Care
Medicine, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA
Michelle Sobremonte-King, MD Department of Pediatric Pulmonary and Sleep
Medicine, The Breathing Institute, Children’s Hospital Colorado, Aurora, CO, USA
Saiprakash B. Venkateshiah, MD Division of Pulmonary, Allergy, Critical Care
and Sleep Medicine, Emory University School of Medicine, Atlanta VA Medical
Center, Decatur, GA, USA
Joanna E. Wrede, MD Department of Pediatrics and Neurology, University of
Washington, Seattle Children’s Hospital, Seattle, WA, USA
 Part I
Neurobiology of Sleep and Wakefulness
Neurobiology of Wakefulness
1
Lourdes M. DelRosso and Marisa Pedemonte

Introduction

The sleep-wake cycle is a biological process found in all animals. The identification
of areas in the brain involved in sleep and wakefulness dates back to the works of Soca
and Constantin von Economo in the early 1900s. Soca described a continuous and
prolonged sleep, easily arousable at the beginning in a young patient with a tumor
located over the sella turcica which compressed the anterior hypothalamic region [1].
Von Economo studied the brains of patients who died of encephalitis lethargica. This
devastating infection manifested in two main forms. One group of patients suffered
from insomnia and a second group fell into a “sleep coma.” Von Economo identified
different areas of the brain associated with sleep and wakefulness. He discovered that
the brains of patients who suffered from profound sleepiness had significant loss of
neurons in the posterior hypothalamus and mesencephalic reticular formation; hence
these two areas were identified as crucial for wakefulness, while the brains of patients
who suffered insomnia had loss of neurons in the anterior hypothalamus and preoptic
forebrain, concluding that these areas were crucial for sleep [2].
Research in sleep neurophysiology has been tremendously influenced by the
invention of electroencephalography by Hans Berger who recorded the first human
EEG in 1924 [3]. In 1936, Frederick Bremer researched EEG patterns in two cat
brain preparations. He transected the cat brain at two levels. The cut between the
medulla and the spinal cord (encephale isole) demonstrated EEG patterns of sleep
and wakefulness. The cut between the inferior and superior colliculi (cerveau isole)
demonstrated persistent sleep waves. In 1949, Moruzzi and Magoun discovered that
stimulation of the “reticular formation” in the brain stem would lead to EEG

L. M. DelRosso (*)
Department of Pediatrics, University of Washington/Seattle Children’s Hospital,
Seattle, WA, USA
M. Pedemonte
Department of Physiology, School of Medicine, CLAEH University, Prado and Salt Lake,
Punta del Este, Maldonado, Uruguay
© Springer Nature Switzerland AG 2021 3
L. M. DelRosso, R. Ferri (eds.), Sleep Neurology,
https://doi.org/10.1007/978-3-030-54359-4_1
4 L. M. DelRosso and M. Pedemonte

LH (Hn) vPAG
(DA)

BF
LDT (ACh)
(ACh,
GABA) TMN
Raphe PPT (ACh)
(His)
(5HT)

LC (NE)

LC: Locus Ceruleus, NE: Norepinephrine, PPT: Pedunculopontine tegmentum, LDT:

laterodorsal tegmentum, Ach: Acetylcholine, vPAG: ventral periaqueductal gray, DA:
Dopamine, TMN: tuberomamilary nucleus, His: Histamine, BF Basal forebrain, LH lateral
hypothalamus, Hn; hypocretin

Fig. 1.1 Nuclei and neurotransmitters involved in the arousal pathways

desynchronization and behavioral arousal. Lesions in the reticular formation of the

brain stem produced persistent sleep [4]. These findings laid the foundations for
what is currently known as the reticular activating system (Fig. 1.1).

Neural Circuits of Wakefulness

Moruzzi and Magoun discovered that wakefulness was achieved through the effects
of the ascending reticular activating system (RAS) on the brain stem and cortex.
RAS is conformed by several nuclei and neuronal projections that originate in the
reticular formation of the brain stem. Brain stem nuclei include the locus ceruleus,
dorsal raphe, median raphe, pedunculopontine nucleus, laterodorsal tegmentum,
and parabrachial nucleus. Non-brain stem nuclei include the thalamic nuclei, hypo-
thalamus, and basal forebrain. These nuclei cannot be clearly isolated from other
structures by neuroimaging although some studies have attempted to demonstrate
RAS fibers and connectivity using diffusion tensor imaging (Fig. 1.2) [5].
1 Neurobiology of Wakefulness 5

Fig. 1.2 (a) Seed regions of interest (ROI) are given on the pontine reticular formation (red color).
The target ROI is given on the intralaminar nuclei of the thalamus at the level of the commissural
plane. ML medial lemniscus, RST rubrospinal tract, RF reticular formation, AC anterior commis-
sure, PC posterior commissure. (b) Pathways of the reconstructed ascending reticular activating
system are shown at each level of the brain in a normal subject (26-year-old male). (From Yeo
et al. [3])
6 L. M. DelRosso and M. Pedemonte

Two nuclei are the major point of origin of the RAS: the pedunculopontine (PPN)
and the laterodorsal tegmentum (LDT). These nuclei contain acetylcholine-­
synthesizing neurons. Every cell in the PPN generates and maintains beta and
gamma activity during wakefulness via membrane oscillations that are mediated by
voltage-dependent calcium channels and modulated by G proteins. These channels
have separate intracellular pathways for wakefulness and for REM sleep (Fig. 1.3) [6].
From the PPT, signals travel via two pathways. The dorsal pathway, thought to
play an important role in the thalamocortical transmission and on the EEG of sleep
and wakefulness, projects to the thalamus (intralaminar, paraventricular, and reticu-
lar nuclei) and then to the cortex [7]. The ventral pathway projects to the hypothala-
mus and basal forebrain.
Arousal is therefore initiated and maintained by multiple brain regions, several
nuclei in the brain stem, and their projections to the thalamus, hypothalamus, and fore-
brain. These nuclei synthesize neurotransmitters (acetylcholine, histamine, serotonin,
norepinephrine, and hypocretin) (Table 1.1) that modulate wakefulness and sleep.

Fig. 1.3 Intracellular pathways and calcium channels differentially related to waking versus REM
sleep. Representation of effects of acetylcholine (ACh) activation of a muscarinic 2 cholinergic recep-
tor (M2R) acting through G protein coupling to phospholipase C (PLC) that in turn cleaves phospho-
lipid phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate (IP3). IP3 is released and
binds to IP3 receptors in the endoplasmic reticulum (ER) to release calcium (Ca2+). One of the intracel-
lular pathways activated involves CaMKII, which modulates P/Q-type calcium channels, and the other
pathway involves cAMP/PKA, which modulates N-type calcium channels. The CaMKII/P/Q-type
pathway mediates beta/gamma band activity during waking, while the cAMP/PKA/N-type pathway
mediates beta/gamma band activity during REM sleep. (From Garcia-Rill E et al. [4])