Respiratory Sleep Medicine: Handbook

handbook
Respiratory
Sleep
Medicine
Editors
Anita K. Simonds
Wilfried de Backer
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PUBLISHED BY
EUROPEAN RESPIRATORY SOCIETY
CHIEF EDITORS
Anita K. Simonds (London, UK)
Wilfried de Backer (Antwerp, Belgium)
AUTHORS
Stefan Andreas Michel Lecendreux Winfried Randerath
Chiara Baglioni Patrick Levy Dieter Riemann
Ferrán Barbé Marie Marklund Renata L. Riha
Maria R. Bonsignore Juan Fernando Masa Daniel Rodenstein
An Boudewiyns Walter T. McNicholas Silke Ryan
Gary Cohen Josep M. Montserrat Zoltan Tomori
Viliam Donic Mary J. Morrell Ha Trang
Athanasios Kaditis Gimbada B. Mwenge Johan Verbraecken
Miriam Katz-Salomon Arie Oksenberg Stijn Verhulst
Brian D. Kent Paolo Palange Maria Pia Villa
Eric Konofal Dirk Pevernagie
ERS STAFF
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© 2012 European Respiratory Society
Design by Claire Turner and Lee Dodd, ERS

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ISBN 978-1-84984-023-1
Contents
Contributors vii
Preface xi
Get more from this Handbook xii
List of abbreviations xiii
Chapter 1 - Physiology and anatomy of sleep and breathing
Neuroanatomy and neurobiology of sleep 1

Mary J. Morrell, Paolo Palange, Patrick Levy and Wilfried De Backer
Breathing during sleep and wakefulness 6
Homeostatic regulation during sleep 13
Chapter 2 - Respiratory conditions
Definitions of sleep disordered breathing 21

Johan Verbraecken
Obstructive sleep apnoea syndrome 25
Johan Verbraecken
Obstructive sleep apnoea: epidemiology and risk factors 26
Johan Verbraecken
Obstructive sleep apnoea: pathophysiology 29
Johan Verbraecke and Wilfried de Backer
Obstructive sleep apnoea: clinical aspects 32
Stefan Andreas
Obstructive sleep apnoea: consequences 35
Stefan Andreas
Central sleep apnoea and Cheyne–Stokes respiration 39
Winfried Randerath
Central sleep apnoea/Cheyne–Stokes respiration: epidemiology 40
and risk factors
Winfried Randerath
Central sleep apnoea/Cheyne–Stokes respiration: pathophysiology 42
Winfried Randerath
Central sleep apnoea/Cheyne–Stokes respiration: clinical aspects 45
Winfried Randerath
Central sleep apnoea/Cheyne–Stokes respiration: consequences 46
Stefan Andreas
Hypoventilation syndromes/chronic respiratory insufficiency in sleep 48
Viliam Donic and Zoltan Tomori
Chapter 3 - Nonrespiratory conditions
Nonrespiratory sleep disorders 52

Renata L. Riha
Insomnia 53
Dirk Pevernagie
Parasomnia and movement disorders during sleep 61
Renata L. Riha
Hypersomnia 67
Renata L. Riha
Circadian rhythm disorders 74
Renata L. Riha
Psychiatric aspects of sleep 80
Chiara Baglioni and Dieter Riemann
Chapter 4 - Clinical assessment
Sleep history 84
Silke Ryan and Walter T. McNicholas
Differential diagnosis 87
Walter T. McNicholas
Questionnaires on sleep 91
Brian D. Kent and Walter T. McNicholas
Predisposing factors 95
Maria R. Bonsignore
Diagnostic algorithms 100
Josep M. Montserrat, Ferrán Barbé and Juan Fernando Masa
Quality of life 107
Maria R. Bonsignore
Surgical and anaesthesia risk assessment 111
Maria R. Bonsignore
Comorbidity assessment 115
Maria R. Bonsignore
Chapter 5 - Diagnostic techniques
Polysomnography 120
Renata L. Riha
Assessment of daytime sleepiness 131
Renata L. Riha
Cardiorespiratory monitoring during sleep 136
Maria R. Bonsignore and Juan Fernando Masa
Chapter 6 - Treatment
Treatment of obstructive sleep apnoea 147

Johan Verbraecken, Arie Oksenberg, Marie Marklund and An Boudewyns
Positive airway pressure treatment 157
Anita K. Simonds
Treatment of central sleep apnoea 164
Winfried Randerath
Treatment of hypoventilation/chronic respiratory insufficiency 169
Anita K. Simonds
Treatment of nonrespiratory sleep disorders 176
Dirk Pevernagie
Chapter 7 - Medicolegal and economic aspects of sleep disorders
Medicolegal and economic aspects of sleep disorders 189

Gimbada B. Mwenge and Daniel Rodenstein
Chapter 8 - Paediatric respiratory sleep medicine
Development of breathing and sleep and physiopathology of 200

apnoea in the first years of life
Gary Cohen, Miriam Katz-Salamon and Ha Trang
Sleep disordered breathing in children 205
Ha Trang and Anita K. Simonds
Comorbid respiratory disorders in children 210
Anita K. Simonds
Nonrespiratory conditions in children 213
Ha Trang, Michel Lecendreux and Eric Konofal
Clinical assessment in children 218
Maria Pia Villa
Diagnostic techniques in children 221
Stijn Verhulst and Wilfried De Backer
Management of sleep disordered breathing in children 228
Athanasios Kaditis, Maria Pia Villa, Anita K. Simonds and Ha Trang
Index 237
Contributors
Editors
Anita K. Simonds Wilfried de Backer
NIHR Respiratory Disease Biomedical Dept of Pulmonary Medicine
Research Unit University and University Hospital of
Royal Brompton and Harefield NHS Antwerp
Foundation Trust Edegem, Belgium
London, UK [email protected]
[email protected]
Authors
Stefan Andreas Chiara Baglioni
Pneumologische Lehrklinik Dept of Psychiatry and Psychotherapy
Universität Göttingen Freiburg University Medical Centre
Göttingen, Germany Freiburg, Germany
[email protected] [email protected]
Ferrán Barbé Maria R. Bonsignore

Respiratory Diseases Research Unit Biomedical Dept of Internal and
Universitari Arnau de Vilanova Specialist Medicine (DiBiMIS)
Lleida, Spain/ University of Palermo
CIBER de Enfermedades Respiratorias Palermo, Italy
Bunyola, Spain [email protected]
[email protected]
An Boudewiyns Gary Cohen

Dept of Otorhinolaryngology Dept of Woman and Child Health
University Hospital Antwerp Karolinska Institutet
Edegem, Belgium Stockholm, Sweden
Viliam Donic Athanasios Kaditis

Dept of Human Physiology and Sleep First Dept of Paediatrics
Laboratory University of Athens School of
School of Medicine Medi cine and Aghia Sophia Children’s
Safarik University Hospital
Kosice, Slovakia Athens, Greece
[email protected] [email protected] vii
Miriam Katz-Salomon Brian D. Kent
Dept of Woman and Child Health, Pulmonary and Sleep Disorders Unit
Karolinska Institutet St. Vincent’s University Hospital
Stockholm, Sweden Dublin, Ireland
Eric Konofal Michel Lecendreux

Paediatric Sleep Disorders Centre, Dept of Child and Adolescent
AP-HP, Hôpital Robert Debré, Psychopathology
Paris, France/ Robert Debré Hospital
Pediatric Clinical Investigation Centre Paris VII University
(CIC 9202) INSERM Paris, France
AP-HP, Hôpital Robert Debré [email protected]
Paris, France
[email protected]
Patrick Levy Marie Marklund

Joseph Fourier University and INSERM Dept of Dentistry/Orthodontics
Grenoble, France University of Umeå
[email protected] Umeå, Sweden
[email protected]
Juan Fernando Masa Walter T. McNicholas

Respiratory Service Pulmonary and Sleep Disorders Unit
Hospital San Pedro de Alcantara St. Vincent’s University Hospital
Cáceres, Spain/ Dublin, Ireland
CIBER de Enfermedades Respiratorias [email protected]
Bunyola, Spain
[email protected]
Josep M. Montserrat Mary J. Morrell

Servei de Pneumologia National Heart & Lung Institute
Hospital Clinic-IDIBAPS Imperial College London
Barcelona, Spain/ Academic Unit of Sleep and Breathing
CIBER de Enfermedades Respiratorias Royal Brompton Hospital
Bunyola, Spain London, UK
vii
Gimbada B. Mwenge Arie Oksenberg
Centre for Sleep Medicine and Sleep Disorders Unit
Pneumology Department Loewenstein Hospital –
Université Catholique de Louvain Rehabilitation Center
Brussels, Belgium Raanana, Israel
[email protected]` [email protected]
Paolo Palange Dirk Pevernagie

Dept of Public Health and Infectious Sleep Medicine Centre
Diseases Kempenhaeghe Foundation
Sapienza University of Rome Heeze, The Netherlands/
Rome, Italy Dept of Internal Medicine
[email protected] University of Gent
Gent, Belgium
[email protected]
Winfried Randerath Dieter Riemann

Centre of Sleep Medicine and Centre of Sleep Medicine and
Respiratory Care Respiratory Care
Bethanien Hospital Bethanien Hospital
Solingen, Germany Solingen, Germany
Medical Centre
Freiburg, Germany
[email protected]
Renata L. Riha Daniel Rodenstein

Department of Sleep Medicine Centre for Sleep Medicine and
Royal Infirmary Edinburgh Pneumology Department
Edinburgh, Scotland Université Catholique de Louvain
[email protected] Brussels, Belgium
[email protected]
Silke Ryan Zoltan Tomori

Respiratory Sleep Disorders Unit Dept of Human Physiology and Sleep
St. Vincent’s University Hospital Laboratory
Dublin, Ireland School of Medicine Safarik University
[email protected] Kosice, Slovakia
[email protected]
ix
Ha Trang Johan Verbraecken
University of Paris-Diderot Dept of Pulmonary Medicine and
Paris, France/ Multidisciplinary Sleep Disorders
AP-HP, Robert Debré Hospital Centre
Paediatric Sleep Centre, Antwerp University Hospital and
Centre of reference for CCHS University of Antwerp
Paris, France Edegem, Belgium
Stijn Verhulst Maria Pia Villa

Paediatric Sleep Lab and Paediatric Regional Sleep Disorders Centre
Pulmonology Sant’Andrea Hospital
Antwerp University Hospital Rome, Italy
Edegem, Belgium [email protected]
[email protected]
x
Preface
“A thing of beauty is a joy for ever: Its loveliness increases; it will never
pass into nothingness; but still will keep a bower quiet for us, and a sleep
full of sweet dreams, and health, and quiet breathing...” John Keats
The ERS Handbook of Respiratory Sleep Medicine furthers the ERS HERMES project to
Harmonise Education in Respiratory Medicine for European Specialists. Sleep medicine
is truly multidisciplinary, and yet the huge expansion in sleep medicine facilities over the
past two to three decades can be attributed to the recognition of and need to manage sleep
disordered breathing, particularly obstructive sleep apnoea. The field is therefore of very great
importance to respiratory physicians and respiratory team members, who are instrumental
in running many European sleep laboratories. Moreover, treatment methods for obstructive
sleep apnoea and nocturnal hypoventilation with continuous positive airway pressure
and noninvasive ventilation have improved and diversified, and the links between sleep
disordered breathing and co-morbidities are now much better understood, making it an area
with an extensive and growing evidence base.
This handbook is part of the planned development of a training programme in sleep
medicine, following the creation of a syllabus and curriculum in respiratory sleep medicine.
Its aim is to help physicians and trainees meet the curriculum requirements. However, it
covers the field extensively with detailed reference to nonrespiratory disorders and paediatric
sleep medicine. As such, it is a valuable resource for any practitioner from a respiratory,
neurology, cardiology, dental or ENT background who sees patients with sleep disorders,
and needs an up-to date reference book that covers succinctly the causes, diagnosis and
management of these conditions.
The Editors are very grateful to the ERS Task Force in Respiratory Sleep medicine, and other
contributors who have written the chapters; and to the ERS staff who helped coordinate both
the Task Force and the book.
Anita K. Simonds, Wilfried de Backer

Editors
xi
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Also available from the ERS
European Respiratory Monograph 50: Sleep Apnoea

Edited by Walter T. McNicholas and Maria R. Bonsignore.
This Monograph takes an in-depth look at sleep apnoea,
focusing on OSA, from pathophysiology and epidemiology
to comorbidities, treatment and future directions. The 24
chapters cover all aspects of the disease, including the lat-
est interventions and new diagnostic technologies. To see
the full table of contents and read the editors’ introduction,
visit erm.ersjournals.com/content/ermsa/1.toc
To buy a copy of this Monograph, please contact
[email protected]
xii
List of abbreviations
(C)HF (congestive) heart failure

(N)REM sleep (non-) rapid eye movement sleep
AHI apnoea–hypopnoea index
ASV adaptive servo venti lation
BMI body mass index
COPD chronic obstructive pulmonary disease
CPAP continuous positive airway pressure
CSA central sleep apnoea
CSR Cheyne–Stokes respiration
ECG electrocardiography
EEG electroencephalography
EMG electromyography
ENT ear, nose and throat
EOG electrooculography
ESS Epworth Sleepiness Scale
ICSD International Classification of Sleep Disorders
MRI magnetic resonance imaging
MSLT Multiple Sleep Latency Test
MWT Maintenance of Wakefulness Test
NIV noninvasive ventilation
OHS obesity hypoventilation syndrome
OSA(S) obstructive sleep apnoea (syndrome)
OSLER test Oxford Sleep Resistance test
PaCO2 arterial carbon dioxide tension
PaO2 arterial oxygen tension
PSG polysomnography
PtcCO2 transcutaneous carbon dioxide tension
SAHS sleep apnoea–hypopnoea syndrome
SaO2 arterial oxygen saturation
SDB sleep disordered breathing
V’E minute ventilation
xiii
Neuroanatomy and
neurobiology of sleep
The neurobiology of sleep electrical potentials. He termed these

recordings electroencephalograms and by
Sleep is a dynamic process involving the mid-1930s the cyclical patterns
complex neural activation. In 1929 the associated with NREM sleep had been
psychiatrist Hans Berger established that categorised. The first observations of REM
brain activity was different during sleep occurred in the 1950s (Aserinsky et al.,
wakefulness and sleep by recording cortical 1953). Understanding of the control
mechanisms of NREM and REM sleep
continues to develop.
Key points
The neural regulation of wakefulness and
arousal from sleep Neurons of the reticular
N Wakefulness is maintained by activating system are central to the
activation of the ascending reticular regulation of wakefulness. Specifically, there
activating system involving several are two ascending pathways: one, a dorsal
neurotransmitters including route from the cholinergic laterodorsal and
glutamate, acetylcholine and the pedunculopontine tegmental nuclei,
monoamines. activates thalamic neurons to promote EEG
N NREM sleep onset is associated with activity via glutamatergic thalamocortical
a reduction in activation of the projections (Saper et al., 2005). The ventral
ascending reticular activating system route through the hypothalamus includes
and an increase in neural activity the aminergic arousal system that originates
within the ventrolateral pre-optic area, from the brainstem with serotonergic
anterior hypothalamus and basal (dorsal raphe nuclei), noradrenergic (locus
forebrain. coeruleus), histaminergic
(tuberomammillary nucleus) and
N REM sleep is triggered by activation of
dopaminergic (ventral periaqueductal grey)
cholinergic neurons in the
neurons (Horner, 2008). Cortical activation
laterodorsal and pedunculopontine
during wakefulness is also influenced by
tegmental nuclei. The suppression of
orexinergic (hypocretin) neurons originating
motor activity in REM sleep is
in the hypothalamus, and cholinergic
generated by glutamate-mediated
neurons from the basal forebrain (fig. 1a).
activation of descending medullary
During wakefulness these pathways allow
reticular formation.
sensory information to be transmitted to
N Cycles of NREM and REM sleep areas of the association cortex via the
alternate throughout the night in a thalamic gate.
predictable manner.
The neural regulation of NREM and REM
N Ageing is associated with difficulty in sleep The transition between wakefulness
maintaining sleep and more frequent and sleep occurs through a process of
arousals. reciprocal inhibition between arousal- and
sleep-promoting neurons by way of a ‘‘flip-flop’’
ERS Handbook: Respiratory Sleep Medicine 1

a)
10 1
9
Olfactory Upper
11
bulb 13 airway
12 14
2 3 • Histaminergic
7
8
• Serotonergic
4 • Noradrenergic
6
5 • Cholinergic
• Orexinergic
b) • Glutaminergic
Upper
airway
• GABAergic
1 Pineal
c) 2 Pons
Upper 3 Medulla oblongata
airway 4 Spinal cord
5 Pituitary
6 Tuberomammillary
nucleus
7 Preoptic area
8 Hypothalamus
9 Corpus callosum
10 Cerebral cortex
11 Hippocampus
12 Thalamus
13 Midbrain
14 Cerebellum
Figure 1. a)Wakefulness-, b) NREM sleep- and c) REM sleep-generating neuronal systems in the rat brain.
Descending projections to the respiratory and hypoglossal motor neurons in the medulla are also shown.
Solid lines indicate active neuronal groups and projections, respectively. Dashed lines and decreased
symbol size indicate suppressed activity. Lines terminating with an arrow indicate excitatory projections,
lines terminating with an oval indicate inhibitory projections and lines terminating in a diamond indicate
mixed excitatory and inhibitory projections for acetylcholine. The progressive suppression of hypoglossal
motor output to genioglossus muscle from wakefulness to NREM and REM sleep is illustrated by reduced
line thickness. Figure adapted from Horner (2008), with permission from the publisher.
2 ERS Handbook: Respiratory Sleep Medicine

Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
0 1 2 3 4 5 6
Hours of recording
Figure 2. A typical overnight sleep hypnogram illustrating the sleep cycles that occur overnight in a young
male. REM sleep is seen approximately every 90 min and there are occasional brief arousals from sleep.
switch (McGinty et al., 2000). This is an NREM sleep is conventionally divided into
all-or-nothing process that prevents the three or four stages according to the
occurrence of intermediate conscious guidelines laid out by the American
states. At sleep onset, neurons in the Academy of Sleep Medicine in 2007. These
ventrolateral pre-optic area (VLPO), stages approximately represent the depth of
anterior hypothalamus and basal forebrain sleep and are analysed using standardised
are activated and inhibit the arousal criteria (see chapter 5).
systems detailed previously. In particular,
the VLPO neurons containing the In adults sleep is most often initiated
inhibitory neurotransmitters c-aminobutyric through NREM sleep and is marked by
acid (GABA) and galanin, project to (and synchronisation of EEG activity (for further
inhibit) the wake-promoting regions of the description of the EEG that defines the
ascending reticular system (Sherin et al., stages of sleep see chapter 5). The overnight
1998) and the descending brainstem sleep patterns in a healthy young adult are
arousal neurons (fig. 1b). shown in figure 2. NREM predominates
early in the night with episodes of REM
REM sleep occurs with activation of sleep occurring in approximately 90-min
cholinergic neurons in the laterodorsal and intervals. The 90-min NREM–REM cycle is
pedunculopontine tegmental nuclei. This repeated approximately three to six times
cholinergic activation occurs when during the night, and the duration of REM
withdrawal of the aminergic arousal systems sleep increases as the night progresses. The
(noradrenergic neurons in the locus preferential occurrence of NREM sleep
coeruleus and serotonergic neurons in the (particularly slow-wave sleep) early in the
dorsal raphe nuclei) produces disinhibition. night is coincidental with sleep
This causes the release of acetylcholine, homeostasis, while the predominance of
which triggers the increased neural activity REM sleep later in the night is thought to be
that is a feature of REM sleep. Suppression associated with the circadian rhythm of core
of motor activity, the other marker of REM body temperature.
sleep, is generated by glutamate-mediated
activation of descending medullary reticular Sleep cycles in ageing Sleep is essential for
formation relay neurons (fig. 1c). The life in humans. Total sleep deprivation over
activity of these neurons is inhibitory to 2–3 weeks impairs thermal regulation,
spinal motor neurons via the release of energy balance and immune function,
glycine and to a lesser extent GABA eventually causing death. The requirements
(Reinoso-Suarez et al., 2001). for sleep vary with age. In infants, active
(REM) sleep dominates in the first 1–
The cycle of wakefulness and sleep The 2 months of life. After 3 months NREM
transition from wake to sleep can be difficult sleep begins to dominate, and by 5 yrs of
to determine as there are typically brief age adult sleep stages are established. The
periods of drowsiness with transient bursts percentage of REM sleep is reduced to adult
of wakefulness before sleep consolidation. levels by 10 yrs of age.

35 increasing age may be due to a reduction in
the amplitude of delta waves detected on
30 ●●
the EEG recordings, meaning that stage 3–4
●
Arousal/hour of sleep
●
sleep is not documented despite the
25 ●
● ● presence of delta waves. Alternatively,

●
20
●
●
disrupted synchronisation of neuronal
●
●
●
●
●
●
activation may occur as a result of an age-
● ●
●
15 ●
●
●●
●
●
●
●
●
●
●
related decline in the neural systems that
●
●
● ● ●● regulate sleep. An increase in the lighter
●
10 ●
r=0.852 sleep partially compensates for the loss of
deep sleep (Van Cauter et al., 2000) but
5 p<0.00001 there is also a reduction in the number of
sleep spindles and K complexes. The
0
0 10 20 30 40 50 60 70 80 duration of REM sleep tends to remain
Age yrs constant throughout adulthood (Landolt
et al., 1996), although a reduction in the
Figure 3. The influence of age on the number of proportion of REM sleep has been reported
arousals (awakenings o3 s) per hour of sleep. by some (Van Cauter et al., 2000).
Reproduced with permission from Boselli et al.
(1998), with permission from the publisher.
Further reading
In adults, optimal sleep duration varies. N Aserinsky E, et al. (1953). Regularly
Sleep restriction to ,5 h a night causes a occurring periods of eye motility, and
reduction in psychomotor vigilance (Dinges concomitant phenomena, during sleep.
et al., 1997), a decline in mood and Science; 118: 273–274.
motivation and a worse performance on N Boselli M, et al. (1998). Effect of age on
memory tests. Increasing sleep opportunity EEG arousals in normal sleep. Sleep; 21:
up to 10 h a night improves cognitive 361–367.
function. Most estimates suggest that 7.5– N Dijk DJ, et al. (2000). Contribution of
8.5 h of sleep are required for optimal circadian physiology and sleep home-
performance. ostasis to age-related changes in human
sleep. Chronobiol Int; 17: 285–311.
Ageing influences sleep cycles, with older N Dinges DF, et al. (1997). Cumulative
people reporting that they experience sleepiness, mood disturbance, and psy-
difficulty in maintaining sleep and increased chomotor vigilance performance decre-
awakenings (fig. 3). Morning preference also ments during a week of sleep restricted to
4–5 hours per night. Sleep; 20: 267–277.
increases with age (Taillard et al., 2004);
N Horner RL. (2008). Neuromodulation of
however, this may be due to changing work
hypoglossal motoneurons during sleep.
schedules or variation in social activities, as
Respir Physiol Neurobiol; 164: 179–196.
well as changes in the physiological N Iber C, et al. (2007). The AASM Manual
requirements for sleep (Dijk et al., 2000). for the Scoring of Sleep and Associated
The increased number of arousals per night Events: Rules, Terminology and Technical
may be a consequence of the decline in the Specifications. 1st Edn. Westchester,
neural systems that regulate sleep or an age- American Academy of Sleep Medicine.
related change in the arousal thresholds to N Klerman EB, et al. (2004). Older people
external stimuli. Interestingly, although awaken more frequently but fall back
older adults experience more awakening asleep at the same rate as younger
during sleep, they do not seem to have any people. Sleep; 27: 793–798.
more problems returning to sleep once N Landolt HP, et al. (1996). Effect of age on
awake (Klerman et al., 2004). the sleep EEG: slow-wave activity and
spindle frequency activity in young and
By the age of 75 yrs there may be no deep middle-aged men. Brain Res; 738: 205–212.
sleep. The loss of the deep sleep with

N McGinty D, et al. (2000). The sleep-wake in the ventrolateral preoptic nucleus of
switch: a neuronal alarm clock. Nat Med; the rat. J Neurosci; 18: 4705–4721.
6: 510–511. N Taillard J, et al. (2004). Validation of
N Reinoso-Suarez F, et al. (2001). Brain Horne and Ostberg morningness-
structures and mechanisms involved in eveningness questionnaire in a middle-
the generation of REM sleep. Sleep Med aged population of French workers. J Biol
Rev; 5: 63–77. Rhythms; 19: 76–86.
N Saper CB, et al. (2005). Hypothalamic N Van Cauter E, et al. (2000). Age-related
regulation of sleep and circadian changes in slow wave sleep and REM
rhythms. Nature; 437: 1257–1263. sleep and relationship with growth hor-
N Sherin JE, et al. (1998). Innervation of mone and cortisol levels in healthy men.
histaminergic tuberomammillary neurons JAMA; 284: 861–868.
by GABAergic and galaninergic neurons

Breathing during sleep and
wakefulness
Control of breathing during sleep and are anatomically distinguished from other
wakefulness respiratory neurons within the ventrolateral
column by expression of neurokinin-1
Neural control of breathing Neurons with receptor (NK1R) (Gray et al., 1999). The
respiratory-related activity are located within gradual loss of the preBötC NK1R-expressing
the ventrolateral medulla in a column neurons may explain why SDB is prevalent in
extending from the facial nucleus to the some people. Studies of human post mortem
upper spinal cord in animals (fig. 1). When tissue have anatomically identified a cluster
isolated, these neurons are able to maintain of NK1R-expressing neurons within the
rhythmic motor nerve output. A bilateral reticular formation of the caudal brainstem
cluster of ventrolateral medullary neurons, and this is presumed to be the site of the
known as the preBötzinger Complex preBötC in humans (Lavezzi et al., 2008).
(preBötC), is essential for this
rhythmogenesis (Smith et al., 1991). A A second cluster of respiratory neurons in
critical subpopulation of preBötC neurons the brainstem has also been identified.
Ventral to the facial nucleus and rostral to
the preBötC, these neurons are called the
Key points retrotrapezoid nucleus (RTN) in adults and
the parafacial respiratory group (pFRG) in
N Neurons with respiratory-related neonates (fig. 1). The anatomical
activity are situated in the boundaries and functional significance of
ventrolateral medulla. these neurons are still under debate and
appear to depend on the experimental
N Sleep onset is associated with a conditions under which the studies are
reduction in the wakefulness drive to performed. The pFRG neurons may have a
breathe, chemosensitivity and primary role in rhythm generation by
metabolism; such that ventilation falls controlling the timing of inspiratory bursts.
and PaCO2 increases above the They are also opiate-insensitive, a property
apnoeic threshold. that distinguishes them from the opiate-
N Patency of the upper airway is sensitive neurons within the preBötC. The
determined by airway size, negative impact of opiates on respiratory rhythm-
intraluminal pressure, extraluminal generating neurons is of interest because of
pressure (such as adipose tissue) their wide spread use in pain control.
and compliance.
The RTN is comprised of glutamatergic,
N Susceptibility of the upper airway to chemosensory interneurons that can be
collapse during sleep is increased by anatomically identified by expression of the
the sleep-related reduction in lung NK1R and the transcription factor Phox2b
volume and the reduction in reflex (Mulkey et al., 2004). The RTN neurons are
activation of the upper airway not rhythmically active, but they are
dilator muscles. chemosensitive and stimulation in vivo
increases ventilation during wakefulness.

In contrast, during sleep there is no
ventilatory response to stimulation. This
differs from central chemosensitive neurons
within the medullary raphe, which have a
CB
greater response to focal CO2 stimulation
during sleep compared with wakefulness
(Nattie et al., 2001). Overall the neurobiology
of central chemosensitivity remains unclear LC
because there are many types of neurons NTS
which contribute to the chemoresponse.
VRC
It has been suggested that developmental
disruption of the RTN neurons (expressing NA
Ventral
Phox2b) results in a loss in CO2/pH VII BC rVG cVG
SO
sensitivity and lethal respiratory abnormalities LRN
at birth (Dubreuil et al., 2008). Clinically,
mutation of the PHOX2B gene (which RTN/pFRG preBötC
Caudal
encodes the transcription factor Phox2b)
causes congenital central hypoventilation
Figure 1. A parasagittal section through the
syndrome (CCHS). Future histological medulla and caudal pons highlighting the
studies will determine whether Phox2b- anatomical arrangement of respiratory neurons
positive neurons in the facial motor nucleus, within the ventrolateral medulla. The
which is presumed to be the site of the human ventrolateral respiratory column (VRC), including
RTN, are deficient in CCHS patients. the Bötzinger complex (BC), preBötzinger
complex (preBötC), rostral ventral respiratory
Control of breathing at the wake/sleep group (rVG) and caudal ventral respiratory group
transition Sleep onset is associated with a (cVG) are shown in pink. The RTN/pFRG and
loss of the wakefulness influences on preBötC, the regions discussed in this chapter, are
breathing, changes in chemosensitivity, and highlighted in red. CB: cerebellum; LC: locus
a sleep-related reduction in metabolism that ceruleus; NTS: nucleus of the solitary tract; NA:
combine to produce the blood gas changes nucleus ambiguus; LRN: lateral reticular nucleus;
described later in this section. The term VII: facial motor nucleus; SO: superior olive.
‘wakefulness drive to breathe’ describes the Taken from McKay et al. (2010), with permission
influence of cerebral activity on the regulation from the publisher.
of breathing. Recent brain imaging studies
have shown that the primary and sensory
The shape of the pharyngeal lumen has been
cortices, basal ganglia and thalamic nuclei are
studied by looking at the anteroposterior
implicated in volitional and behavioural
and tranverse diameters at these levels. The
control and activation of these centres are
factors that influence the prevalence of OSA,
presumably lost during sleep. The ability to
such as obesity, age and sex may change the
maintain stable breathing during sleep onset
upper airway anatomy.
is a function of how the respiratory control
system responds to ventilatory perturbations The shape of the oropharynx and
that occur at this time. hypopharynx becomes more spherical
Anatomy and function of the upper airway (compared with the normal oval shape) with
increasing BMI, mainly due to a decrease in
Anatomy The upper airway can be divided the transverse axis. Moreover, in lean OSA
into the nasopharynx (from cranial base to patients the anatomy of the upper airway is
posterior border of the hard palate), the correlated with the AHI, indicating that the
oropharynx (from posterior border of the anatomy of the upper airway in obese
hard palate to the tip of the soft palate) and patients is only one of several factors
the hypopharynx (from the tip of the soft influencing the upper airway occlusion
palate to the tip of the epiglottis). (Mayer et al., 1996).

Older OSA patients have larger airways at all Fat deposition around the airway can also be
pharyngeal levels, compared with younger measured using MRI. The volume of the soft
patients, although this does not appear to tissue structures surrounding the upper
prevent sleep-related airway collapse, since airway is larger in patients with OSA
the prevalence of OSA increases with age. compared with healthy people (Schwab et al.,
Interestingly, ageing correlates closely and 2003) with the volume of the lateral
positively with pharyngeal resistance in men, pharyngeal walls and total soft tissue being
but not in women (White et al., 1985). significantly larger in OSA patients,
compared with healthy people. This
The anatomy of the upper airway is phenomenon influences the upper airway
correlated with the AHI in lean OSA patients volume per se, but also influences the
(BMI ,27 kg?m-2), indicating that the characteristics, mainly collapsibility, of the
anatomy of the upper airway in obese upper airway.
patients is only one of several factors
influencing the upper airway occlusion The upper airway volume (in absolute terms)
(Mayer et al., 1996). is larger in men than in women, although men
have a greater tendency to collapse their
The size of the tongue can be measured by
airways, which may explain the differences in
calculating the interhypoglossal length and
OSA prevalence between men and women.
the genioglossal width. This approach can
Overall there is a relationship between the
further be optimised by looking at a three-
upper airway volume and collapsibility, and
dimensional reconstruction of the upper
this relationship is sex specific.
airway lumen from computed tomography
(CT) or magnetic resonance images and Reflex activation of upper airway dilator
calculating the airway volume at the three muscles The patency of the upper airway is
levels (fig. 2) (De Backer et al., 2008). dependent on the upper airway size, negative
Beyond looking at the upper airway volume intrapharyngeal pressures and compliance.
in three dimensions, one can also construct These factors are influenced by hypoxia and
a computational grid starting from the hypercapnia, sleep/wake transitions, blood
segmented upper airway and calculate pressure and sex-specific hormones.
resistance using computational fluid dynamics. Moreover, the reflex activation of the upper
airway dilator muscles also determines airway
Alternative methods of describing the upper
patency. Specifically, the reflex activation
airway anatomy, such as cephalometry, give
responses are important to explain the
less direct information regarding the airway
differences in upper airway resistance
dimensions, but it is striking to see that
observed between healthy people and OSA
there are still significant differences for a
number of cephalometric measures between patients, and between men and women.
OSA and snorers for instance (Mayer et al., Influence of lung volumes on upper airway
1996). Using cephalometry, the distance geometry Lung volumes may influence the
from the mandibular plane to the hyoid activation of the pharyngeal dilator muscles.
(MP-H) can be measured; the posterior An association between upper airway calibre
airway space can also be measured from the and changes in upper airway volumes has
dorsum of the tongue to the posterior been described for both healthy people and
pharyngeal wall, as well as the length of the OSA patients during wakefulness. Reduced
soft palate. In male OSA patients the posterior lung volumes lead to increased pharyngeal
airway space is narrow, and the tongue and resistance. During sleep, reduced lung volume
soft palate are enlarged with the hyoid bone leads to increased inspiratory airflow
inferiorly positioned (measured with the resistance and increased genioglossus muscle
MP-H) (Kapsimalis et al., 2002; Kapsimalis activation. Specifically, the pharynx is more
et al., 2002a). When women with OSA were collapsible during sleep at low lung volumes.
compared with men, they had shorter soft
palates, but the MP-H distance was similarly Critical closing pressure Overall, both upper
abnormal in both men and women. airway geometry and neuromuscular

Lateral
view Nasopharynx (NP)
Nostrils Oropharynx (OP)

Mandible Choanae
Tongue (CH) Overlap
Region Hypopharynx
Pharyngeal airway
Epiglottis (OL) (HP)
N NP OP
CH OL
HP
Trachea (T)
Mandible
Caudal view
O P
L
Figure 2. Three-dimensional reconstruction of the upper airway from CT and MRI scans. L: larynx; O:
oropharynx; P: pharynx. Reproduced from De Backer et al. (2008), with permission from the publisher.
activation will contribute to the upper airway directly, or by lowering lung volumes.
collapsibility, which can be measured using Weight loss can reduce active Pcrit by
the critical closing pressure. This recovery of active neuromuscular control.
measurement is based on the principle that
the upper airway can be modelled as a Visceral adiposity is related to a decrease in
collapsible segment or Starling resistor. The neuromuscular control by an increase in the
collapsible segment is subject to the amount of circulating inflammatory
surrounding or critical pressure (Pcrit) that cytokines such as tumour necrosis factor
determines the collapse. The airway (TNF)-a, TNF-a receptor I, interleukin (IL)-6
collapses when the intraluminal pressure and IL-1b. In addition, inflammation of the
drops below the Pcrit. Elevations in Pcrit in upper airway structures themselves may
OSA patients can be related to anatomic lead to cell infiltration and remodelling of
factors and/or disturbances in the extracellular matrix in the upper airway
neuromuscular control. Passive Pcrit producing neurosensory deficits. The latter
may impair protective reflex responses to
(measured shortly after reducing upper
negative intraluminal pressures and, thus,
pressure) and active Pcrit (after a longer time
also compromise the neuromuscular
period of pressure drop when
responses (Schwartz et al., 2010).
neuromuscular activation occurs in
response to the airflow obstruction) are Anatomy as a predictor of therapeutic
generally considered to be different interventions All treatments for OSA that
measurements. Active Pcrit reflects increase upper airway volume will help to
neuromuscular activation, while passive Pcrit protect the airway from collapse. Measuring
reflects collapsibility related only to upper airway volume, however, is not
anatomic characteristics. Active responses sufficient to predict the response to
that can compensate for high passive Pcrit treatment since some interventions may
are blunted in OSA patients. Thus, OSA increase overall upper airway volume, but
patients have disturbed passive and active still induce an increase in upper airway
Pcrit. Obesity may enhance passive Pcrit resistance, by narrowing the upper airway at

Table 1. Changes in ventilatory parameters in the utilised. These studies helped to identify the
transition from wakefulness to sleep in normal techniques required to diagnose patients
individuals. with respiratory disorders during sleep.
NREM REM In healthy young individuals, the transition
V9E Q QQ from wakefulness into sleep is associated
VT Q QQ
with significant changes in lung mechanics
and ventilation (see table 1 for summary).
RR « « A reduction in tidal volume (VT) occurs with
VT/TI « Q deepening levels of NREM sleep. A further
reduction in VT, up to 25% compared with
RR: respiratory rate.
the awake state, has been described during
REM sleep (Douglas et al., 1982a). The
reduction in VT produces a comparable
a specific point. Therefore, predicting the
reduction in V9E during the different sleep
effect of upper airway interventions is not
phases. The results of Douglas et al. 1982a,
possible by simply measuring the overall
were obtained at an altitude of 1600 m and
increase in upper airway volume. There is a
by the use of a face mask; however, they
need to study the effect on the upper airway
were partially confirmed by Stradling et al.
resistance. Changes in upper airway
1985, who found a 20% reduction in alveolar
resistance following interventions are more
ventilation (VA) and 13% reduction in VT
sensitive and specific for the improvement
during REM sleep. The reduction in VT was
in the upper airway collapsibility than
attributed to a reduction in ventilatory drive
changes in upper airway volume alone
as reflected by the decrease in VT/inspiratory
(De Backer et al., 2007).
time (TI) ratio, again during REM, whereas
Overall, the upper airway anatomy and size respiratory rate was substantially unchanged.
is a crucial factor for upper airway function.
In early studies the reduction in V9E during
A larger airway may protect against collapse,
sleep was attributed, at least in part, to a
but this phenomenon should be considered
as sex specific since women have a reduced reduction in metabolic rate, although the
tendency to upper airway collapse even observation of an increase in PaCO2 and the
proportional decrease in PaO2 favoured a
though they have anatomically smaller
reduced ventilatory drive. Further studies
upper airways. Neuromuscular control of
the upper airway, reflected as the responses clarified that the ventilatory response to
to applied negative pressure, also has an hypercapnia and hypoxia are reduced during
sleep, particularly during phasic REM, when
important effect on the maintenance of
upper airway patency. motor output is reduced and variable in
response to a rising chemoreceptor sensory
Respiratory mechanics and ventilation input. The sleep-related reduction in
chemosensitivity is shown in figure 3.
Interest in sleep-related respiratory changes
has increased progressively from the early During sleep upper and lower airway calibre
1980s. This was mainly due to the is reduced, as discussed previously. Central
recognition of the clinical relevance of sleep- drive to upper airway dilator muscles, e.g. the
related respiratory diseases. In addition, the genioglossus and the alae nasi, and to
availability of technologies has increased. In respiratory pump muscles e.g. the
early studies, small cohorts of healthy young diaphragm, is also reduced during the
volunteers were studied, and mouthpieces transition from wakefulness to sleep. As a
or face masks were utilised to track changes consequence, a small increase in total
in breathing pattern. The problem with these pulmonary resistance of ,3 cmH2O?L-1?s-1
studies was that the measurement can be observed in young non-obese
techniques influenced the results (e.g. a face individuals. The drive to upper airway
mask increasing levels of inspired CO2). muscle is further reduced during the
Later on, less invasive approaches were transition from NREM to REM sleep. Also,

20 Awake Further reading
N De Backer JW, et al. (2007). Functional
imaging using computational fluid
15 dynamics to predict treatment success
of mandibular advancement devices in
Ventilation L·min-1
Stage 3/4 sleep-disordered breathing. J Biomech;

40: 3708–3714.
10 Stage 2 N De Backer JW, et al. (2008). Novel
REM sleep imaging techniques using computer
methods for the evaluation of the upper
airway in patients with sleep-disordered
5 breathing: a comprehensive review. Sleep
Med Rev; 12: 437–447.
N Douglas NJ, et al. (1982a). Respiration
during sleep in normal man. Thorax; 37:
0
30 35 40 45 50 840–844.
End-tidal PCO2 mmHg N Douglas NJ, et al. (1982b). Hypercapnic
ventilatory response in sleeping adults.
Am Rev Respir Dis; 126: 758–762.
Figure 3. The relationship between ventilation and N Dubreuil V, et al. (2008). A human
end-tidal CO2 tension measured during mutation in Phox2b causes lack of CO2
wakefulness, NREM (light stage 2, and deep stage chemosensitivity, fatal central apnea, and
3/4) and REM sleep in 12 healthy people. specific loss of parafacial neurons. Proc
Reproduced from Douglas et al. (1982b), with Natl Acad Sci USA; 105: 1067–1072.
permission from the publisher. N Gray PA, et al. (1999). Modulation of
respiratory frequency by peptidergic input
to rhythmogenic neurons in the pre-
Botzinger complex. Science; 286: 1566–1568.
N Kapsimalis F, et al. (2002). Gender and
phasic REM can lead to a reduction and
obstructive sleep apnea syndrome, part 2:
fractionation of the diaphragm’s activity mechanisms. Sleep; 25: 499–506.
during inspiration (Pack, 1995). As a N Kapsimalis F, et al. (2002a). Gender and
consequence of reduced muscle activity, obstructive sleep apnea syndrome, part 1:
upper airway patency is at risk particularly clinical features. Sleep; 25: 412–419.
during REM sleep. In addition to N Lavezzi AM, et al. (2008). Functional
predisposing anatomical factors, two main neuroanatomy of the human pre-
physiological abnormalities seem to play a Botzinger complex with particular refer-
significant role in the development of upper ence to sudden unexplained perinatal and
airway obstruction during sleep: 1) the infant death. Neuropathology; 28: 10–16.
reduced dilator activity of the genioglossus N Mayer P, et al. (1996). Relationship
and 2) a reduction in lung volumes between body mass index, age and upper
(discussed previously). The role of the airway measurements in snorers and
sleep apnoea patients. Eur Respir J; 9:
reduced activity of the genioglossus is well
1801–1809.
documented in the literature; the effect of
N McKay LC, et al. (2010). Physiology and
the reduction in lung volumes on upper neural control of breathing during sleep.
airway patency is still under investigation. Eur Respir Monogr; 50: 1–16.
N Mulkey DK, et al. (2004). Respiratory
All the above-mentioned abnormalities in
control by ventral surface chemoreceptor
the respiratory responses during sleep are neurons in rats. Nat Neurosci; 7: 1360–1369.
more pronounced in elderly individuals, with N Nattie EE, et al. (2001). CO2 dialysis in
associated more frequent episodes of the medullary raphe of the rat increases
periodic breathing and apnoeas during ventilation in sleep. J Appl Physiol; 90:
sleep, which may result in ‘‘normal’’ 1247–1257.
transient hypoxaemia (Shore et al., 1985).

N Pack AI. (1995). Changes in respiratory N Shore ET, et al. (1985). Ventilatory and
motor activity during REM sleep. In: arousal patterns during sleep in normal
Dempsey J, Pack AI, eds. Regulation of young and elderly subjects. J Appl Physiol;
breathing. New York, Marcel Dekker; pp. 59: 1607–1615.
983–1002. N Smith JC, et al. (1991). Pre-Botzinger
N Schwab RJ, et al. (2003). Identification complex: a brainstem region that may
of upper airway anatomic risk factors generate respiratory rhythm in mammals.
for obstructive sleep apnea with volu- Science; 254: 726–729.
metric magnetic resonance imaging. N Stradling JR, et al. (1985). Changes in
Am J Respir Crit Care Med; 168: ventilation and its components in normal
522–530. subjects during sleep. Thorax; 40: 364–370.
N Schwartz AR, et al. (2010). Obesity and N White DP, et al. (1985). Pharyngeal resistance
upper airway control during sleep. J Appl in normal humans: influence of gender, age,
Physiol; 108: 430–435. and obesity. J Appl Physiol; 58: 365–371.

Homeostatic regulation
during sleep
Autonomic and cardiovascular regulation system. Pre-ganglionic cell bodies originate

in the thoracic and lumbar regions of the
The autonomic nervous system (ANS) acts as spinal cord, and synapse with post-
a motor system undertaking a large number ganglionic fibres that are conveyed by
of specialised tasks, stimulatory and peripheral nerves to their targets. The
inhibitory, in a wide range of target organs, parasympathetic division arises in the brain
tissues, blood vessels, glands and even single stem and supplies the seventh, ninth and
units such as mast cells. Closely associated tenth cranial nerves.
with the efferent nerves is a complex network
of afferent fibres that relay sensory Sleep onset is associated with marked
chemoreceptor, mechanoreceptor, cardiorespiratory changes. Depending on
nociceptor, thermoreceptor, baroreceptor and the stage of sleep, different patterns of
osmoreceptor signals back to central nervous haemodynamic and autonomic responses
system (CNS) centres where the complex are observed. During NREM sleep there are
homeostatic reflex arcs are regulated. decreases in heart rate, systolic blood
pressure and cardiac output of up to 15%.
The ANS can be divided into three based on These changes, which are most marked in
anatomical and physiological slow-wave sleep, are thought to occur as a
considerations. The sympathetic division result of changes in autonomic activity. Data
forms the major part of the ANS, innervating on autonomic function during sleep in
more structures than the parasympathetic humans are still limited owing to
methodological problems (Smith et al., 1998).
Key points Methodological issues In view of the

anatomical position of the ANS, directly
N Sleep onset is associated with measuring autonomic activity, particularly
changes in the ANS that reduce heart during sleep, is not easy. Advances in
rate, systolic blood pressure and technology and pharmacology have allowed
cardiac output. the knowledge base of autonomic activity in
humans to expand significantly. Techniques
N OSA causes hypertension with elevated are available to directly measure
sympathetic outflow to the vasculature. sympathetic activity to muscle relatively
N Circadian rhythms regulate the release noninvasively (Smith et al., 1998) and a
of many hormones during sleep, such number of easily measured surrogate
as cortisol, growth hormone, and markers of ANS activity, such as pulse
leptin and ghrelin. transit time (PTT) (Smith et al., 1999) and
R–R variability (Ferini-Strambi et al., 1992;
N Sleep deprivation influences metabolic Roche et al., 1999; Khoo et al., 2001), are
regulation and is associated with feasible. However, for many ANS
glucose intolerance and dysregulation parameters, significant variations may exist
of appetite hormones. even in healthy populations and between
age groups. Intra-individual variability may

also be present. In view of this variation, care several studies establishing a very close
needs to be taken when interpreting data relationship between parasympathetic and
from studies with small samples or those with delta activities (fig. 1) (Jurysta et al., 2003)
normal volunteer subjects who are not although this is modulated by age (Jurysta
representative of the general population. et al., 2006).
Heart rate variability Accurately measuring Autonomic ‘stress tests’ There is a number of
parasympathetic activity is difficult and, to tests of autonomic dysfunction that are
date, vagal–cardiac nerve traffic has not been simple, do not require sophisticated
directly measured in humans. Quantification technology and can be performed at the
of vagal activity therefore has to be measured bedside. However, a major limitation is the
indirectly using variations in cardiovascular lack of standardisation. The earliest tests
parameters. Increased vagal tone may were devised by Ewing et al. (1980) for
produce a varying pulse rate, atrioventricular clinical evaluation of diabetics and consisted
dissociation or even transient sinus arrest. of the heart rate responses to the Valsalva
The sinoatrial node is also under the influence manoeuvre, standing up and breathing
of the sympathetic system. Whereas the deeply, and the blood pressure responses to
response of heart rate to vagal stimulation is standing up and sustained hand gripping.
prompt (,0.25 s), the response to The outcomes are usually expressed as
sympathetic activity takes ,5 s, with an even dichotomous (positive or negative). They
longer delay in the decay of the effect. can suffer from poor reproducibility and lack
Heart rate variability (HRV) analysis, which of standardisation, which may limit their
can be performed easily and noninvasively, usefulness. Nevertheless, they have been
can therefore give an insight into both powerful enough to detect abnormalities in
sympathetic and parasympathetic activity a population of OSA patients that were
during sleep (Stein et al., 2012). Using R–R distinct from normal controls (Veale et al.,
interval analysis by fast Fourier 1992) and that are corrected by CPAP
transformation, a number of different therapy (Veale et al., 1996). The acetylcholine
patterns can be identified. A cyclical pattern sweat-spot test has been proposed as an
relating to respiratory rate (sinus alternative test that is a more reproducible
arrhythmia; ,0.3 Hz) is correlated with and sensitive marker of parasympathetic
vagal tone. There are also lower frequency dysfunction (Stewart et al., 1994). When
patterns associated with baroreflex control performing any of the above tests, it is
of heart rate mediated via both sympathetic important to take into account concurrent
and parasympathetic efferents (0.15 Hz), cardiopulmonary disease and drug therapy,
and an even slower component relating to which may interfere with interpretation.
humoral and thermodynamic control of the
Blood pressure monitoring Blood pressure
cardiovascular system (0.05 Hz). Acute
change is a surrogate marker of sympathetic
changes in the R–R interval can also be
activity and considerable data on this topic
detected without the need for fast Fourier
have been accumulated from both animal
transformation technology and, in patients
and human studies. Continuous beat-to-
with OSA, have been used as indirect
markers of sympathetic and vagal activity beat monitoring is necessary to follow the
(Stein et al., 2012). The ratio of the longest fluctuating haemodynamic changes that can
R–R interval before a body movement occur over a number of seconds and this
during sleep to the shortest in the period can be performed noninvasively using an
immediately after movement has been used infrared plethysmographic volume clamp
as an index of sympathetic activity. Likewise, (Portapres1; Finapres Medical Systems BV,
the sleep/wake R–R ratio has been used to Amsterdam, the Netherlands) (Imholz et al.,
estimate parasympathetic tone. 1993) method, which produces a trace
similar to an intra-arterial line. This
The effects of the different sleep stages on technique, which takes measurements from
R–R variability have been illustrated by the digital artery, gives values that are not

REM
Awake
I
II
III
IV
Delta P (nu)
1.5
1
0.5
0
0.8
0.6
HFnu
0.4
0.2
0
0 30 60 90 120 150 180 210 240 270 300 330
Time min
Figure 1. Sleep recording evidencing a close correlation between ECG high frequencies (as measured by
HRV) and delta activity in the EEG. Reproduced from Jurysta et al. (2003), with permission from the
publisher. Delta P: delta EEG power; nu: normalised units; HFnu: normalised high frequency.
quite the same as the true systemic pressure detecting acute changes in blood pressure
and are affected by hand position. It is associated with sympathetic activation
therefore not accurate at determining absolute during arousal and with the pulsus paradoxus
blood pressure recordings, but it is very good generated by the high pleural pressure
at tracking changes in blood pressure. swings (Pitson et al., 1998) encountered in
increased upper airway resistance during
PTT and peripheral arterial tonometry Pulse sleep (Argod et al., 2000). Many of the
transit time (PTT) is the time taken for the changes in measured PTT in response to a
arterial pressure wave to travel from the large inspiratory effort appear, in fact, to be
aortic valve (measured by the ECG R-wave) due to lengthening of the PEP rather than of
to the periphery (measured by finger the true PTT. PTT is a marker of inspiratory
photoplethysmography). With rises in blood effort (amplitude of the oscillations in time
pressure, the arterial wall tension increases with respiration) (Pitson et al., 1998) and of
and becomes stiffer and, hence, transmits autonomic activation at point of arousal (dip
this pressure wave more swiftly. PTT is in baseline level corresponding to surge in
therefore inversely correlated to changes in blood pressure at apnoea termination)
blood pressure (Smith et al., 1999). Using (Pepin et al., 2005).
the ECG R-wave as the starting point for PTT
inevitably creates a small error as the pre- Peripheral arterial tonometry (PAT) was
ejection systolic period (PEP) will also be introduced into the field of sleep medicine
included in the interval measured. The PEP by Pillar et al. (2002). Upper airway
may also be affected by factors that obstruction (O’Donnell et al., 2002) and
influence blood pressure and not necessarily arousals (Pillar et al., 2003) have been
in the same direction as the true PTT. As a shown to be adequately identified by this
consequence, PTT is not particularly good at technique. This led to the concept of a
predicting absolute beat-to-beat blood screening technique (Penzel et al., 2004;
pressure values as there is a tendency of the Zou et al., 2006). In addition, the PAT
relationship between PTT and blood technique enables REM sleep recognition
pressure to drift over time (Smith et al., (Lavie et al., 2000; Dvir et al., 2002;
1999). This does not affect its ability to Herscovici et al., 2007). This
detect short-term changes in blood pressure plethysmographic technique measures
and PTT has been shown to be capable of peripheral arterial tone. The device envelops

the finger up to and beyond its tip with a correlated to the blood pressure changes
uniform pressure field. Pressure within the observed in humans during sleep (Somers
probe originates from a pressurised balloon et al., 1993) and surgical sympathectomy has
located over its outside wall. Pulsatile been observed to attenuate the decrease in
volume signals are recorded as optical blood pressure associated with NREM sleep
density changes from the finger’s palmar (Baccelli et al., 1969). Parasympathetic
surface within the applied pressure field. activity tends to increase during NREM
sleep (Jurysta et al., 2003; Furlan et al.,
REM sleep has been shown to be associated 1990) and is largely responsible for the
with considerable attenuation of the PAT decrease in heart rate and accentuation of
signal. The decrease in amplitude began any sinus arrhythmia. Not uncommonly,
during NREM sleep and reached a nadir this increase in vagal tone may induce
during REM sleep (Lavie et al., 2000). This first-degree heart block or even
demonstrated that REM sleep in humans atrioventricular dissociation.
was associated with considerable peripheral
vasoconstriction (Lavie et al., 2000). REM- The haemodynamic changes that occur
related vasoconstriction may, for instance, during REM sleep include erratic increases
predispose patients with compromised in pulse rate and blood pressure. Somers
coronary arteries to ischaemic events during et al. (1993) recorded instability in heart rate
sleep (Hanly et al., 1993). and blood pressure, which was associated
with a level of sympathetic traffic significantly
Microneurography The development of higher than that observed during wakefulness
microneurographic techniques has enabled in normal healthy people. It is possible that
monitoring of sympathetic autonomic this higher level of sympathetic activity and
activity to be performed relatively cardiovascular load associated with REM
noninvasively in humans. A microelectrode sleep could trigger platelet aggregation,
is passed into a superficial nerve or muscle atheromatous plaque rupture or coronary
and a recording taken that is thought to vasospasm, and explain why the incidence of
represent the sympathetic vasoconstrictor myocardial infarction and ischaemic stroke is
signal. This technique is not without higher in the early morning hours when REM
drawbacks in that any muscle activity in the sleep is more prevalent.
vicinity of the probe may render readings
meaningless and caution is required when The increases in blood pressure and muscle
extrapolating recordings of sympathetic sympathetic activity tend to coincide with
traffic taken from superficial sites to that of the phasic eye movements of REM sleep and
deeper tissues. However, microneurography become less pronounced as the duration of
has proven to be a highly effective research REM sleep increases. Overall, the increases
tool in tracking the acute and chronic observed in the haemodynamic
changes in sympathetic activity occurring as measurements underestimate the increase
a consequence of OSA (Somers et al., 1995). in sympathetic activity during REM sleep.
The technique has evidenced the changes in Whether this is due to the sympathetic
sympathetic activity occurring during the outflow to the cardiovascular system and
various sleep stages as well as sympathetic skeletal muscle being dissociated or to the
activation associated with sleep baroreceptor reflexes buffering this response
fragmentation and sleep apnoea (Somers with increased parasympathetic activity, is
et al., 1993; Leuenberger et al., 1995; not clear. Nevertheless, REM sleep is a
Waradekar et al., 1996; Grassi et al., 2005; period of labile sympathetic and
haemodynamic activity.
Carlson et al., 1993; Hedner et al., 1995).
Physiological data: insights into OSA Arousals from NREM sleep are associated
pathophysiology with transient increases in heart rate and
blood pressure, which are thought to be
Physiological changes Sympathetic traffic brought about by a rise in sympathetic
measured by microneurography has been activity and a withdrawal of parasympathetic

tone (Somers et al., 1993). Indeed, arousal Metabolic regulation
stimuli that produce K-complexes on EEG
have been associated with the same Circadian rhythmicity and sleep/wake
haemodynamic changes and increases in homeostasis both have profound effects on
muscle sympathetic traffic (Pillar et al., metabolic regulation. The release of growth
2002; O’Donnell et al., 2002; Somers et al., hormone (GH) and cortisol, as well as other
1993). The recurrent activation of this hormones that control appetite regulation,
sympathetic and haemodynamic response such as leptin and ghrelin, are influenced by
in OSA patients may be an important factor circadian and sleep/wake processes
explaining the enhanced cardiovascular (Leproult et al., 2011; Morselli et al., 2012).
morbidity associated with this condition. Circadian rhythmicity is generated in the
Most of the human studies on the suprachiasmatic nuclei of the
sympathetic system during sleep have been hypothalamus, and transmitted to other
areas of the brain and to the periphery via
performed using recordings of skeletal
direct neuronal connections and via
muscle nerve traffic and it is not clear
sympathetic and hormonal signalling. By
whether these findings are representative of
contrast, the molecular mechanisms by
activity in other vascular beds such as in the
which sleep/wake homeostasis influences
heart or brain. The neural effector
the metabolic and hormonal responses have
mechanisms controlling the short-term
not been fully elucidated. Experimental
haemodynamic changes during sleep appear
studies, involving sleep deprivation during
to be highly complex. For instance, there is a
the night and sleep recovery during the day,
marked modulation of baroreceptor
sensitivity during the different phases of
sleep (Conway et al., 1983). a)
ANS assessment and OSA pathophysiology

Although it remains uncertain what
facilitates cardiovascular disease in apnoeic b)
patients, OSA is recognised as a cause of
hypertension (Baguet et al., 2005; Peppard
et al., 2000), and the development of
hypertension might be the initiating factor
that results in the comorbidities of c) 35.5
ischaemic stroke, cardiac ischaemia and 32.0
●
MSNA bursts·min-1
chronic heart failure (McNicholas et al., 28.5 ●
2007). Elevated tonic sympathetic outflow ●

25.0 ●
to the vasculature elicited by sleep apnoea
21.5 ■
persists into the waking daytime hours ●
●
18.0 ● ●
(Somers et al., 1995; Grassi et al., 2005) ■
●
and this, it is thought, may mediate the 14.5 ●

●
elevated pressure seen in those with OSAS 11.0 ●
(Fletcher et al., 1992a, b). Recently, we 7.5

Pre-exposure Post-exposure
described a new model exposing normal
volunteers to intermittent hypoxia (Tamisier
Figure 2. Exposure to intermittent hypoxia after 13
et al., 2009). Using this model, we have nights led to an increase in sympathetic activity
shown that intermittent hypoxia is measured by muscle sympathetic nerve activity
associated with an increase in sympathetic (MSNA). Representative MSNA neurograms from
activity (fig. 2) and a persistent increase in healthy subjects a) before and b) after exposure to
blood pressure during daytime (Tamisier intermittent hypoxia. c) Sympathetic activity
et al., 2011). This supports the role of expressed as MSNA bursts before and after
sympathetic activation in hypertension exposure. Reproduced from Tamisier et al. (2011),
genesis in OSA patients. with permission from the publisher.

have been used to study the effect of sleep prolonged total sleep deprivation (i.e. .120 h),
on metabolism and endocrine systems. but not with shorter total sleep deprivation
Evidence for a modulatory effect of sleep on duration. Glucose tolerance is also altered
metabolic pathways is well documented. GH with total sleep deprivation, irrespective of
and cortisol production, glucose tolerance the duration of sleep deprivation. Finally,
and insulin release, and production of leptin reduced insulin sensitivity, after a glucose
and ghrelin are influenced by sleep timing, load, has been reported as the
duration and quality. consequence of total sleep deprivation.
Insulin sensitivity was found to be reduced
Sleep and glucose metabolism For energy after sleep loss, but also after recovery
generation, the brain depends entirely on sleep. The intravenous glucose tolerance
blood glucose delivered by the circulation. test has mainly been used to demonstrate
Glucose homeostasis is controlled by the the effect of partial sleep deprivation on
level of insulin, which lowers blood glucose glucose metabolism. Studies using partial
levels, and by hormones such as GH, sleep deprivation, a model that better
glucagon, cortisol and catecholamines, which represents real lifestyles, demonstrated a
increase glucose levels in the blood. In reduction in glucose tolerance and insulin
healthy individuals, GH levels increase during sensitivity associated with sleep debt
sleep, particularly during NREM sleep, (Spiegel et al., 1999; Buxton et al., 2010).
whereas they are markedly decreased with
sleep deprivation. Sleep/wake homeostasis
Sleep and regulation of appetite During the
has little influence on cortisol release,
past 10 yrs, evidence has accumulated on
although sleep onset is associated with a
the modulatory effect of sleep on appetite
short-term inhibition of cortisol release and
regulation mediated through the release of
awakenings induce small increases.
hormones, such as the adipocyte-derived
By contrast, glucose metabolism is leptin (that inhibits the ‘hunger’ signal) and
significantly influenced not only by circadian stomach-derived ghrelin (that inhibits the
rhythmicity, but also by sleep. Despite ‘satiety’ signal) (Spiegel et al., 2004). Leptin
prolonged fasting, glucose levels in the levels are influenced by both circadian
blood remain relatively constant during rhythmicity and sleep/wake homeostasis.
sleep, thus preventing a reduction in Leptin levels increase at night and during
glucose-mediated energy production in the sleep, facilitating overnight fasting. The
brain. Both nocturnal and daytime sleep are relationship between sleep and leptin seems
associated with increased glucose levels. to be bidirectional, as demonstrated by
Moreover, studies using constant-rate animal studies: leptin administration
intravenous glucose infusion have shown increases NREM duration and decreases
deterioration in glucose tolerance during REM sleep, whereas leptin deficiency
sleep. Because insulin also increases during disrupts sleep architecture.
sleep, the most likely explanation for the
reduction in glucose tolerance is a reduction In contrast to leptin, ghrelin stimulates
in tissue glucose utilisation, including that hunger and food intake. Very few studies
of the brain (Boyle et al., 1994). The have examined the effect of sleep deprivation
reduction in glucose utilisation seems to on nocturnal ghrelin release in normal
occur mainly during NREM sleep. By individuals. The results of these studies were
contrast, during REM sleep, blood glucose not univocal; however, they suggested a
and insulin decrease toward normal levels. reduction in ghrelin levels induced by sleep
deprivation (Dzaja et al., 2004). These results
Both total and partial sleep deprivation are apparently in contrast with those
protocols have been used in experimental obtained in animals, where sleep deprivation
studies. Fasting glucose levels increase after promotes food intake.

Further reading N Fletcher EC, et al. (1992b). Repetitive,
episodic hypoxia causes diurnal elevation
N Argod J, et al. (2000). Comparison of of blood pressure in rats. Hypertension;
esophageal pressure with pulse transit 19: 555–561.
time as a measure of respiratory effort for N Furlan R, et al. (1990). Continuous 24-
scoring obstructive nonapneic respiratory hour assessment of the neural regulation
events. Am J Respir Crit Care Med; 162: of systemic arterial pressure and RR
87–93. variabilities in ambulant subjects.
N Baccelli G, et al. (1969). Neural and non- Circulation; 81: 537–547.
neural mechanisms influencing circula- N Grassi G, et al. (2005). Obstructive sleep
tion during sleep. Nature; 223: 184–185. apnea-dependent and -independent adre-
N Baguet JP, et al. (2005). Night-time and nergic activation in obesity. Hypertension;
diastolic hypertension are common and 46: 321–325.
underestimated conditions in newly diag- N Hanly P, et al. (1993). ST-segment depres-
nosed apnoeic patients. J Hypertens; 23: sion during sleep in obstructive sleep
521–527. apnea. Am J Cardiol; 71: 1341–1345.
N Boyle PJ, et al. (1994). Diminished brain N Hedner J, et al. (1995). Reduction in
glucose metabolism is a significant sympathetic activity after long-term CPAP
determinant for falling rates of systemic treatment in sleep apnoea: cardiovascular
glucose utilization during sleep in normal implications. Eur Respir J; 8: 222–229.
humans. J Clin Invest; 93: 529–535. N Herscovici S, et al. (2007). Detecting
N Buxton OM, et al. (2010). Sleep restric- REM sleep from the finger: an automatic
tion for 1 week reduces insulin sensitivity REM sleep algorithm based on peripheral
in healthy men. Diabetes; 59: 2126–2133. arterial tone (PAT) and actigraphy. Physiol
N Carlson JT, et al. (1993). Augmented Meas; 28: 129–140.
resting sympathetic activity in awake N Imholz BP, et al. (1993). Feasibility of
patients with obstructive sleep apnea. ambulatory, continuous 24-hour finger
Chest; 103: 1763–1768. arterial pressure recording. Hypertension;
N Conway J, et al. (1983). Involvement of the 21: 65–73.
baroreceptor reflexes in the changes in N Jurysta F, et al. (2003). A study of the
blood pressure with sleep and mental dynamic interactions between sleep EEG
arousal. Hypertension; 5: 746–748. and heart rate variability in healthy young
N Dvir I, et al. (2002). Evidence for fractal men. Clin Neurophysiol; 114: 2146–2155.
correlation properties in variations of N Jurysta F, et al. (2006). The link between
peripheral arterial tone during REM sleep. cardiac autonomic activity and sleep delta
Am J Physiol Heart Circ Physiol; 283: power is altered in men with sleep apnea-
H434–H439. hypopnea syndrome. Am J Physiol Regul
N Dzaja A, et al. (2004). Sleep enhances Integr Comp Physiol; 291: R1165–R1171.
nocturnal plasma ghrelin levels in healthy N Khoo MC, et al. (2001). Cardiac auto-
subjects. Am J Physiol Endocrinol Metab; nomic control in obstructive sleep apnea:
286: E963–E967. effects of long-term CPAP therapy. Am J
N Ewing DJ, et al. (1980). Assessment of Respir Crit Care Med; 164: 807–812.
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variability during sleep in snorers with N Leproult R, et al. (2011). Effect of 1 week of
and without obstructive sleep apnea. sleep restriction on testosterone levels in
Chest; 102: 1023–1027. young healthy men. JAMA; 305: 2173–2174.
N Fletcher EC, et al. (1992a). Sympathetic N Leuenberger U, et al. (1995). Surges of
denervation blocks blood pressure eleva- muscle sympathetic nerve activity during
tion in episodic hypoxia. Hypertension; 20: obstructive apnea are linked to hypoxe-
612–619. mia. J Appl Physiol; 79: 581–588.

N McNicholas WT, et al. (2007). Sleep N Somers VK, et al. (1995). Sympathetic
apnoea as an independent risk factor for neural mechanisms in obstructive sleep
cardiovascular disease: current evidence, apnea. J Clin Invest; 96: 1897–1904.
basic mechanisms and research priori- N Somers VK, et al. (1993). Sympathetic-
ties. Eur Respir J; 29: 156–178. nerve activity during sleep in normal
N Morselli LL, et al. (2012). Sleep and meta- subjects. N Engl J Med; 328: 303–307.
bolic function. Pflugers Arch; 463: 139–160. N Spiegel K, et al. (1999). Impact of sleep
N O’Donnell CP, et al. (2002). The effect of debt on metabolic and endocrine func-
upper airway obstruction and arousal on tion. Lancet; 354: 1435–1439.
peripheral arterial tonometry in obstruc- N Spiegel K, et al. (2004). Sleep curtail-
tive sleep apnea. Am J Respir Crit Care ment in healthy young men is associ-
Med; 166: 965–971. ated with decreased leptin levels,
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recording of sleep apnea using peripheral hunger and appetite. Ann Intern Med;
arterial tonometry. Conf Proc IEEE Eng 141: 846–850.
Med Biol Soc; 5: 3856–3859. N Stein PK, et al. (2012). Heart rate
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events and microarousals in children. N Stewart AG, et al. (1994). Autonomic
Chest; 127: 722–730. nerve dysfunction in COPD as assessed
N Peppard PE, et al. (2000). Prospective by the acetylcholine sweat-spot test. Eur
study of the association between sleep- Respir J; 7: 1090–1095.
disordered breathing and hypertension. N Tamisier R, et al. (2009). A new model of
N Engl J Med; 342: 1378–1384. chronic intermittent hypoxia in humans:
N Pillar G, et al. (2003). An automatic effect on ventilation, sleep, and blood
ambulatory device for detection of pressure. J Appl Physiol; 107: 17–24.
AASM defined arousals from sleep: the N Tamisier R, et al. (2011). 14 nights of
WP100. Sleep Med; 4: 207–212. intermittent hypoxia elevate daytime
N Pillar G, et al. (2002). Autonomic arousal blood pressure and sympathetic acti-
index: an automated detection based on vity in healthy humans. Eur Respir J; 37:
peripheral arterial tonometry. Sleep; 25: 119–128.
543–549. N Veale D, et al. (1992). Autonomic stress
N Pitson DJ, et al. (1998). Value of beat-to- tests in obstructive sleep apnea syn-
beat blood pressure changes, detected by drome and snoring. Sleep; 15: 505–513.
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the obstructive sleep apnoea/hypopnoea nomic stress responses in obstructive
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N Roche F, et al. (1999). Reduced cardiac continuous positive airway pressure. Eur
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pressure in obstructive sleep apnoea treatment on muscle sympathetic nerve
syndrome. Clin Physiol; 19: 127–134. activity in sleep apnea. Am J Respir Crit
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system. Sleep Med Rev; 2: 69–92. Sleep; 29: 367–374.

Definitions of sleep disordered
breathing
Johan Verbraecken
Sleep disordered breathing (SDB) is a term transient reduction in (hypopnoea), or

used to describe a spectrum of respiratory complete cessation of (apnoea) breathing.
disturbances that occur during sleep. The According to the American Academy of
International Classification of Sleep Sleep Medicine (AASM) criteria from 1999, a
Disorders (ICSD-2) has defined the three hypopnoea can be defined as a decrease
major categories of SDB: obstructive sleep from baseline in the amplitude of a valid
apnoea syndrome (OSAS), central sleep measure of breathing during sleep that
apnoea syndrome (CSAS) and sleep-related either reaches .50% with an oxygen
alveolar hypoventilation. The fundamental desaturation of 3% or an arousal, or
difference between the first two major alternatively a 30% reduction with 4%
categories is the pathophysiological oxygen desaturation. Central sleep apnoea
mechanism that causes the respiratory (CSA) refers to the cessation of ventilation
disturbance. In OSAS, the upper airway lasting for o10 s (in adults) due to transient
obstruction is most often caused by loss of neural output to the respiratory
abnormal anatomy and/or abnormal control muscles. The degree of severity is defined on
of the muscles that maintain the patency of the basis of the number of apnoeas and
the upper airway. In CSAS, dysfunction of hypopnoeas occurring during 1 h of sleep
ventilatory control in the central neurons is (this is the apnoea–hypopnoea index (AHI))
involved, resulting in loss of ventilatory and the severity of daytime symptoms.
effort (fig. 1). An obstructive apnoea/ According to ICSD-2, the criteria for the
hypopnoea can be defined as an event that diagnosis of a clinically significant
lasts for o10 s and is characterised by a obstructive sleep apnoea–hypopnoea
syndrome are: presence of criteria A, B and
D, or C and D (see table 1). Based on these
Key points criteria, sleep apnoea occurs in 4% of men
and 2% of women aged 30–60 yrs. The
N OSAS is characterised by recurrent definition of OSAS using two components,
episodes of partial or complete upper daytime symptoms and breathing pattern
airway collapse during sleep. disturbances during sleep, indicates that
N UARS is no longer considered as an there are also subjects who present with
independent disease, but as part of sleep apnoea without symptoms. These
OSAS. cases are referred to as obstructive sleep
apnoea (OSA) and have an even higher
N Minimal diagnostic criteria exist for prevalence, recently estimated to be 20% in
OSAS and CSAS. the male population.
N OHS is also part of the spectrum of
OSAS can be subdivided into adult and
sleep disordered breathing.
paediatric types, since the diagnostic criteria
N Hypoventilation syndromes can occur and clinical presentation for abnormal
independent of obesity. breathing during sleep are different for
adults and children. Obstructive breathing

a) Central apnoea b) Obstructive hypopnoea
EEG EEG
Arousal Arousal
Airflow Airflow
Effort Effort
Ribcage Ribcage
Effort Effort
Abdomen Abdomen
Effort Effort
Oesophageal 0
-20
Oesophageal -200
pressure -40 pressure -40
-60 -60
(cmH2O) (cmH2O)
100 100
Sa,O2 75
50
Sa,O2 75
50
10 s 10 s
c) Obstructive apnoea d) Upper airway resistance
EEG EEG
Arousal Arousal
Airflow Airflow
Effort Effort
Ribcage Ribcage
Effort Effort
Abdomen Abdomen
Effort Effort
Oesophageal
0
-20
Oesophageal -200
pressure -40 pressure -40
-60 -60
(cmH2O) (cmH2O)
100 100
Sa,O2
75
50
Sa,O2 75
50
10 s 10 s
Figure 1. Different presentations of apnoeas and hypopnoea. a) Central event; b–d) obstructive events.
events may include apnoeas, hypopnoeas, is characterised by increased upper airway

or respiratory effort-related arousals resistance, followed by frequent arousals,
(RERAs). A RERA can be defined as a resulting in daytime sleepiness. It has the
sequence of breaths characterised by following essential PSG features: absence of
increasing respiratory effort leading to obstructive sleep apnoeas, an AHI
arousal from sleep, but not meeting the ,5 events?h-1, and a lack of significant
criteria for apnoea or hypopnoea. Moreover, oxygen desaturation, which differ from the
these events present with a pattern of laboratory findings of OSAS. At present, the
progressively more negative oesophageal term UARS is no longer used as an
pressure, terminated by a sudden change in independent disease, but is subsumed
pressure to a less negative level and an under the diagnosis of OSAS because its
arousal. Oesophageal pressure is pathophysiology does not significantly differ
recommended as the measurement method from that of OSAS.
of choice (AASM 2007), but the flattening of
the flow curve obtained by nasal pressure is The diagnosis of CSAS is made by criteria
explicitly mentioned, together with induction recommended by the ICSD-2 manual.
plethysmography, as a feasible alternative. Patients with primary CSA present with: a)
In reality, nasal pressure is the method of excessive daytime sleepiness; or b) frequent
choice for more than 90% of sleep nocturnal arousals and awakenings during
laboratories. These events last 10 s or more. sleep or insomnia complaints; or c)
Upper airway resistance syndrome (UARS) awakening short of breath, combined with 5

Table 1. Criteria for the diagnosis of a clinically significant obstructive sleep apnoea–hypopnoea syndrome (ICSD-2
criteria).
A. At least one of the following applies:
i. The patient complains of unintentional sleep episodes during wakefulness, daytime
sleepiness, unrefreshing sleep, fatigue or insomnia.
ii. The patient wakes with breath holding, gasping or choking
iii. The bed partner reports loud snoring, breathing interruptions or both during the patient’s
sleep
B. PSG recording shows the following:
i. o5 scoreable respiratory events (i.e. apnoeas, hypopnoeas, or RERAs) per hour of sleep
ii. Evidence of respiratory effort during all or a portion of each respiratory event
OR
C. PSG recording shows the following:
i. o15 scoreable respiratory events (i.e. apnoeas, hypopnoeas, or RERAs) per hour of sleep
ii. Evidence of respiratory effort during all or a portion of each respiratory event
D. The disorder is not better explained by another current sleep disorder, medical or neurological
disorder, medication use, or substance use disorder
or more central apnoeas per hour of sleep. A last group in the spectrum of SDB is called
The disorder should not be better explained sleep-related hypoventilation/hypoxaemic
by another current sleep disorder, medical syndrome. Sleep-induced hypoventilation is
or neurological disorder, medication use, or characterised by elevated PaCO2 of
substance use disorder. Many patients with .45 mmHg while asleep, or
CSAS have mild hypocapnia or disproportionately increased relative to
normocapnia, but rarely hypercapnia and levels during wakefulness. This group
hypoventilation are also observed. A comprises idiopathic sleep-related
periodic pattern of waxing and waning of nonobstructive alveolar hypoventilation,
ventilation with periods of hyperventilation congenital central alveolar hypoventilation
alternating with central apnoea/hypopnoea syndrome, and sleep-related hypoventilation
is termed Cheyne–Stokes respiration (CSR). due to a medical condition (pulmonary
According to the ICSD-2 manual CSR can be parenchymal or vascular pathology, lower
considered if: a) polysomnography shows at airway obstruction, neuromuscular and
least 10 central apnoeas and hypopnoeas chest wall disorders). Obesity
per hour of sleep in which the hypopnoea hypoventilation syndrome (OHS) is
has a crescendo–decrescendo pattern of probably the most common clinical
tidal volume accompanied by frequent presentation of this syndrome. This disorder
arousals from sleep and derangement of is defined as the association of obesity
sleep structure; b) the breathing disorder (body mass index .30 kg?m-2) and SDB
occurs in association with a serious medical with daytime hypersomnolence and
illness, such as heart failure, stroke, or renal hypercapnia (PaCO2 .45 mmHg) in the
failure; c) the disorder is not better absence of any other respiratory disease.
explained by another current sleep disorder, There is however no commonly accepted
medication use or substance use disorder. definition for OHS.
Although symptoms are not mandatory to Different definitions have been published by
make this diagnosis, patients often report the AASM for the different entities of SDB
excessive daytime sleepiness, frequent (ICSD-2 versus AASM Scoring Manual),
arousals and awakenings during sleep, which may complicate the understanding of
insomnia complaints, or awakening short the problem. In this article, the ICSD-2
of breath. criteria have been used. The Task Force of

the AASM (1999) also states that there are for syndrome definition and measure-
common pathogenetic mechanisms for ment techniques in clinical research.
obstructive apnoea syndrome, central Sleep; 22: 667–689.
apnoea syndrome, Cheyne–Stokes breathing N Banno K, et al. (2007). Sleep apnea:
and sleep hypoventilation syndrome. It is clinical investigations in humans. Sleep
more preferable to discuss each of these Med; 8: 400–426.
separately, although they could be placed N Bloch KE, et al. Central sleep apnoea.
under the common denominator of ‘‘sleep In: Palange P, Simonds A, eds. ERS
disordered breathing syndrome’’. Handbook of Respiratory Medicine.
Sheffield, European Respiratory Society,
2010; pp. 410-413.
Further reading N De Backer W. Obstructive sleep apnoea/
hypopnoea syndrome. In: Palange P,
N American Academy of Sleep Medicine. Simonds A, eds. ERS Handbook of
The AASM Manual for the Scoring of Respiratory Medicine. Sheffield, European
Sleep and Associated Events: Rules, Respiratory Society, 2010; pp. 410-413.
Terminology and Technical Specifica- N Muir JF. Hypoventilation syndromes.
tions. Westchester, American Academy In: Palange P, Simonds A, eds. ERS
of Sleep Medicine, 2007. Handbook of Respiratory Medicine.
N The International Classification of Sleep Sheffield, European Respiratory Society,
Disorders. Second edition. Diagnostic and 2010; pp. 410-413.
Coding Manual. Westchester, American N Strollo PJ, Jr, et al. (1996). Obstructive
Academy of Sleep Medicine, 2005. sleep apnea. N Engl J Med; 334: 99–104.
N Task Force of the American Academy of N Young T, et al. (1993). The occurrence of
Sleep Medicine. (1999). Sleep-related breath- sleep-disordered breathing among middle-
ing disorders in adults: recommendations aged adults. N Eng J Med; 328: 1230–1235.

Obstructive sleep apnoea
syndrome
Johan Verbraecken
OSAS is highly prevalent and represents an death from any cause in middle-aged adults,
increasing part of clinical respiratory especially men. OSA is closely related to
practice in developed countries. OSAS is increases in body weight and, as a result,
now recognised as one of the most common there is a tendency to produce or worsen
chronic respiratory disorders in adults, with upper airway obstruction during sleep.
only asthma and possibly COPD having a Upper airway collapse is multifactorial.
higher prevalence. Questions about risks, Upper airway size, which is significantly
diagnosis and treatment options are of affected by obesity and craniofacial
importance to both the clinician and to characteristics, is known to play a major
healthcare policy makers. As the medical role. The pathophysiological basis of OSAS
community and the general public have is also partly genetic in origin, to which
become more aware of the relationships acquired factors, such as obesity, also
among snoring, excessive daytime contribute. Increased upper airway
sleepiness, cardiovascular disease and collapsibility and impaired neuromuscular
OSAS, physicians are seeing an increasing response both contribute, as well as
number of patients with these problems. pharyngeal neuropathy, ventilatory
Excessive daytime sleepiness is one of the instability and described more recently,
major symptoms. Untreated OSA has possible fluid shift towards the pharynx. It is
dangerous health consequences. Severe obvious that OSAS has different phenotypes
OSA is associated with an increased risk of and that there are substantial sex differences
and important ageing effects. Moreover, the
condition carries significant morbidity and is
associated with an increased risk of
Key points hypertension, arrhythmias, myocardial
infarction, stroke, metabolic and
neurobehavioural consequences.
N OSAS is now recognised as one of the
most common chronic respiratory
disorders in adults. Further reading
N Physicians are seeing an increasing N Decramer M, et al. (2011). Chapter 1.
number of patients with OSAS. Prevention. In: European Respiratory Road-
map. Sheffield, European Respiratory
N Untreated OSA has dangerous health
Society; pp. 9–26.
consequences. N Lévy P, et al. (2011). Sleep apnoea syn-
N Upper airway collapse is drome in 2011: current concepts and future
multifactorial. directions. Eur Respir Rev; 20: 134–146.
N McNicholas WT, et al. (2010). Sleep
N There are substantial sex differences apnoea: Introduction. Eur Respir Monogr;
and important ageing effects. 50: vii–ix.

Obstructive sleep apnoea:
epidemiology and risk factors
Johan Verbraecken
The landmark report which clarified the Age

prevalence of OSAS in the general middle-
aged population showed that OSAS affects Several papers have shown a higher
,4% of males and 2% of females, but the prevalence of OSAS in the elderly. The Sleep
prevalence is increasing because of the Heart Health Study showed that 25% of
recent obesity epidemic. Common risk males and 11% of females in the 40–98-yr-
factors of OSAS are obesity, sex, ageing, and old age group had an AHI .15 events?h-1.
comorbidities, such as enlarged tonsils and However, daytime symptoms may be less
adenoids and craniofacial abnormalities. common with increasing age. The influence
of male sex and BMI on OSAS tends to wane
Obesity with age and the overall prevalence of OSAS
seems to plateau after age 65 yrs. In
Approximately 80% of OSAS patients are contrast, the age distribution of patients
obese and obesity is a recognised risk factor first diagnosed with OSAS generally peaks at
for OSAS. A very close relationship has been age 50 yrs.
observed between body weight change and
AHI: a 10% weight gain has been shown to Sex
predict an approximate 32% increase in AHI;
a 10% weight loss predicts a 26% decrease Epidemiological studies have shown that
in the AHI; and a 10% weight gain predicts a OSAS is much more prevalent in males. A
six-fold increase in the odds of developing referral bias and sex differences in clinical
moderate-to-severe OSA. Obesity causes presentation may have resulted in more
airway narrowing as a result of excess fat in males than females being diagnosed. Males
the (peri and para) pharyngeal tissues. with OSAS are more likely to have
symptoms of snoring, witnessed apnoeas or
sleepiness. Females with OSAS have more
Key points symptoms of depression or morning
headache. Recent evidence provides
N OSAS is highly prevalent with an rationale for clinicians to consider the
estimated prevalence of at least 4% in likelihood of OSAS in obese females with a
males and 2% in females. history of insomnia, depression or
hypothyroidism.
N Obesity has a very close relationship
with AHI. Other comorbidities
N The influence of male sex and BMI on A number of other factors may contribute to,
OSAS tends to wane with age. and can be considered as, risk factors for
OSAS. These are summarised in table 1.

Table 1. Factors promoting upper airway (UA) collapse.
Abnormal anatomy of the UA
Skeletal factors
Maxillary and/or mandibular hypoplasia or retroposition
Hyoid position (inferior displacement)
Soft tissue factors
Increased volume of soft tissues
Adenotonsillar hypertrophy
Macroglossia
Thickened lateral pharyngeal walls
Increased fat deposition
Pharyngeal inflammation and/or oedema
Increased vascular volume
Increased muscle volume
Pharyngeal muscle factors
Insufficient reflex activation of UA dilator muscles
Impaired strength and endurance of pharyngeal dilators
Pharyngeal compliance
Increased UA collapsibility
Sensory function
Impaired pharyngeal dilator reflexes
Impaired mechanoreceptor sensitivity
Lung volume dependence of UA cross-sectional area
Increased below functional residual capacity
Ventilatory control system factors
Unstable ventilatory control
Increased ventilatory responses and loop gain
Sex factors
Male influences
Centripetal pattern of obesity
Absence of progesterone
Presence of testosterone
Weight
Obesity causing peripharyngeal fat accumulation
Reproduced from Verbraecken et al. (2009), with permission from the publisher.

Further reading from that in middle-aged adults? Sleep;
19: 529–530.
N Banno K, et al. (2007). Sleep apnea:
clinical investigations in humans. Sleep N Young T, et al. (2002). Sleep Heart Health
Med; 8: 400–426. Study Research Group. Predictors of
N Peppard PE, et al. (2000). Longitudinal study sleep-disordered breathing in community-
of moderate weight change and sleep- dwelling adults: the sleep Heart Health
disordered breathing. JAMA; 284: 3015–3021. Study. Arch Intern Med; 162: 893–900.
N Verbraecken J, et al. (2009). Upper airway N Young T, et al. (1996). The gender bias in
mechanics. Respiration; 78: 121–133. sleep apnea diagnosis. Are women missed
N Young T. (1996). Sleep-disordered breath- because they have different symptoms?
ing in older adults: is it a condition distinct Arch Intern Med; 156: 2445–2451.

pathophysiology
Johan Verbraecken and Wilfried De Backer
The narrowing or occlusion of the upper decrease internal skull volume being found
airway (UA) during sleep has been to correlate with OSAS. Reported differences
attributed to several factors. An abnormal are a retroposition of the mandible or the
anatomy of the UA, pathological and maxilla, micrognathia and differences in
insufficient reflex activation of UA dilator hyoid bone position. These findings are
muscles and increased collapsibility of the confirmed by the high prevalence of OSA in
passive UA have all been demonstrated to patients with craniofacial disorders.
occur and contribute to the UA collapse. UA
dysfunction in OSA is a progressive In addition to narrowing of the airway by the
evolution, starting with snoring and flow lateral pharyngeal walls caused by oedema
limitation, that can lead to mechanical and fat deposition, enlargement of the
traumata that progressively injure the UA tonsils, uvula or tongue can contribute to
tissues. Recently, it has been shown that UA the occlusion of the UA during sleep. The
collapse occurs during the terminal phase of latter are not the classical risk factor for
the expiration preceding the apnoea. OSAS in adults (although they are in
children), but it can be expected that
Craniofacial and upper airway morphology
increased soft tissue sizes will decrease
Several studies have correlated skeletal airway lumen dimensions and increase the
dimensions with the prevalence and severity risk of OSAS.
of OSAS, with anatomical variations that
Moreover, recent evidence has
demonstrated that a fluid shift from the
lower limbs to the upper airways takes place
Key points in OSA at night, contributing to UA oedema.
With detailed MRI techniques, it has been
N OSAH patients are characterised by a demonstrated that the volume of the tongue
compromised upper airway anatomy, and the lateral walls are an independent risk
involving more than one specific site factor for sleep apnoea, while the variations
in most patients, with abnormal in the velopharyngeal area during the
collapsibility, leading to a passive respiratory cycle are greater in apnoeic
narrowing at the end of expiration. patients than in controls. However,
structural narrowing of the UA at one
N OSAH patients have a sleep-induced
specific location is unlikely to be a major
loss of compensatory mechanisms
cause of OSA. Studies have shown that
(high upper airway muscle activity,
the UA collapse is not restricted to one
negative pressure upper airway reflex).
place, but is a dynamic phenomenon
N Ventilatory control (loop gain) and starting at a particular level and spreading
sleep instability (arousal threshold) caudally. UA obstruction involves more than
contribute to upper airway instability. one specific site of the upper airway in the
majority of patients.

Function and dysfunction of upper airway pressure (Pcrit) remains low relative to the
muscles pressure upstream of the collapsible
segment (Pu). Closure of the upper airway
Upper airway dilator muscle activation in occurs when Pu falls below the surrounding
OSAS patients is quite adequate and even tissue pressure (Pcrit). In the model of the
intensified during wakefulness. This is Starling resistor, maximal flow (V9max)
mainly the result of reflex activation becomes a function of the pressure gradient
provoked by negative intrapharyngeal and the resistance in the segment upstream
pressures that are more pronounced in to the collapsible segment (Ru), such that
OSAS patients due to the smaller airway. V9max5(Pu-Pcrit)/Ru. The collapse of the UA
Several other mechanisms are involved, then finally occurs during expiration when,
however, including a decrease in lung due to the absence of dilator muscle, Pcrit
volume and a high neuromodulator rate exceeds the upstream pressures. Prolonged
(acetylcholine, adenosine, ATP, nitric oxide, expiratory time, as occurs during central
norepinephrine, orexin, serotonin, apnoeas, therefore predisposes to collapse.
substance P, thyrotropin-releasing hormone
and vasopressin). This reflex is quite active Central respiratory control mechanisms
during wakefulness but declines significantly Both arousal threshold and loop gain (as a
during sleep. Particularly during NREM marker of the degree of respiratory control
sleep, this negative pressure reflex is system instability) may contribute to apnoea
substantially diminished or lost completely. presence and severity. An obstructed UA can
Studies of genioglossal muscle activity reopen due to a reflex, without arousal, if
suggest that patients with OSAS have a chemical drive is allowed to reach a
much greater reduction in the genioglossal threshold, but this is often pre-empted by a
EMG than normal subjects. Due to the loss low arousal threshold. The relation between
of this compensatory reflex activation of the chemical and arousal thresholds, as well as
UA dilator muscles, the UA of OSAS the lung-to-carotid circulation time and the
patients may narrow significantly or collapse rate of rise of chemical drive during the
during inspiration when asleep, with the obstructive event determine the magnitude
development of flow limitation. These of ventilatory overshoot at the end of an
mechanisms have been described as the event and, by extension, whether initial
‘‘balance of forces’’ model. It is likely that a obstructive events will be followed by stable
combination of UA mechanical loads and breathing, slow evolving hypopnoeas with
disturbances in neuromuscular mechanisms occasional arousals or repetitive events.
account for the pathogenesis of OSAS. For OSAS patients may have a higher chemical
example, in a group of OSA subjects, one- drive (hypercapnic ventilatory response) that
third of the variability in OSAS severity was can contribute to the increased loop gain.
ascribed to mechanical loads, suggesting Moreover, cyclic changes in arterial CO2
that neuromuscular mechanisms accounted around the CO2 threshold for activation of
for the remaining two-thirds. However, there UA motor neuron activity could lead to an
is increasing evidence that the collapse of imbalance of forces acting on the pharyngeal
the UA occurs during expiration. airway and favour closure.
Furthermore, it has been convincingly
shown that the UA behaves like a Starling Further reading
resistor, making the collapse independent of N Ciscar MA, et al. (2001). Magnetic
the suction force brought about by the resonance imaging of the pharynx in
diaphragm, but rather dependent on the OSA patients and healthy subjects. Eur
balance between the UA pressure and the Respir J; 17: 79–86.
tissue pressure at the collapsible site. The N Dempsey JA, et al. (2010). Pathophy-
airway remains patent, regardless of the siology of sleep apnea. Physiol Rev; 90:
excessive pressure applied, as long as the 47–112.
critical pressure of positive end-expiratory

N Fogel RB, et al. (2001). Genioglossal N Schwab RJ, et al. (2003). Identification of
activation in patients with obstruc- upper airway anatomic risk factors for
tive sleep apnea versus control sub- obstructive sleep apnea with volumetric
jects. Mechanisms of muscle control. magnetic resonance imaging. Am J Respir
Am J Respir Crit Care Med; 164: Crit Care Med; 168: 522–530.
2025–2030. N Verbraecken J, et al. (2009). Upper airway
N Mezzanotte WS, et al. (1992). Waking mechanics. Respiration; 78: 121–133.
genioglossal electromyogram in sleep N Vos WG, et al. (2010). Correlation
apnea patients versus normal controls (a between the severity of sleep apnea and
neuromuscular compensatory mechan- upper airway morphology in pediatric and
ism). J Clin. Invest; 89: 1571–1579. adult patients. Curr Opin Allergy Clin
N Schellenberg JB, et al. (2000). Physical Immunol; 10: 26–33.
findings and the risk for obstructive sleep N Younes M. (2003). Contributions of upper
apnea. The importance of oropharyngeal airway mechanics and control mechan-
structures. Am J Respir Crit Care Med; 162: isms to severity of obstructive apnea. Am J
740–748. Respir Crit Care Med; 168: 645–658.

clinical aspects
Stefan Andreas
OSA is a disease of developed countries, cardiovascular risk factors, heart disease

where chronic excess of calorie intake can and stroke is mandatory in the assessment
lead to accumulation of body fat. Clearly, of OSA. Similarly, respiratory diseases such
obesity is the main risk factor for OSA. For as COPD or restrictive lung disease should
the consequences of OSA discussed in be searched for, as they aggravate OSA and
‘‘Obstructive sleep apnoea: consequences’’, are amenable to treatment.
it should be kept in mind that obesity itself
Symptoms
increases the risk of cardiovascular disease
and is a cause of daytime sleepiness. For Symptoms of OSA can be divided into
pneumologists, with their clear focus on the symptoms recognised by the bed partner
burden of cigarette smoking, it should also and symptoms experienced by the patient
be mentioned that smoking not only themselves. Snoring with periods of silence
increases the risk of cardiovascular disease and choking can make the diagnosis, if
but is also a risk factor for snoring and OSA witnessed and reported by the bed partner.
itself, although the latter association has not Typically, these symptoms are more obvious
been firmly investigated (Franklin et al., in the supine position or after alcohol
2004). Conversely, physical activity and consumption. Upper airway dysfunction in
weight reduction ameliorate not only OSA has a progressive evolution, starting
cardiovascular disease, but also OSA with snoring, and mechanical trauma due to
(Peppard et al., 2004). The growing obesity snoring and flow limitation progressively
epidemic should remind us that prevention injure the upper airway tissues. The patient
is key in most common diseases and themselves will mostly experience the more
certainly is in OSA. discreet and less specific daytime
symptoms, such as sleepiness, falling asleep
As OSA can be considered a risk factor for inadvertently during the day, impaired
cardiovascular disease, a history vigilance and mood disturbance, mainly
encompassing arterial hypertension, other depression. A dramatic consequence of
daytime sleepiness is traffic accidents,
which occur about four times more often in
OSA than in controls (Tregear et al., 2010).
Key points
Questionnaires are helpful in daily practice
N Obesity is the main risk factor for to supplement oral history. The Berlin
OSA. Questionnaire is only one example, with the
N Questionnaires are helpful in daily following questions being predictive of OSA
practice to supplement oral history. (Netzer et al., 1999).
N Every patient suspected of OSA N Has your weight changed?

should undergo an examination of the N Do you snore?
upper airways. N Snoring loudness.
N Snoring frequency.

Table 1. Symptoms in OSA.
Night-time symptoms Daytime symptoms
N Witnessed apnoeas N Excessive daytime sleepiness

N Snoring N Fatigue
N Nocturnal choking N Morning dry mouth
N Disturbed unrefreshing sleep N Morning headache
N Thirst during the night N Difficulty concentrating
N Nocturnal diuresis, enuresis N Irritability, mood changes
N Nocturnal sweating
N Impotence
N Excessive salivation
N Gastro-oesophageal reflux
Reproduced from Tkacova et al. (2010).
N How often have your breathing pauses cardiovascular sequelae of OSA discussed
been noticed? later mainly apply to this cohort. The female
N Are you tired during wake time? OSA phenotype is less archetypical: male
N Have you ever fallen asleep while driving? bed partners are less likely than females to
N Do you have high blood pressure? report snoring and apnoeas to a medical
professional. Furthermore, symptoms
Since daytime sleepiness is important, a experienced by female OSA patients are less
specific questionnaire, such as the ESS, specific and include insomnia, headache
should be used. The ESS comprises only and mood disturbance. Thus, female OSA
eight items on a four-point scale. patients are less likely to be diagnosed and
Questionnaires and clinical impression treated than males. Similarly, the elderly
alone, however, have limited sensitivity and (.70 yrs of age) will present with less
specificity, and the diagnosis is usually specific history and daytime symptoms
obtained by polygraphy or PSG. Other more (Martinez-Garcia et al., 2009).
objective tests to evaluate daytime Unsurprisingly, comorbidities have a large
sleepiness, like the MSLT or the MWT, are impact on daytime sleepiness and quality of
covered in detail in ‘‘Assessment of daytime life in the elderly.
sleepiness’’, later in this book. Although
sleepiness is difficult to quantify, it is Physical examination
important to decide whether CPAP
treatment should be instituted to treat On physical examination, heart rate, blood
daytime sleepiness. Furthermore, the effect pressure and smoking status must be
of CPAP on objective measures such as determined. Since obesity is the main
blood pressure clearly depends on the treatable cause of OSA (Foster et al., 2009),
degree of daytime sleepiness (see measures of obesity, such as weight, height,
‘‘Obstructive sleep apnoea: treatment’’). BMI or neck circumference, must be
evaluated. For example, a neck
Generally, it should be kept in mind that circumference .48 cm indicates a
most research has been performed in 50– substantial risk of having OSA. There are
60-yr-old, clearly overweight male patients simple clinical prediction models that allow
with moderate-to-severe OSA. Thus, the estimation of the likelihood of OSA using
symptoms and neurobehavioural and these simple measures in addition to sex

and age. However, while these prediction Prader–Willi and Pierre Robin syndromes,
models have reasonable sensitivities, they are also more likely to develop OSA.
have relatively low specificities. Thus, a
definite diagnosis should be reached by an
Further reading
objective sleep study.
N Foster GD, et al. (2009). A randomized
As in other diseases, a general examination study on the effect of weight loss on obstruc-
is useful to ensure pulmonary, tive sleep apnea among obese patients
cardiovascular, neurological, skeletal and with type 2 diabetes: the Sleep AHEAD
facial abnormalities, hypothyroidism, or study. Arch Int Med; 169: 1619–1626.
storage diseases are not overlooked. N Franklin KA, et al. (2004). The influence
However, it is more likely to find sequelae of of active and passive smoking on habitual
overweight and OSA, such as heart failure. snoring. Am J Respir Crit Care Med; 170:
799–803.
Every patient suspected of OSA should N Martinez-Garcia MA, et al. (2009).
undergo an examination of the upper Obstructive sleep apnea has little impact
airways. This does not necessarily have to be on quality of life in the elderly. Sleep Med;
performed by an ENT specialist. However, 10: 104–111.
the dentures, the pharyngeal arch and the N McNicholas WT, et al., eds. (2010). Sleep
tonsils must be visualised. Albeit very Apnoea. Eur Respir Monogr 50.
uncommon, abnormalities such as N Netzer NC, et al. (1999). Using the Berlin
macroglossia (in acromegaly) or tumours Questionnaire to identify patients at risk
should be recognised. The degree of for the sleep apnea syndrome. Ann Int
Med; 131: 485–491.
pharyngeal narrowing can be quantified, e.g.
N Peppard PE, et al. (2004). Exercise and
by the Malapati score. Strikingly, impaired
sleep-disordered breathing: an associa-
nasal breathing can favour OSA and, more tion independent of body habitus. Sleep;
importantly, can make treatment of OSA by 27: 480–484.
a nasal mask impossible. Thus, nasal N Tregear S, et al. (2010). Continuous
breathing should be checked, typically for positive airway pressure reduces risk of
the right and left nostril separately. motor vehicle crash among drivers with
obstructive sleep apnea: systematic
Craniofacial conditions, such as review and meta-analysis. Sleep; 33:
retrognathia, mandibular hypoplasia, 1373–1380.
micrognathia and inferior displacement of N Tkacova R, et al. (2010). Clinical presen-
the hyoid, can contribute to upper airway tations of OSA in adults. Eur Respir
occlusion. Individuals with rare hereditary Monogr; 50: 86–103.
syndromes, such as Alpert, Down, Hunter,

consequences
Stefan Andreas
Neurobehavioural (sleepiness, cognitive since OSA causes arterial hypertension and

and psychiatric) is a cardiovascular (CV) risk factor (see
later), a high apnoea burden can cause
The concept of ‘sleeping on a problem’ is cerebrovascular disease, with stroke being
old and well known. Indeed, recent evidence the most obvious.
shows that memory reprocessing during
sleep is important in consolidating and To better understand the effects of OSA on
forming our declarative, procedural and neurobehavioural aspects, treatment studies
cognitive memories, and brain processes are of importance. A recent meta-analysis
(Stickgold, 2005). Thus, it comes as no concluded that CPAP is clearly effective in
surprise that OSA, with consecutive sleep reducing objective and subjective daytime
disturbance, has detrimental effects on sleepiness. Furthermore, some cognitive
cerebral function. This is most striking in functions, particularly executive functions
children and adolescents, where the brain is linked to daytime sleepiness, were improved
still developing. Studies using positron with CPAP. Depression occurs in 40% of
emission tomography (PET) or functional OSA patients, but this is not related to OSA
MRI indicate sleep loss is the primary cause severity and CPAP has no consistent effect
of neurocognitive deficits (mainly a basal on depression. Further well-designed, long-
slowing of information processing), more so term studies are needed to better delineate
than hypoxaemia (Verstraeten, 2007). the negative effects of OSA on complex
cerebral functions, such as cognition and
Whether there are not only functional, but mood. At least for younger patients with
also anatomical, sequelae of OSA is more good treatment compliance, CPAP will
difficult to establish, since the pervasive normalise all aspects of brain function.
effects of decreased alertness on higher
cognitive functioning mimic cerebral OSA is common in patients with stroke.
damage due to hypoxia. Moreover, CPAP treatment is inherently difficult in
measures of daytime sleepiness are not patients following stroke and two randomised
associated with objective measures of trials failed to show meaningful improvement
apnoea burden, such as the AHI, of physical or cognitive function in those
hypoxaemia or sleep parameters. However, patients (Bradley et al., 2009).
Cardiovascular
Key points CV disease (CVD) is the main cause of
morbidity and mortality in the ageing
N OSA has detrimental effects on western population. Older people suffer
cerebral function. particularly from CVD. CVD encompasses
N OSA has multiple negative effects on coronary artery disease (CAD), HF and
the CV system. cerebrovascular disease/stroke. Although
mortality due to CAD has decreased slightly
N OSA affects the metabolic syndrome. in the past decade, CAD remains the most
common cause of death, with an incidence

of ,400 myocardial infarctions per 100,000 media thickness, carotid plaques and
person-yrs between the ages of 36 and alterations of the coronary arteries. All these
64 yrs. The prevalence of HF is ,2%, rising alterations are ultimately related to clinically
to .10% in subjects .70 yrs of age. The overt CV disease in different vascular beds.
mean age of HF patients in the community
is 75 yrs. About half of the patients Nowadays, OSA is accepted as an
presenting with the clinical syndrome of HF independent risk factor for arterial
have a normal left ventricular ejection hypertension (Haentjens et al., 2007). Arterial
fraction. These cases are defined as HF with hypertension is a risk factor for CAD as well as
preserved ejection fraction (HFprEF) and HF, especially HFprEF, and is a strong risk
left ventricular diastolic dysfunction is factor for stroke. This association makes it
considered to be a common underlying difficult to prove a causal relation between
OSA and CVD independent of arterial
pathology. HFprEF typically occurs in the
hypertension in epidemiological studies.
elderly and is associated with classical risk
factors, such as arterial hypertension, Large epidemiological cross-sectional and
diabetes mellitus and atrial fibrillation. The longitudinal studies have described an
prognosis of HFprEF patients, once association between OSA and CVD morbidity
hospitalised for HF, is similarly poor to that and mortality, independently of confounders
in systolic HF, but has, in contrast to such as obesity. Furthermore, a dose–
systolic heart failure, not improved during response relationship has been established.
the past few decades. Similar to diastolic Independent of other risk factors, such as
HF, cerebrovascular disease and stroke are obesity and arterial hypertension, the
more common in the elderly. The main risk likelihood of dying from CV causes doubles in
factor for stroke is arterial hypertension. patients with moderate/severe OSA. This has
been shown for a variety of major CV end-
OSA occurs frequently in patients with CAD, points, such as CV death, acute myocardial
HF and stroke. Several studies on patients infarction, stroke, occurrence of HF,
with CAD who are slightly overweight yielded hospitalisation for CVD, left ventricular
an incidence of OSA between 30% and 50% diastolic dysfunction, complex ventricular
(Lüthje et al., 2008). A high incidence of arrhythmias and sudden cardiac death.
OSA has also been found in patients with
arterial hypertension, stroke and HF The most convincing evidence for OSA
(Bradley et al., 2009). OSA and CVD share having negative CV effects and being an
common risk factors, such as obesity, male important CV risk factor stems from
sex, smoking and advanced age. treatment trials: CPAP therapy markedly
reduces nocturnal sympathetic activation,
In recent decades, research has revealed thereby reducing heart rate, blunting blood
multiple negative consequences of OSA on pressure surges, and improving vascular
the CV system. The pathophysiological stiffness and left ventricular diastolic
interaction between OSA and CVD is function. Furthermore, CPAP therapy has a
complex, and comprises neural, humoral, positive effect on oxidative stress,
mechanical, haemodynamic and circadian endothelial dysfunction, leptin levels,
rhythm components. Oxidative stress and interleukins, tumour necrosis factor (TNF)-
endothelial dysfunction are main a, C-reactive protein (CRP), platelet
mechanisms leading to CVD in OSA. aggregability and fibrinogen levels in well-
Another important effect of OSA is an controlled studies. CPAP reduces not only
increase in sympathetic activity, which nocturnal but also diurnal blood pressure in
persists during the day. Well-controlled OSA (Haentjens et al., 2007). These effects
studies have shown effects of OSA on are more pronounced in patients with good
different aspects of early vascular treatment adherence, high initial AHI,
dysfunction. These comprise vascular arterial hypertension and daytime
responses to different stimuli, arterial sleepiness, and are also present in patients
stiffness, pulse wave velocity, carotid intima with CVD, such as HF.

In conclusion, current data suggest that explained by a pro-inflammatory state
OSA increases the risk of developing CVD related to stress and neurohumoral
and that its treatment has the potential to activation. In a broader context, the current,
diminish such risk. This has been well-received ‘selfish brain’ theory holds that
recognised in guidelines for the treatment of chronic stress alters the way the brain
arterial hypertension and HF. secures its own energy supply. Thereby,
energy uptake from the environment is
Metabolic
chronically increased in most individuals,
The metabolic syndrome is tightly associated ultimately leading to obesity. However, in
with obesity and its sequelae. According to a epidemiological studies, a causal
2009 joint statement, metabolic syndrome is relationship between sleep duration and
defined as the presence of three or more of obesity is difficult to prove and, indeed, is
the following: waist circumference o88 cm not established at present.
in females or o102 cm in males; high blood
The mechanisms through which OSA may
pressure (BP) (systolic o130 and/or
worsen metabolism are complex, and
diastolic o85 mmHg) or antihypertensive
encompass sympathetic and neurohumoral
treatment; high fasting blood glucose (
activation, glucose homeostasis,
o5.6 mmol?L-1) or antidiabetic treatment;
inflammation, and oxidative stress mainly
high triglycerides (o1.7 mmol?L-1) or lipid-
due to chronic intermittent hypoxia. Cross-
lowering treatment; reduced high-density
sectional studies estimate a five-fold risk of
lipoprotein (HDL)–cholesterol
the metabolic syndrome in OSA patients
(,1.3 mmol?L-1 in females or ,1 mmol?L-1 in
compared with controls. Accordingly,
males) or lipid-lowering treatment. The
markers of the metabolic syndrome, such as
World Health Organization definition is
leptin, are increased and correlate with OSA
slightly more complex and emphasises the
severity. However, due to the strong
direct measurement of insulin resistance.
confounding effect of obesity, causality
Unsurprisingly, the metabolic syndrome is a
cannot be derived. A recent review (Lévy
strong CV risk factor.
et al., 2009) concluded that despite the
White adipose tissue is a major endocrine abundance of cross-sectional evidence for
and secretory organ, and plays a key role in the link between OSA and abnormal glucose
the metabolic syndrome. Adipose tissue control, further well-designed longitudinal
releases a large number of peptides, such as and interventional studies are needed to
leptin and other factors, collectively termed prove causality.
adipocytokines. Harmful free fatty acids and
angiotensin II are also released and As in hypertension or CVD, intervention
contribute to inflammation and negative CV studies using CPAP therapy could help to
effects. In obesity, the secretory activity of disentangle causality. In OSA patients
adipose tissue is increased and altered. A without type 2 diabetes mellitus and, thus,
reason for the altered adipocytokine release mostly without obesity, CPAP improved
is assumed to be relative hypoxia in clusters glucose control and insulin sensitivity.
of adipocytes that become distant from the However, in the typical overweight OSA
vasculature as adipocyte cell size increases. patient, CPAP treatment does not
These negative effects are mostly caused by significantly affect the metabolic status.
intra-abdominal or visceral adipose tissue Similarly, the effects of CPAP on the
rather than subcutaneous adipose tissue. metabolic syndrome in type 2 diabetic
patients with OSA are controversial.
Sleep impacts on adipocyte activity and the Furthermore, there is no convincing
metabolic syndrome. In healthy subjects, evidence that visceral fat decreases
experimental sleep restriction caused insulin following CPAP treatment. These studies
resistance, reduced leptin and increased resemble findings in CVD, where the effects
ghrelin plasma concentrations, and of CPAP are most striking in young,
increased appetite (Lévy et al., 2009). This is otherwise healthy male OSA patients.

While discussing the effects of OSA on the N Haentjens P, et al. (2007). The impact of
metabolic syndrome, we should be aware of continuous positive airway pressure on
the fact that at least three large, well- blood pressure in patients with obstruc-
controlled randomised trials showed a tive sleep apnea syndrome: evidence
clinically meaningful reduction in body from a meta-analysis of placebo-con-
weight of ,20 kg with intensive counselling trolled randomized trials. Arch Int Med;
and a low-energy diet. The reduction in body 167: 757–764.
weight was accompanied by a clear N Lévy P, et al. (2009). Sleep, sleep-
improvement of OSA in .60% of patients. disordered breathing and metabolic con-
Furthermore, all aspects of the metabolic sequences. Eur Respir J; 34: 243–260.
N Lüthje L, et al. (2008). Obstructive sleep
syndrome are strikingly improved by weight
apnea and coronary artery disease. Sleep
reduction. Long-term treatment studies are
Med Rev; 12: 19–31.
now needed to validate weight loss as a N McNicholas WT, et al., eds. (2010). Sleep
primary treatment strategy for OSA. Apnoea. Eur Respir Monogr 50.
N Stickgold R. (2005). Sleep-dependent
memory consolidation. Nature; 437:
Further reading 1272–1278.
N Verstraeten E. (2007). Neurocognitive
N Bradley TD, et al. (2009). Obstructive effects of obstructive sleep apnea syn-
sleep apnoea and its cardiovascular drome. Curr Neurol Neurosci Rep; 7(2):
consequences. Lancet; 373: 82–93. 161–166.

Central sleep apnoea and
Cheyne–Stokes respiration
Winfried Randerath
ventilatory impulses generated by the brain

Key points stem are lacking in CSA. The typical findings
of paradoxical breathing and flattening of
N CSAs are characterised by a lack of the inspiratory flow curve in OSA do not
ventilatory impulses generated by the characterise CSA. CSA syndromes include
brain stem. primary CSA, CSR, CSA due to high-altitude
periodic breathing and CSA caused by brain
N Paradoxical breathing and flattening
stem lesions or drugs and substances. CSR,
of the inspiratory curve do not
or periodic breathing, is characterised by
characterise CSAs.
recurrent apnoeas and hypopnoeas and a
crescendo–decrescendo pattern of flow and
effort. The cycle length averages 60–90 s in
Awareness of sleep-related breathing CSR, while it is shorter in other forms of CSA
disorders has grown rapidly in recent years. (Tkacova et al., 1997).
Sleep-related breathing disorders have been
acknowledged as independent risk factors Further reading
for cardiovascular disorders. They are
significantly associated with increased N American Academy of Sleep Medicine
morbidity and mortality. Therefore, the (2005). International Classification of
diagnosis and treatment of OSA and CSA is Sleep Disorders. 2nd Edn. Westchester,
of major interest in cardiac patients. American Academy of Sleep Medicine.
N Tkacova R, et al. (1997). Left ventricular
CSA is defined by recurrent cessations of volume in patients with heart failure and
airflow and simultaneous reduction of the Cheyne–Stokes respiration during sleep.
breathing effort (American Academy of Am J Respir Crit Care Med; 156: 1549–1555.
Sleep Medicine, 2005). In contrast to OSA,

Central sleep apnoea/
Cheyne–Stokes respiration:
epidemiology and risk factors
Winfried Randerath
It is estimated that 10% of breathing events are frequently accompanied by

disturbances during sleep are of central breathing disturbances during sleep (Parra
origin. CSA is more prevalent in the elderly. et al., 2000). Within the first 72 h .70% of
However, this might be associated with the the patients showed an AHI .10 events?h-1
increasing relevance of cardiovascular and 28% an AHI .30 events?h-1. While
diseases in this group, which predisposes during the initial phase 26% of the patients
them to CSA. A large cohort study of the showed CSA, the amount was reduced to 7%
general population showed that the male sex after 3 months.
is another risk factor for CSA (Bixler et al.,
Other risk factors include chronic medication
2001). There are differences in the apnoea
or use of opioids. They are associated with
threshold between the sexes; women have a
central apnoeas, periodic breathing and
lower apnoeic threshold, which stabilises
atactic breathing (Wang et al., 2005).
respiration (Skatrud et al., 1983).
CSR is a subgroup of CSA. It is characterised Further reading

by a periodic shift of overshooting and
undershooting of the ventilation, which N Bixler EO, et al. (2001). Prevalence of
results in the typical pattern of periodic sleep-disordered breathing in women:
breathing (crescendo-decrescendo pattern). effects of gender. Am J Respir Crit Care
Med; 163: 608–613.
The most relevant risk factors for central N Javaheri S, et al. (1998). Sleep apnea in 81
breathing disturbances during sleep are ambulatory male patients with stable
cardiovascular diseases, such as arterial heart failure. Types and their prevalences,
fibrillation, heart failure and stroke (Solin et consequences, and presentations. Circula-
tion; 97: 2154–2159.
al., 1999; Lanfranchi et al., 2003). Javaheri et
N Lanfranchi PA, et al. (2003). Central sleep
al. (1998) showed a prevalence of 51% of
apnea in left ventricular dysfunction:
sleep-related breathing disorders in stable prevalence and implications for arrhyth-
HF, mostly central. Sin et al. (1999) analysed mic risk. Circulation; 107: 727–732.
the data of 450 consecutive patients with HF N Parra O, et al. (2000). Time course of
and found that male sex, atrial fibrillation sleep-related breathing disorders in first-
and hypocapnia were significantly ever stroke or transient ischemic attack.
associated with CSA. Cerebral ischaemic Am J Respir Crit Care Med; 161: 375–380.
N Sin DD, et al. (1999). Risk factors for
central and obstructive sleep apnea in
Key points 450 men and women with congestive
heart failure. Am J Respir Crit Care Med;
N The risk of CSA is increased in the 160: 1101–1106.
elderly and in males. N Skatrud JB, et al. (1983). Interaction of
sleep state and chemical stimuli in
N Cardiovascular disorders and the use sustaining rhythmic ventilation. J Appl
of opioids predispose to CSA. Physiol; 55: 813–822.

N Solin P, et al. (1999). Influence of N Wang D, et al. (2005). Central sleep
pulmonary capillary wedge pressure on apnea in stable methadone main-
central apnea in heart failure. Circulation; tenance treatment patients. Chest; 128:
99: 1574–1579. 1348–1356.

pathophysiology
Winfried Randerath
CSA due to hypoventilation CSA due to hyperventilation
Central apnoeas may appear in patients with The pathophysiology of CSA due to
increased or decreased ventilation. hyperventilation is not yet fully understood.
Hypoventilation syndromes include Nevertheless, several pathophysiological
diseases with reduced central respiratory aspects can be described including the loop
drive or the inability to translate breathing gain of the ventilatory response, the apnoea
impulses into thoracic movements. These threshold and the instability of the
include disorders of the central nervous respiratory control systems during sleep.
system such as inflammatory or ischaemic During wakefulness, ventilation is primarily
diseases of the brain stem, neuromuscular regulated by behavioural factors. In contrast,
diseases (e.g. amyotrophic lateral sclerosis) during sleep, it is mainly influenced by
or thoraco-skeletal disorders (e.g. metabolism, the production and elimination
kyphoscoliosis). Central apnoeas appear of CO2. While an increase in PaCO2
during sleep in these patients as the (hypercapnia) stimulates ventilation,
ventilatory drive and muscle function are breathing is diminished during hypocapnia.
more severely reduced during sleep NREM sleep physiologically reduces
compared with the wake state. ventilatory drive and V9E. Thus, CSA appears
predominantly during NREM sleep. The
influence of the carbon dioxide level is
alleviated during REM sleep as muscle
activity and arousability are reduced.
Key points
Loop gain
N Central disturbances due to
hyperventilation and hypoventilation The ventilatory control system can be
should be discriminated. compared to a loop gain known from
engineering. The actual PaCO2 is influenced
N Central disturbances due to by any disturbance of respiration, e.g.
hypoventilation appear in diseases stimulation of ventilation by noise, pain or
with reduced respiratory drive or cortical impulses. V9E can be described as
failure of thoracic movements. the plant gain, where increases or decreases
N Central disturbances due to in V9E result in variations in CO2. These
hyperventilation depend on changes are measured at the feedback gain,
overshooting of the ventilation, represented by the chemoreceptors in the
changes of the apnoea threshold and ventilatory system. The perception of these
increased chemosensitivity. variations can be influenced by a circulatory
delay in cardiovascular disorders. The
N Central disturbances are closely chemoreceptors stimulate the respiratory
related to HF, atrial fibrillation and control system in the brain stem, the
brain infarction. controller gain, which urges the plant gain
(lungs and thorax) to change ventilation.

A strong response to breathing disturbances significantly increased in CSA patients
characterises a high loop gain. It results in compared with healthy subjects, HF patients
overshooting of ventilation, a shift between without breathing disturbances and HF
hyperventilation and hypocapnia on the one patients with OSA. Therefore, hyperreactivity
hand and apnoeas and hypercapnia/hypoxia of the chemoreceptors is a typical marker,
on the other. As muscle activity and a not of HF in general, but only in patients
tendency to arousal are reduced during REM with associated central breathing
sleep, ventilatory overshoot is more often disturbances. From a clinical point of view,
present during NREM sleep. hyperreactivity of the chemoreceptors leads
to a higher increase of V9E in response to a
Apnoea threshold given PaCO2, resulting in hypocapnia.
The extent of V9E is determined by the PaCO2. Hypocapnia is followed by a reduction of
If the prevailing PaCO2 falls below a definite ventilation, apnoea and hypoxia. A vicious
circle of overshooting and undershooting is
level, breathing ceases. This level of the
generated.
PaCO2 is called the apnoea threshold. During
normal breathing the PaCO2 exceeds the The role of delayed circulation time in the
apnoea threshold. Whenever the distance pathophysiology of central breathing
between the actual PaCO2 and the apnoea disturbances is unclear. Based on animal
threshold is narrowed, the probability of an trials it has been suggested that a delayed
apnoea increases. On the one hand, the perception of blood gas changes might
apnoea threshold has been shown to be induce decelerated reactions of the
elevated in CSA, without relevant change in ventilation. However, it is difficult to
PaCO2. On the other hand, hyperventilation translate these finding to humans.
brings PaCO2 closer to the apnoea threshold,
which is a typical finding in patients with Other factors seem to play a minor role in
unstable breathing. In this case, small the pathophysiology of CSA, including
variations in ventilation lead to oscillations central chemoreception. The cerebral blood
in PaCO2 above and below the apnoea flow differs between healthy subjects and
threshold resulting in a pattern of periodic CSA patients. Hypercapnia increases the
breathing. Chemical irritation of the cerebral blood flow, but the vasoreactivity is
pulmonary tissue receptors increases the diminished in CSA patients. The variations
central ventilatory drive in animals. This of the cerebral blood flow physiologically
reflex activation is transmitted by vagal counterbalance changes of the H+
afferent nerves. Interstitial inflammatory concentration in the cerebral fluid. If these
processes can stimulate irritant receptors in reflexes are dampened, cerebral alkalosis
humans. However, this irritation is much might be intensified leading to a reduction
more common in HF patients induced by of the ventilatory drive and central apnoea.
pulmonary congestion. Therefore, In contrast, increases of cerebral acidosis
pulmonary congestion, represented by an induce ventilatory overshoot and
increase of the pulmonary wedge pressure hyperventilation and thus unstable breathing.
as a measure of left ventricular failure,
correlates with the AHI and the ventilatory Arousals
drive. Consecutively, improvement of Arousals restore the waking state of non-
cardiac function reduces hyperventilation chemical control of ventilation, lower the
and the AHI. CO2 set point and increase ventilatory
Hypoxic and hypercapnic ventilatory reactivity in healthy persons and in OSA. The
response PaCO2 level during sleep is higher compared
with the new set point in the sleep/wake
The sensitivity of the peripheral and central transition. As a consequence, ventilation is
chemoreceptors also influences the stability rapidly elevated during an arousal.
of the respiratory control system. The Moreover, arousals increase the tone of the
ventilatory response to hypercapnia is upper airway muscles. These factors

normalise the patency of the upper airways N Solin P, et al. (1999). Influence of
and terminate obstructive breathing pulmonary capillary wedge pressure on
disturbances. However, in central apnoea, central apnea in heart failure. Circulation;
arousals perpetuate the elevated loop gain. 99: 1574–1579.
Due to the higher sensitivity of the N Solin P, et al. (2000). Peripheral and
chemoreceptors, increases of the ventilation central ventilatory responses in central
aggravate the overshoot and therefore sleep apnea with and without congestive
increase breathing disturbances. heart failure. Am J Respir Crit Care Med;
162: 2194–2200.
N Wellman A, et al. (2003). Respiratory
Further reading system loop gain in normal men and
women measured with proportional-
N Bradley TD, et al. (1992). Central sleep assist ventilation. J Appl Physiol; 94:
apnea. Clin Chest Med; 13: 493–505. 205–212.
N Crowell JW, et al. (1956). Basic oscillating N Xie A, et al. (2002). Apnea-hypopnea
mechanism of Cheyne–Stokes breathing. threshold for CO2 in patients with con-
Am J Physiol; 187: 395–398. gestive heart failure. Am J Respir Crit Care
N Hanly P, et al. (1993). Pathogenesis of Med; 165: 1245–1250.
Cheyne–Stokes respiration in patients with N Xie A, et al. (2005). Cerebrovascular
congestive heart failure. Relationship to response to carbon dioxide in patients
arterial PCO2. Chest; 104: 1079–1084. with congestive heart failure. Am J Respir
N Lorenzi-Filho G, et al. (2002). Relation- Crit Care Med; 172: 371–378.
ship of carbon dioxide tension in arterial N Xie A, et al. (1994). Interaction of
blood to pulmonary wedge pressure in hyperventilation and arousal in the patho-
heart failure. Eur Respir J; 19: 37–40. genesis of idiopathic central sleep apnea.
N Naughton M, et al. (1993). Role of Am J Respir Crit Care Med; 150: 489–495.
hyperventilation in the pathogenesis of N Yu J, et al. (1998). Stimulation of breath-
central sleep apneas in patients with ing by activation of pulmonary peripheral
congestive heart failure. Am Rev Respir afferents in rabbits. J Appl Physiol; 85:
Dis; 148: 330–338. 1485–1492.
N Phillipson EA. (1978). Control of breath- N Yumino D, et al. (2008). Central sleep
ing during sleep. Am Rev Respir Dis; 118: apnea and Cheyne-Stokes respiration.
909–939. Proc Am Thorac Soc; 5: 226–236.

clinical aspects
Winfried Randerath
controls, while CSA patients perform worse

Key points in objective tests. This discrepancy may be
due to the overwhelming symptoms of the
N CSA patients often do not report underlying disease. Thus, central breathing
sleep-related symptoms. disturbances cannot be excluded if patients
N Objective measures of sleepiness do not report daytime symptoms. Careful
show limitations in CSA compared questioning, additional tests such as driving
with controls. simulators, OSLER test or MWT and PSG
are mandatory.
N CSA cannot be differentiated from
other breathing disturbances based There are no clinical signs which allow for
on clinical findings. differentiation between CSA and other types
of breathing disturbances during sleep.
Further reading
The typical clinical findings of patients with N Arzt M, et al. (2006). Sleepiness and
OSA are daytime sleepiness, neurocognitive sleep in patients with both systolic heart
deficits and limitations in daily life. These failure and obstructive sleep apnea. Arch
symptoms of disrupted sleep may also Intern Med; 166: 1716–1722.
characterise CSA. However, often they are N Hastings PC, et al. (2006). Symptom
not noticed and mentioned spontaneously burden of sleep-disordered breathing in
by the patient. Subjective measures of mild-to-moderate congestive heart failure
daytime sleepiness often show less patients. Eur Respir J; 27: 748–755.
limitation in CSA patients compared with

consequences
Stefan Andreas
Neurobehavioural (sleepiness, cognitive treatment of CSA while others have not. To

and psychiatric) make things more complex, cause and effect
are complicated by the fact that HF itself
While there is convincing evidence that OSA causes daytime sleepiness.
has detrimental neurobehavioural
consequences, as alluded to in the section The absence of a clear causal association
of this book on ‘‘Obstructive sleep apnoea: between CSA and neurobehavioural
consequences’’, there is no such evidence sequelae is not unexpected. Patients with
for CSA in HF. Indeed, in a large, random HF are mostly elderly and, thus, their sleep
community sample, patients with HF had is more disturbed compared to younger
less daytime sleepiness (as measured by patients. Similarly, HF itself, older age or
lower ESS scores) than controls, despite other conditions affecting general health
reduced total sleep time (Arzt et al., 2006). impair subjective and objective sleep. This
Similarly, other cross-sectional studies association is related to sympathetic
found no correlation between ESS and AHI activation and oxidative stress. As discussed
in HF. However, these studies showed in more detail later, CSA, unlike OSA, does
correlations between ESS and the severity of not cause striking sympathetic activation.
HF. This resembles a number of other
Cardiovascular
diseases that are accompanied by
daytime sleepiness independently of sleep When considering the effects of CSA on
and breathing. cardiovascular (CV) disease, it should be
considered that this is a very different story
For the treatment of CSA, most studies
to the effects of OSA on CV disease for two
found less stage 1 and more stage 2 sleep
reasons. First, patients with CSA already
with active treatment. However, slow-wave
have severe HF, since HF is the main cause
sleep, REM sleep and arousals were
of CSA (see the section of this book on
relatively unaffected by treatment. Thus, it is
‘‘Central sleep apnoea/Cheyne–Stokes
not clearly established whether CSA
respiration: pathophysiology’’). Secondly,
profoundly disturbs sleep or only affects
the oscillation of ventilation, heart rate,
conventional sleep scoring. Some controlled
oxygen saturation, etc. around a mean
trials have found an improvement in
characteristic for CSA is clearly distinct from
daytime sleepiness with successful
obstructive apnoeas with negative pressure
swings and consecutive hypoxia. A failing
Key points heart with reduced ejection fraction,
diastolic dysfunction and increased filling
N There is no clear association of CSA pressure is more vulnerable to stressors
with neurobehavioural sequelae. such as increased blood pressure (afterload)
or sympathetic activation compared with a
N In contrast to OSA, the CV sequelae of healthy heart. This is the reason why OSA is
CSA are not well established. especially detrimental in patients with
established HF.

For CSA, the CV consequences are less whether there is a causal association
clear, and controversy remains as to whether between CSA and CV disease (see ‘‘Treating
CSA contributes to morbidity and mortality CSA’’). For the time being, it is fair to
in CHF patients or whether it is simply an conclude that the sequelae of CSA on the CV
epiphenomenon. While some studies have system are far less detrimental than those of
described an association between CSA and OSA. When considering treatment of HF, it
mortality independent of confounders, other should be kept in mind that successful
studies were not able to replicate this treatment of HF also improves central and
observation (Pinna et al., 2009). Since CHF obstructive apnoeas. HF management is
is a complex disease related to CSA by a complex, and comprises pharmacological
variety of mechanisms (see ‘‘Central sleep and electrophysiological therapy. Indeed,
apnoea/Cheyne–Stokes respiration: cardiac resynchronisation therapy on top of
pathophysiology’’) this does not come conventional medical therapy has shown a
as a surprise. clear improvement of left ventricular
function, exercise capacity and CSA in a
This might be due to the fact that CSA, number of well-controlled studies.
unlike OSA, is not characterised by negative
intrathoracic pressure swings. Furthermore,
although there are clearly oxygen
desaturations during CSA, the average Further reading
oxygen saturation is still in the normal range
in most patients due to the periods with N Arzt M, et al. (2006). Sleepiness and
hyperventilation with concomitant high sleep in patients with both systolic heart
oxygen saturations. Indeed, CSA in CHF failure and obstructive sleep apnea. Arch
Intern Med; 166: 1716–1722.
patients seems not to cause the striking
N Bradley TD, et al. (2005). Continuous
sympathoexcitation and daytime sleepiness
positive airway pressure for central sleep
that occur with OSA (Spicuzza et al., 2003). apnea and heart failure. N Engl J Med; 353:
Likewise, noradrenaline spill-over and brain 2025–2033.
natriuretic protein (BNP) were associated N Mansfield D, et al. (2003). Raised sympa-
with the severity of HF but not CSA in CHF thetic nerve activity in heart failure and
patients (Mansfield et al., 2003). central sleep apnea is due to heart failure
severity. Circulation; 107: 1396–1400.
Important insights into possible CV
N McNicholas WT, et al., eds. (2010). Sleep
sequelae of CSA in CHF can also be gained
Apnoea. Eur Respir Monogr 50.
from therapeutic interventions. A large N Pinna GD, et al. (2009). Pathophy-
randomised controlled trial using CPAP to siological and clinical relevance of sim-
treat CSA was clearly negative for the main plified monitoring of nocturnal breathing
end-point, transplantation-free survival, disorders in heart failure patients. Eur J
while surrogate end-points (noradrenaline Heart Fail; 11: 264–272.
and ejection fraction) were still positive N Spicuzza L, et al. (2003). Autonomic
(Bradley et al., 2005). However, CPAP modulation of heart rate during obstruc-
reduced CSA by only ,50%. Other large tive versus central apneas in patients with
randomised controlled trials using more sleep-disordered breathing. Am J Respir
effective treatment modalities are still Crit Care Med; 167: 902–910.
running, and might give insights into

Hypoventilation syndromes/
chronic respiratory
insufficiency in sleep
Viliam Donic and Zoltan Tomori
Hypoventilation syndromes of the upper airway, increasing resistance to

ventilation. The accessory respiratory
Sleep-related hypoventilation syndromes muscles and intercostal muscles are also
(SRHS) form part of the SDB spectrum, in affected, which impacts adversely on
addition to OSA and CSA. They are respiratory mechanics. The resulting shallow
characterised by elevated PaCO2 breathing increases dead space ventilation.
(.45 mmHg) during sleep or As a consequence of all these changes, gas
disproportionately increased PaCO2 relative exchange worsens during sleep, particularly
to levels in wakefulness (Muir, 2010). There in neuromuscular disease, chest wall and
is accompanying arterial oxygen chronic obstructive airway diseases. The
desaturation during sleep, usually decreased tidal volume and V9E result in
demonstrated by an SaO2 ,90% for more alveolar hypoventilation, hypoxaemia and
than 5 min with a nadir of 85% or lower carbon dioxide retention. These changes
(Caples et al., 2005). This ventilatory trigger sleep fragmentation, frequent
derangement is associated with excessive arousals and daytime sleepiness, fatigue
daytime sleepiness, tiredness, morning and possible cognitive impairment (De
headaches and poor sleep quality as a result Backer, 1995). If this sequence is not
of frequent interruption of sleep with addressed, over time deteriorating alveolar
repetitive arousals and CO2 retention. ventilation–perfusion with increased
According to the International classification pulmonary vascular resistance can cause
of Sleep Disorders (ICSD-2; American pulmonary hypertension, with consequent
Academy of Sleep Medicine, 2005) and right ventricular impairment and cor
other sources, hypoventilation disorders can pulmonale. Early diagnosis and effective
be divided into three major categories: a) treatment are crucial to prevent these severe
hypoventilation syndromes; b) comorbid complications.
respiratory disorders; and c) comorbid
nonrespiratory disorders. Respiratory-related sleep disruption is
generally not significant until the
Pathophysiology of ventilatory changes diaphragmatic function is markedly
during sleep impaired. In this situation, for instance in
Hypoventilation and chronic respiratory Duchenne muscular dystrophy,
insufficiency Hypoventilation and chronic hypoventilation and oxygen desaturation
respiratory insufficiency caused by a range occur, initially during REM sleep, but
of pathologies are characterised by hypoventilation progresses into NREM sleep
hypercapnia and hypoxia, which worsen as muscle strength deteriorates.
during sleep. The ventilatory response to Central hypoventilation syndromes
hypercapnia and hypoxemia decrease during
sleep. During REM sleep in healthy people, Congenital central alveolar hypoventilation
general muscle hypotonia develops, with the syndrome (CCHS or Ondine’s curse)
exception of the diaphragm. This increases represents a failure of central respiratory
the collapsibility and decreases the patency drive. Hypoventilation begins in infancy and

it is worse during sleep than during examination should exclude lesions of the
wakefulness (see also the section of this brain, heart and neuromuscular disorders,
book on ‘‘Sleep disordered breathing in and investigation will demonstrate an
children’’). Persons afflicted with CCHS impaired ventilatory response to
classically suffer from hypoventilation, which hypercapnia and decreases in PaO2.
may culminate in respiratory arrest during Polysomnography shows that hypoventilation
sleep. CCHS is exhibited typically from birth is most marked during NREM sleep (an
or in infancy, and should be distinguished important differential point from patients with
from rare central hypoventilation disorders neuromuscular disorders in whom
acquired as a consequence of severe brain hypoventilation worsens in REM sleep). In
or spinal trauma (e.g. after an automobile more marked cases, however, hypoventilation
accident or stroke, or as a complication of is also present progressively during other
neurosurgery or meningo-encephalitis). sleep stages and even in wakefulness. Most
CCHS reflects a diffuse dysregulation people with CCHS do not survive infancy,
process within the autonomic system and unless they receive ventilatory assistance,
affected individuals may have tracheostomy and lifetime mechanical
Hirschsprung’s disease or cardiac ventilation at least during sleep, but
arrhythmias and develop tumours of neural prognosis has improved with early recognition
crest origin. Mutations in the homeobox and care. This improvement in outcome has
gene PHOX2B were identified as the cause been aided by the creation of national
of CCHS in 2003. More than 90% of CCHS registries and the formation of a network of
patients have mutations that add extra specialised centres in some countries, which
alanines to the polyalanine tracts in the provide optimal multidisciplinary surveillance
PHOX2B gene. These are called polyalanine and management.
repeat mutations (PARMs); the remaining
Several other genetic syndromes can be
,10% of cases have a non-PARM missense,
associated with central hypoventilation.
nonsense or frameshift mutation (Weese- They include myelomeningocele with
Mayer et al. 2009). It is notable that the non- Arnold–Chiari malformation, skeletal
PARM mutations tend to occur de novo and dysplasia, Prader–Willi syndrome and
result in a severe phenotype with the inborn errors of the metabolism such as
requirement for continuous ventilatory pyruvate dehydrogenase deficiency and
support. A relationship between PARM carnitine deficiency.
genotypes and phenotypic expression is also
becoming evident. The genotype is denoted Sleep-related hypoventilation or hypoxaemia
with reference to the normal 20-pair alanine may occur also as a result of pulmonary
tract (expressed as 20/20 in individuals parenchymal or vascular pathology. This is
without mutation). Individuals with 20/27 caused by interstitial lung disorders such as
and 20/33 genotypes frequently require interstitial pneumonitis or sickle cell
ventilatory support. Late-onset cases with haemoglobinopathies.
mild hypoventilation may present with
respiratory failure after a general anaesthetic There is also a rare category of idiopathic
or ingestion of respiratory depressants or sleep-related nonobstructive alveolar
following a chest infection, and are more hypoventilation. This refers to decreased
alveolar ventilation resulting in sleep-related
likely to have the 20/24 or 20/25 genotypes.
arterial oxygen desaturation and
Such cases may be adequately treated with
hypercapnia in patients with normal
nocturnal NIV, in contrast to more severe
mechanical properties of the lungs.
congenital variants.
Obesity hypoventilation syndrome
About 1 in 200,000 live-born children have
CCHS. Severe cases develop life-threatening OHS is an increasingly recognised disorder,
episodes of hypoventilation or apnoea with characterised by symptoms present in the
cyanosis, usually in the first months of life. previously described Pickwickian syndrome.
In typical congenital cases, medical Daytime hypercapnia (PaCO2 .45 mmHg) is

a cardinal sign of OHS, reflecting reduced of thoracoplasty for tuberculosis and other
ventilation during sleep that persists during diseases belong to the class of chest wall
wakefulness, hence the definition of OHS is disorders. Chronic respiratory muscle failure
obesity (BMI .30 kg?m-2 accompanied by usually develops slowly over a period of
SDB and waking hypercapnia. Other causes years. ALS and Creutzfeldt–Jacob disease
of hypoventilation as described in this can progress rapidly toward death, but
chapter should be excluded. In the majority familial dysautonomia and other autonomic
of OHS cases, obstructive apnoeas are seen, disorders can have a slower evolution.
but others have an AHI of ,5 events?h-1 and Poliomyelitis can alter central and peripheral
experience pure hypoventilation as respiratory function, being evident as
confirmed by an increase in PaCO2 during muscle atrophy and restricted ventilation.
sleep of 10 mmHg above waking value. A Hereditary/sensory polyneuropathies and
mild restrictive ventilatory defect is neuromuscular junction impairment (e.g.
commonly seen on pulmonary function congenital and acquired myasthenia) also
testing, due to increased thoracic impedance. result in disorders of breathing. Muscular
Respiratory muscle strength measurements disease (myotonic dystrophy) may manifest
show variable results due either to normal with periods of alveolar hypoventilation
muscles working at a mechanical resulting from additional impairment of
disadvantage or to a degree of weakness. central respiratory drive. Other myopathies
Compared with normocapnic OSA patients, (Duchenne muscular dystrophy, maltase
OHS patients have a worse quality of life and deficiency, myopathy and myotonic
greater propensity to pulmonary hypertension dystrophy) also cause hypoventilation
(Mokhlesi et al., 2007). resulting in progressive muscle weakness.
High spinal injuries may cause tetraplegia
Obese normocapnic subjects and OHS
and respiratory paralysis, as well as spinal
patients have similar hypercapnic ventilatory
muscular atrophy.
response (HCVR), measured by the
occlusion pressure technique, and in both Orthopnoea is a common complaint in ALS
values are higher than in normal subjects. and can compound sleep disruption. During
However, OHS patients are unable to REM sleep, there is a post-synaptic
increase HCVR in response to a hypercapnic inhibition of somatic motor neurons or even
challenge compared with obese loss of tone in ribcage and other accessory
normocapnic subjects. Obesity, genetic respiratory muscles. The diaphragm is
causes, SDB and leptin resistance are relatively unaffected. The breathing
thought to explain the blunted HCVR. Early disorders manifest with prolonged
work suggests that serum leptin levels may hypoventilation or central and obstructive
decrease following OHS therapy with bi-level apnoeic episodes, depending on the type of
NIV, accompanied by an increase in HCVR. neuromuscular impairment. In slowly
Neuromuscular disorders progressive neuromuscular disorders,
respiratory failure usually advances in three
Neuromuscular disorders are diseases stages. In stage 1, alveolar hypoventilation
caused by impairment of the motor unit develops during only REM sleep; in stage 2,
comprising the motor neuron, nerve root, it is present during REM and NREM sleep;
myoneural junction and muscle. Sleep- and in stage 3, it develops during both sleep
related hypoventilation or hypoxaemia result and wakefulness. The gradual transition
from neuromuscular disease or chest wall from stage 1 to stage 3 respiratory failure is
disorders. They include myasthenia, acid characteristic of Duchenne muscular
maltase deficiency, Duchenne muscular dystrophy, in which there is a progression in
dystrophy, amyotrophic lateral sclerosis respiratory muscle weakness over a decade
(ALS), myotonic myopathy, poliomyelitis, or so. In other disorders (congenital
high spinal injuries with tetraplegia and muscular dystrophy) respiratory
respiratory paralysis, and spinal muscular insufficiency is present, but varies according
atrophy. OHS, kyphoscoliosis and sequelae to disease subtypes. In other diseases,

respiratory muscle weakness may be N Caples SM, et al. (2006). Central sleep
extremely severe, with presentation of stage apnea, hypoventilation syndromes and
3 respiratory failure, e.g. rapid-onset periodic breathing disorders. In:
Guillain–Barré syndrome. Randerath WJ, et al. Sleep Apnea. Basel,
Karger; pp. 180–191.
Nocturnal hypoventilation is found in a N De Backer WA. (1995). Central sleep
subset of COPD patients, but does not apnoea, pathogenesis and treatment: an
usually occur unless FEV1 is ,1 L, and is overview and perspective. Eur Respir J; 8:
less likely in pure emphysema patients 1372–1383.
unless they are in end-stage disease. N Mokhlesi B, et al. (2007). Recent
Increased work of breathing, overloaded advances in obesity hypoventilation syn-
respiratory mechanics, inadequate nutrition drome. Chest; 132: 1322–1336.
resulting in respiratory muscle weakness, N Muir JF. Hypoventilation syndromes. In:
concurrent OSA and genetically low Palange P, Simonds AK, eds. ERS
ventilatory drive are precipitating factors. Handbook of Respiratory Medicine.
Nocturnal hypoventilation in cystic fibrosis Sheffield, European Respiratory Society,
is described in the section of this book on 2010; pp. 414–416.
‘‘Comorbid respiratory disorders in children’’. N Piper AJ. (2007). Current perspectives on
the obesity hypoventilation syndrome.
Curr Opin Pulm Med; 13: 490–496.
Further reading
N Weese-Mayer DE, et al. (2009).
N American Academy of Sleep Medicine. Congenital central hypoventilation syn-
(2005). International Classification of drome from past to future: model for
Sleep Disorders. 2nd Edn. Westchester, transitional autonomic medicine. Paediatr
American Academy of Sleep Medicine. Pulmonol; 44: 521–535.

Nonrespiratory sleep
disorders
Renata L. Riha
recognition of the impact that psychiatric

Key points illness can have on sleep is vital. Depression
or other affective disorders can compromise
N It is essential that respiratory sleep sleep states and can also mimic sleep
physicians can recognise non- disorders such as those classified under the
respiratory sleep disorders. central hypersomnias.
N Psychiatric illness can have a major This section of the handbook focuses on the
impact on sleep, and its effects can nosology, diagnosis and management of
mimic those of sleep disorders. nonrespiratory disorders of sleep. The
reader is referred to the International
Classification of Sleep Disorders, 2nd
Edition, Diagnostic and Coding Manual
Nonrespiratory sleep disorders comprise a (American Academy of Sleep Medicine,
large proportion of the problems presenting 2005). It provides an extensive and succinct
to any sleep department. It is essential to be classification of both respiratory and non-
able to identify them and either to treat respiratory conditions and can also be used
them appropriately or to refer them for more as a guide in conjunction with the overview
specialised assessment. Many of these presented here.
disorders will require more extensive
investigations, including extended EEG Further reading
montage and overnight monitoring using
video telemetry. N American Academy of Sleep Medicine.
(2005). International Classification of
Disorders such as chronic insomnia are Sleep Disorders. 2nd Edn. Westchester,
among the most common within the American Academy of Sleep Medicine.
community and can overwhelm services if N Winkelman JW, et al. (2008). American
they are not appropriately managed. A Academy of Sleep Medicine Case Book of
number of simple strategies outlined in Sleep Medicine (ICSD-2). Westchester,
this chapter can be used in dealing with American Academy of Sleep Medicine.
patients with insomnia. Furthermore,

Insomnia
Dirk Pevernagie
The essence of insomnia is a predominant Supposedly, NRS pertains to decreased

complaint of dissatisfaction with either sleep quality, and is therefore believed to be
duration or quality of sleep. Insufficient a manifestation of insomnia.
sleep duration may be due to difficulties
Diagnosis
initiating sleep (DIS), difficulties
maintaining sleep (DMS), or awakening too To establish a diagnosis of insomnia, three
early in the morning. Nonrestorative sleep fundamental criteria must be met: 1)
(NRS) denotes a feeling of being recurring difficulties with sleep; 2) adequate
unrefreshed after a sufficiently long and opportunities for sleep; and 3) impairment
consolidated nocturnal sleep period. of daytime functioning.
A poor night of sleep is a nuisance that

Key points everyone experiences sooner or later.
Mostly, it is a transient situation that
N Insomnia consists of a predominant requires no medical attention. When sleep
complaint of dissatisfaction with disturbances are persistent and occur on
either duration or quality of sleep. most nights of the week, a diagnosis of
Difficulties with sleep are recurrent, insomnia can be made.
occur despite adequate opportunities
Adequate time allocation and environmental
for sleep, and are associated with
amenities conducive to obtaining optimal
impairment of daytime functioning.
sleep are important, and must be considered
N Chronic insomnia occurs in ,10% of in the differential diagnosis of insomnia. If
the adult population. Psychiatric these conditions are not met, the sleep
illness and SDB are the most disturbance may be ascribed to external
common comorbidities. factors or inadequate sleep hygiene or may be
labelled as insufficient sleep syndrome.
N Insomnia is considered a disorder,
Correction of these restrictive factors should
whether it is primary (without
result in improvement of sleep.
co-existing disease) or comorbid
(associated and interacting with Another obligatory diagnostic criterion is the
medical or psychiatric disease). presence of daytime dysfunction, which
N Assessment of insomnia is based on results from too little sleep or an inferior
careful history, clinical examination, a quality of sleep. Daytime complaints consist
two-week sleep/wake diary and, if of fatigue, impaired cognitive abilities
needed, additional tests such as PSG (e.g. decreased memory and concentration)
and actigraphy. and mood disturbances (e.g. irritability and
dysphoria). Because these symptoms may
N Insomnia that is comorbid with SDB persist for prolonged time periods, chronic
is a particular condition, characterised insomnia may lead to complications such as
by more severe symptoms. sociofamilial disharmony and lost work
productivity. Insomniacs are typically

preoccupied with their inability to sleep. insomnia. Insomnia is in this situation both
Their health-related quality of life is a symptom and a disorder that calls for
impaired. Because of the daytime specific treatment in addition to the
dysfunction, insomnia may increase the risk management of the associated medical or
of accidents at work or on the road. psychiatric disorder. The controversy of
Treatment with hypnosedative drugs, cause–consequence relationships will be
especially the longer-acting ones, may cause resolved with the future publication of the
residual drowsiness during the daytime and Diagnostic and Statistical Manual of Mental
thus jeopardise safety aspects of working Disorders (DSM-5). The use of the term
and driving. ‘insomnia disorder’ will be proposed
whenever diagnostic criteria are met,
The symptoms of daytime dysfunction
should improve with adequate treatment of whether or not there are co-existing
insomnia. This concept is essential to psychiatric, medical, or other sleep disorders.
corroborate the diagnosis, because daytime Insomnia may co-exist with other primary
impairment may be due to other medical sleep disorders such as sleep apnoea,
conditions, e.g. other primary sleep disorders narcolepsy and restless legs syndrome. The
and somatoform disorders, such as chronic
resulting clinical picture may be complex
fatigue syndrome and fibromyalgia.
and difficult to tackle diagnostically and
Subjects who have curtailed nocturnal sleep, therapeutically. Comorbid insomnia in SDB
but who perform normally during the is an enigma par excellence, because
daytime, do not suffer from insomnia: they treatment of insomnia with hypnotics may
are referred to as habitual short sleepers. have detrimental effects on breathing,
whereas application of CPAP for sleep
Primary, secondary and comorbid insomnia apnoea may aggravate insomnia.
Insomnia may be a solitary manifestation
In this section, some essentials of
without any demonstrable associated
prevalence, pathogenesis, classification,
medical or mental illness. This condition,
assessment and relation with SDB are
named primary insomnia, is classified as an
elaborated. The treatment options for
independent disorder. Often, however,
insomnia are described in Module 6 of
insomnia is an epiphenomenon of an
this handbook.
ailment that is associated with mental or
bodily discomfort. Lying awake or waking up
Prevalence
is then the consequence of a nuisance that
negatively interferes with sleep. Accordingly, The prevalence of insomnia in
insomnia is a very common complaint in epidemiological studies depends highly on
chronic medical or psychiatric diseases. the diagnostic criteria used and on the
Sleeplessness due to obvious causes is target population. While in population-
referred to as secondary insomnia. In this based surveys up to 30% of adults report at
case, insomnia is a symptom rather than an least one of the symptoms of insomnia
autonomous condition. Then again, chronic (DIS, DMS, waking up too early and NRS),
insomnia may play a contributing role in the adding the diagnostic criterion of daytime
pathogenesis or aggravation of mental and dysfunction reduces the prevalence to
somatic diseases. In other words, the approximately 10%. An increased prevalence
relationship between the sleep disorder and of insomnia is associated with the female
the associated illness may be bidirectional. sex and older age. The most common
Often, it is not clear from the history comorbidities are psychiatric illness and
whether insomnia has preceded the SDB. Current estimates indicate that 40% of
associated disease or vice versa. The all insomnia patients have a co-existing
entwined co-existence between disordered anxiety or depression disorder, and
sleep and the associated disease insomnia is a diagnostic symptom of
manifestations is termed comorbid these conditions.

Pathophysiology time, three pathogenetic groups of factors
are implicated (fig. 1). Predisposing factors
Evidence is accumulating that insomnia is are trait characteristics that may be
associated with inappropriately elevated genetically determined. They are static over
physiological arousal. This state, known as time within individual patients. These
hyperarousal, appears to be present factors relate to proneness to insomnia and
throughout the 24-h period. It has been encapsulate the risk for developing
shown that insomnia is associated with insomnia in the pre-morbid phase.
increased metabolic rates of brain and body, Precipitating factors are acute occurrences
elevated heart rates, augmented secretion of or stressors that trigger the onset of
stress hormones, increased insomnia. These triggers are related to
electroencephalographic activity in the high- stressful life events (e.g. professional and
frequency spectrum, and activation of the social mishaps and also health-related
sympathetic nervous system during sleep. incidents). The third group (the
Therefore, chronic insomnia may be perpetuating factors) refers to the cognitive
associated in the long term with increased and behavioural issues that constitute the
risk for cardiovascular diseases and self-perpetuating mechanism of chronic
depression. Animal research and human insomnia. Precipitating and perpetuating
brain metabolic studies in insomnia models factors are non-static, and changes in their
suggest that brain sites controlling sleep are relative intensities will modulate the
activated simultaneously with arousal systems. expression of chronic insomnia over the
course of time. This 3P model provides the
Hyperarousal comprises physiological,
fundamentals on which the nosological
cognitive and emotional features. The
classification and the cognitive behavioural
cognitive arousal model implies that worries
treatment strategies for insomnia are built.
about problems in daily life negatively
interfere with the ability to sleep. Once the Nosological classification
sleep difficulties are settled, the focus of
worrying shifts from life events to concerns Several types of insomnia are listed in the
about sleep itself and about the daytime International Classification of Sleep
consequences of not getting enough sleep. Disorders (ICSD-2). The first four entities
The experience of daytime impairment belong to the group of primary insomnia.
reinforces the patients’ yearning for good
Adjustment (acute) insomnia has a sudden
sleep and incites them to try to regain
onset and is caused by an obvious stressful
control over their sleep. Paradoxically, this
event. The sleep disturbance is expected to
intention further stimulates arousal
be of short duration (not longer than
mechanisms and impedes mental relaxation
3 months), and usually remits with the
that is needed to fall asleep. From a
disappearance of the precipitating factor.
physiological point of view, excessive
attempts to obtain sleep are associated with Psychophysiological insomnia is the
increased somatised tension, e.g. increased prototype of insomnia that is maintained by
muscular tone. Frustration and anxiety when the influence of perpetuating factors, i.e.
lying awake are typical emotional hyperarousal and learnt maladaptive
expressions of heightened arousal in behaviour. Wakefulness is promoted by
insomnia. The recurrent problem of negative anticipation, muscle tension,
disturbed sleep leads the insomnia patient frustration and ruminating thoughts. Indivi-
into a vicious spiral, sustained by duals are typically preoccupied about sleep
conditioned hyperarousal, dysfunctional difficulties and their adverse consequences
beliefs about sleep and learnt maladaptive on performance during the daytime.
behaviour, as a consequence of which sleep
is further disabled. Paradoxical insomnia refers to a complaint
of severe insomnia that is not on a par with
In a time-honoured model explaining the objective evidence of sleep disturbance.
dynamic development of insomnia over Typically, patients claim to have been awake

Perpetuating
Precipitating
Predisposing
Insomnia intensity %
0
Pre-morbid Acute insomnia Early insomnia Chronic insomnia
Figure 1. The Spielman model or 3P model of insomnia (see text for explanation). The threshold line
delineates the level above which insomnia is severe enough to become a prominent complaint. AU:
arbitrary units. Reproduced from Spielman et al. (1991), with permission from the publisher.
for most of the night, while PSG shows little arousal or directly interfere with sleep.
or no abnormalities in the hypnogram. Common examples are irregular sleep/wake
Formerly, this condition was known as sleep scheduling, use of nicotine or caffeine or
state misperception. It is currently unknown engaging in activities that are not conducive
whether the complaint is based on the to sleep (working on the computer, watching
patient’s inadequate awareness of being exciting movies, etc.).
asleep, or whether there is an, as yet,
unidentified intrinsic disturbance of sleep. Insomnia due to a drug or substance
Because the suspicion of unawareness may implies an inappropriate use of prescription
compromise the patient’s credibility, the medicine, recreational or illicit drugs.
term misperception is no longer used. Typically, the insomnia will remit following
discontinuation of the substance.
Idiopathic insomnia is diagnosed when the
inability to sleep persists from early life and Insomnia due to a medical condition is a
no major periods of spontaneous sustained term used in the context of a comorbid
remission have occurred. Idiopathic insomnia medical disorder. Although complaints
is a prototype of a sleep disturbance that is about sleep are often present in various
due to predisposition (constitutional factors), medical conditions, this diagnosis is
with little or no contribution of precipitating restricted to patients in whom insomnia is
or perpetuating factors. caused by the medical disorder and is
associated with significant distress that
Insomnia due to mental disorder refers to requires specific medical care.
sleeplessness that occurs in the course of a
psychiatric disease. This insomnia is Insomnia that is not related to substance
thought to be caused by that disease and is abuse or known physiological conditions
severe enough to cause distress and to (nonorganic insomnia) or that is related to
warrant special treatment. unspecified physiological conditions
(organic insomnia) are the last entities of
A diagnosis of inadequate sleep hygiene is the ICSD-2 insomnia classification. These
made when voluntary behaviour impairs diagnoses are typically used when further
adequate sleep. Such activities may induce assessment is required to identify

particular disease contexts, or when the defined by cut-off criteria, indicators for
patient doesn’t meet the criteria for a relevant insomnia are an average sleep
specific sleep disorder. latency exceeding 30 min, wake after sleep
onset exceeding 30 min, sleep efficiency
Assessment of insomnia ,85%, and/or total sleep time ,6.5 hours.
Fourth, nocturnal symptoms and behaviours
The evaluation of insomnia is founded on are reviewed. The bed partner should be
classical clinical principles, including a involved in this part of the history, as the
detailed patient history and examination, with patient may be unaware of the issues. Such
special attention to the sleep and waking information may be useful to further
functions. In addition, an inventory is made of document the factors associated with
current medical, psychiatric and medication- insomnia (e.g. anxiety), but also to discover
or substance-related comorbidities. symptoms that may point to co-existent
Additional technical investigations may be primary sleep disorders (e.g. SDB and
performed where appropriate. parasomnias). Finally, questions on daytime
performance should be asked. The answers
First, the primary complaint is addressed. may provide clues to potential causes and
Attention is paid to the type of sleep consequences of insomnia. Information
disturbance, whether DIS, DMS, early should be obtained on fatigue, somnolence,
awakening or NRS. Although the complaint napping, work schedules and
may be limited to only one of these circumstances, coping with work, coping
symptoms, a combination of symptoms is with social life, lifestyle, quality of life, mood,
often extant and the complexity of the cognitive function and mutual influence
clinical presentation may change over time. between insomnia and comorbid disorders.
Details about the various features of
insomnia must be carefully noted. Past and The sleep history is complemented with a
current issues that precipitate or perpetuate general medical and psychiatric history and
insomnia are inquired, as well as previous a record of currently used drugs and
therapies and the responses to treatment. substances. A general physical examination
Second, the circumstances and activities of is carried out. In the further workup, the use
the pre-sleep period are scrutinised. Sleep- of specific questionnaires for sleep quality,
incompatible activities such as watching TV, insomnia, sleepiness, psychological
computer use, eating in bed, etc. are assessment and quality of life should be
documented. Elements of the sleeping considered. The use of a 2-week sleep/wake
environment that are favourable or adverse diary (fig. 2) is standard. It is an excellent
to sleep must be identified. Also, knowing means to supplement the oral history and to
the state of mind with respect to being characterise the different insomnia
relaxed versus aroused at bedtime is helpful components (complaint type, duration,
in understanding the situational intricacies frequency, severity, daytime dysfunction,
that affect sleep. Third, the day-to-day effects of consuming food, beverages,
variability of insomnia, the extreme natural stimulants and hypnotic
differences between good and bad nights medication). Moreover, the sleep/wake diary
and the evolution over time are important may disclose circadian rhythm sleep
variables that must be recorded. Sleep disorders that are co-existent with, or that
latency, number of awakenings, wakefulness exclude, the diagnosis of insomnia.
after sleep onset, total sleep duration and Actigraphy for a period of 2–4 weeks may
taking naps during the daytime are variables be indicated when the information from
that can be assessed on average by taking a the sleep/wake diary is doubtful or
retrospective history. To obtain an incomplete. Laboratory testing and PSG are
approximation of the nightly variability of not routinely indicated in the evaluation of
these parameters, a prospective assessment insomnia but may be appropriate in patients
with sleep/wake diaries should be carried in whom comorbid medical or sleep
out. Although insomnia disorder is not disorders are suspected.

Figure 2. The sleep/wake diary should be recorded during a period of at least 2 weeks. This figure shows a
1-week log. For each day, the following variables are derived from the diary: bedtime, sleep latency (time to
fall asleep following bedtime; hatched bars), awakenings and duration of each awakening (hatched bars),
periods of sleep with duration (black bars), time out of bed and duration (empty bars), wakefulness after
sleep onset (the sum of all awakenings and time out of bed), time in bed (time from bedtime to getting
out of bed), total sleep time (time in bed minus (sleep latency plus wakefulness after sleep onset)), sleep
efficiency (total sleep time divided by time in bed, expressed as a percentage), time out of bed, nap times
(frequency, times and durations). The diary may also include reports of perceived sleep quality, daytime
functioning, medications, and caffeine and alcohol consumption for each 24-hour period.
Management of insomnia evidence points out that these two disorders

co-occur in a substantial number of
The multifactorial mechanisms involved in patients. Insomnia and SDB show a high
the initiation and maintenance of insomnia prevalence in the general population and are
have provided the connecting points for the the two most common sleep disorders.
multimodal treatment methods that have Because of inconsistencies in assessment
emerged in recent decades. The different techniques, target populations and study
treatment modalities are based on design, reliable epidemiological figures on
pharmacological and nonpharmacological the combined occurrence of insomnia and
interventions. A comprehensive review of SDB are not available. From the existing
insomnia treatment is included in Module 6. data, it is estimated that 39–58% of patients
Special interest for the respiratory sleep with an established SDB diagnosis also
physician: insomnia as a comorbid suffer from insomnia, and, conversely, 29–
condition in SDB 67% of insomnia patients have an AHI
exceeding 5 events?h-1. Data regarding the
While the relationship between insomnia influence of age and sex on the combined
and SDB (mostly OSA) has received little appearance of these conditions are
attention in the medical literature, recent conflicting.

In fact, SDB and insomnia are dissimilar each of the constituent conditions.
from a clinical and pathophysiological point Increased levels of sleep deprivation may in
of view. From a clinical perspective, these return contribute to increased upper airway
disorders can be modelled as paradoxical collapsibility, thus inducing a higher number
(orthogonal) conditions because insomnia of respiratory events. There may be a role for
is associated with increased arousal and sympathetic, metabolic and neuro-
alertness, whereas in SDB excessive daytime endocrine mechanisms that typically take
sleepiness is the most characteristic feature. effect in SDB, to also induce or aggravate
It could be plausible that both disorders are insomnia disorders. In summary, reciprocal
unrelated to each other and, given the high feedback mechanisms could be operational
prevalence, their co-occurrence is due to in the co-occurrent SDB–insomnia situation,
coincidence. This would imply that insomnia thus explaining the detrimental additions to
and SDB should be managed separately. the clinical profile.
Recent studies, however, shed a different To assess the diverse clinical dimensions of
light on the SDB–insomnia relationship. It SDB-plus, a careful diagnostic approach is
appears that the co-occurrence of both needed. PSG, which is not routinely
disorders brings about additive negative recommended for the assessment of
effects in terms of increased insomnia, is mandatory in SDB-plus
symptomatology. The situation in which patients to demonstrate the combination of
symptoms of SDB are aggravated by the SDB and reduced total sleep time. PSG will
co-existence of insomnia is referred to, at clearly show the patterns of DIS and DMS in
least by some authors, as ‘‘SDB-plus’’. The the hypnogram. Polygraphy (PG), lacking
clinical presentation is actually worse than neurophysiological leads, is obviously an
what can be expected from the single unsuitable method to assess the features of
contribution of each individual disorder. insomnia. Moreover, the AHI will be
Additional negative effects are underestimated with PG, because
demonstrated with respect to subjective wakefulness is not taken into account. The
sleep quality, sleep consolidation and total diagnosis of insomnia should be made
sleep time. While DIS may be present, DMS appropriately, in line with the assessment
seems to be more problematic. techniques described previously. This
Furthermore, these patients suffer from implies the mastering by the managing
greater functional impairment during the physician of pertinent knowledge and skills
daytime. Sleepiness and neurocognitive that extend beyond the limits of the
functions are worse and there are higher respiratory sleep domain. Finally, the
levels of mood disturbance. SDB-plus importance of an integrated,
patients also endure more worrying and interdisciplinary approach to SDB-plus must
dysfunctional beliefs about sleep, including be emphasised.
negative anticipation towards health
consequences in the long term.
Further reading
Whether SDB intensifies pathogenetic
N American Academy of Sleep Medicine.
factors of insomnia, and vice versa, is
(2005). The International Classification of
currently unknown. However, insomnia and
Sleep Disorders. 2nd Edn. American
SDB share arousal from sleep as a common Academy of Sleep Medicine, Westchester.
feature in their respective N Bonnet MH, et al. (2010). Hyperarousal
pathophysiologies. In SDB, short arousals and insomnia: state of the science. Sleep
terminate episodes of obstructed breathing, Med Rev; 14: 9–15.
whereas insomnia is characterised by longer N Luyster FS, et al. (2010). Comorbid
periods of awakening from sleep. It may be insomnia and obstructive sleep apnea:
hypothesised that co-occurrence of challenges for clinical practice and
insomnia and SDB may influence the research. J Clin Sleep Med; 6: 196–204.
predominant arousal patterns that occur in

N Morin CM, et al. (2003). Insomnia: a N Schutte-Rodin S, et al. (2008). Clinical
clinical guide to assessment and treat- guideline for the evaluation and manage-
ment. 1st Edn. New York, Kluwer ment of chronic insomnia in adults. J Clin
Academic/Plenum Publishers. Sleep Med; 4: 487–504.
N Riemann D, et al. (2010). The hyperar- N SpielmanAJ,etal.(1991).Thevariednature of
ousal model of insomnia: a review of the insomnia. In: Hauri PJ, ed. Case studies of
concept and its evidence. Sleep Med Rev; insomnia. New York, Plenum Press; pp. 1–15.
14: 19–31. N Stone KC, et al. (2008). Nonrestorative
N Roth T. (2007). Insomnia: defini- sleep. Sleep Med Rev; 12: 275–288.
tion, prevalence, etiology, and con- N Wickwire EM, et al. (2010). Insomnia and
sequences. J Clin Sleep Med; 3: Suppl. 5, sleep-related breathing disorders. Chest;
S7–S10. 137: 1449–1463.

Parasomnia and movement
disorders during sleep
Renata L. Riha
Parasomnias are disorders resulting in A number of factors can trigger parasomnias

abnormal events during the night such as or increase the frequency of occurrence,
sleepwalking, sleep terrors and bruxism. including: fever, alcohol, sleep deprivation,
They can be divided into primary physical activity, emotional stress and
parasomnias, arising directly from sleep and medications. Parasomnias can also be
specific to a particular stage of sleep, and worsened by pregnancy and menstruation
secondary parasomnias, which arise from as well as SDB. There is often an interaction
pathology arising during sleep, such as between genetic and environmental factors
nocturnal epilepsy, nocturnal leg cramps to cause these problems. Bizarre sleep-
and sudden cardiac death. related activities can occur in the general
population with no underlying comorbidities
Primary parasomnias can arise from either or known predisposition to parasomnias
REM or NREM sleep but some are not and usually do not warrant further
confined to any particular sleep stage. investigation or treatment. However,
medical advice should be sought if
Table 1 lists what are considered to be behaviours are potentially violent/injurious
normal events during NREM and REM (forensic cases too), extremely disruptive to
sleep, generally requiring only reassurance, household or family, result in complaints of
and also lists abnormal events arising excessive daytime sleepiness or are
during these sleep stages, which may associated with medical, psychiatric or
require further investigation and that are neurological symptoms and signs.
considered to be potentially more disruptive.
When diagnosing parasomnias, a history of
Other primary parasomnias include the behaviour is taken and it is helpful if bed
nocturnal groaning (catathrenia), bruxism, partners or witnesses to the behaviour are
enuresis, rhythmic rocking movement also present. PSG with video recording with
disorder, sleep talking and sleep eating. extended montage may be useful. Events do
These parasomnias can occur throughout all not always occur on the night of the study,
sleep stages. which may thus need to be repeated.
Telemetry over a number of nights may be
useful in conditions more diagnostically
Key points challenging, including frontal lobe epilepsy.
Referral to a specialised sleep centre is
N Parasomnias occur commonly. advisable in less clear-cut cases as well as in
forensic cases, particularly in respect of
N Abnormal nocturnal behaviour can accurate diagnosis.
arise out of NREM or REM sleep.
REM-related disorders
N Complex or difficult cases require
specialist investigation and Of the REM-related parasomnias, the most
management. important diagnostically is REM behaviour
disorder (RBD).

Table 1. Normal and abnormal events during NREM and REM sleep.
NREM sleep REM sleep
Normal events Normal events
Sleep starts (hypnic myoclonus) Hypnagogic/hypnopompic hallucinations
Exploding head syndrome Sleep paralysis
Explosive tinnitus
Abnormal events Abnormal events
Confusional arousals Dream anxiety attacks (nightmares)
Excessive fragmentary myoclonus REM behaviour disorder
Sleep-related eating disorder REM-related painful erections
Sleep sex
Sleep terrors
Sleepwalking
Classification RBD was first described by in Western populations (Frauscher et al.,

Schenck et al. (1986), and is classified as 2010). RBD occurs in both sexes, with the
idiopathic or secondary. The existence of majority of patients presenting with the
idiopathic RBD is currently under debate, disease after the age of 50 yrs. It is
but it has been used by sleep specialists to characterised by abnormal and often violent
describe RBD not associated with, or behaviours emerging during REM sleep,
preceding, other disorders. Secondary RBD usually in the context of dream mentation.
can be related to neurodegenerative Behaviours can include talking, punching,
disorders and tauopathies such as kicking, flinging or hitting out and can result
Alzheimer’s disease, corticobasilar in involuntary self-harm or harm to a bed
degeneration and progressive supranuclear partner. Between 33% and 65% of RBD
palsy; other neurological disorders such as patients have reported a sleep-related injury,
Guillain–Barré syndrome, stroke and spino- ranging from bruises to subdural
cerebellar ataxia; sleep disorders such as haematomas (Boeve, 2010). The violence in
narcolepsy; medications such as selective RBD relies on proximity of physical contact
serotonin re-uptake inhibitor and can be directed inadvertently at a bed
antidepressants and b-blockers; and partner in the context of the dream.
withdrawal states from alcohol or drugs of Diagnosis RBD is diagnosed from a
abuse. However, secondary RBD is most suggestive history and supportive PSG. The
closely associated with a-synucleinopathies. diagnostic features on PSG comprise loss of
Longitudinal follow up of RBD patients has normal EMG atonia characterised by
shown that 38–65% develop a sustained muscle activity during REM sleep
synucleinopathy between 10 and 29 yrs from and excessive transient muscle activity in
diagnosis. The most frequent either the chin or limb EMG. Use of video
synucleinopathy is Parkinson’s disease (PD) during PSG recording is helpful in recording
but Lewy body disease (LBD) and multi- any behaviour.
system atrophy (MSA) may also occur.
Likewise, 70% of patients with MSA, 40% of Pathophysiology The pathophysiology of
patients with LBD and 15–33% of patients RBD is unknown, but is being extensively
with PD will have RBD. Patients should be researched using human and animal
appraised of the link between disorders. models. Therapeutic approaches have thus
focused on symptomatic treatment of the
Prevalence and presenting features RDB is disorder, with the primary aim being to
thought to have a prevalence of 0.38–0.5% minimise sleep disruption and prevent

violent behaviour that may result in Dreamlike mentations can occur during
significant harm. sleepwalking and sleep terrors in adults that
do not require significant executive
Management Apart from modifying the functioning of the frontal cortex. Current
bedroom environment (Level A evidence), opinion suggests that disorders of arousal
the two most frequently recommended
are triggered largely by physiological
treatments for RBD comprise clonazepam
changes occurring during the arousal state
and melatonin. Clonazepam is considered
rather than by any dream activity preceding
the treatment of choice by clinicians for
the state per se.
patients with RBD irrespective of
comorbidities. However, clonazepam does Only one case report exists of an imaging
not work in all patients with RBD and can session in a sleepwalker, which showed the
cause unacceptable side-effects that include posterior cingulate cortex (part of the
excessive daytime somnolence, excessive emotional processing network) and the
muscle relaxation in the elderly, poor sleep anterior cerebellum being activated during
quality, cognitive impairment, depressed sleepwalking (Bassetti et al., 2000).
mood and worsening of concurrent sleep
apnoea. A recent randomised, controlled The most common psychiatric disorders
trial has shown that melatonin is also associated with sleep disorders are
effective in RBD (Kunz et al., 2010). Apart depression and anxiety with comorbid mood
from clonazepam and melatonin, there is disorders found in 30.4 % of night terrors
little evidence to support the use of other and 14.6 % of sleepwalkers (Mahowald
medications. Referral to a specialist sleep et al., 2005).
service is recommended for diagnosis and
management advice. Sleepwalking (somnambulism) Sleepwalking
consists of a series of complex behaviours
Non-REM-related disorders that are initiated in slow-wave sleep and
result in walking during sleep. The
The focus in this section is on disorders behaviour may terminate spontaneously or
of arousal arising out of slow-wave sleep.
the sleepwalker may return to bed.
They are among the most frequently
Occasionally, there is also inappropriate
encountered parasomnias.
behaviour such as smoking, cooking and
Classification and epidemiology Parasomnias preparing food. Falls and injuries may occur
arising from slow-wave sleep are classified if walking into dangerous situations, e.g. out
in the International Classification of Sleep of the door onto the street. Rarely,
Disorders, 2nd Edition (ICSD2) as arousal aggressive behaviour occurs, often as a
disorders. Disorders that fall under this response to attempts to restrict the
subheading include: sleepwalking, sleepwalker’s mobility; homicide or suicide
confusional arousals, sleep terrors, sleep- has been reported. Sleepwalking occurs
related eating disorder and sexsomnia. always or often in 1–3% of children and
Arousal disorders occur in up to 20% of occasionally in 6–29% of children. It will
children and up to 4% of adults (Hublin usually disappear after adolescence. In
et al., 2003). Confusional arousals, adults, sleepwalking occurs always or often
sleepwalking and sexsomnias have all been in 0.1–0.6% and occasionally in 0.9–3% of
associated with forensic behaviour. Sleep the population. Sleepwalking is hereditary
talking can occur throughout all stages of and about 85% of adult sleepwalkers
sleep. sleepwalked in childhood.
Pathophysiology There is often a strong Night terrors Night terrors are characterised
family history suggesting a genetic by a sudden arousal from slow-wave sleep
predisposition. Arousal disorders can be with a piercing scream or cry, accompanied
exacerbated by alcohol, sleep fragmentation by manifestations of intense fear. The attack
and co-occurrence with other sleep usually resolves spontaneously. Night
disorders (namely sleep apnoea). terrors occur always or often in 3% of

children and occasionally in 3.5–15% of common and can co-exist with or even
children. They usually resolve during mimic sleep disorders. Sleep deprivation
adolescence and less than 1% of adults can increase the incidence of seizure activity
experience them. and, conversely, seizures can affect the
sleep/wake cycle.
Diagnosis Arousal disorders are diagnosed
from a suggestive history and supportive There is increasing evidence that OSA
PSG. Use of video during PSG recording is co-exists in epilepsy: in 10% of unselected
helpful in recording any behavioural adults with epilepsy, 20% of children with
manifestations of the disorder and multiple epilepsy and 30% of drug-resistant epilepsy
night studies may be necessary. Extended patients. Seizures and parasomnias can co-
PSG montage is recommended to exclude exist in the same patients. Arousal disorders
nocturnal seizures, dissociation and other can co-exist with frontal lobe epilepsy,
parasomnias. Collateral history from a bed making diagnosis difficult. Nocturnal frontal
partner, household member and family lobe epilepsy, which can occur exclusively in
member is important. A family history of sleep, manifests with bizarre/dramatic
arousal disorders should always be asked behaviours, which if not recognised (often
about. Attention should also be paid to any the EEG is unhelpful) can make treatment
potential aggravating factors for the behaviour. and management difficult (Derry et al., 2009).
Management If the behaviours occur RBD has been documented as a comorbidity
infrequently, then no specific treatment is in up to 12% of elderly epilepsy patients.
usually necessary apart from simple safety
precautions in the bedroom and house. If Management A careful history with
the behaviours are disrupting relationships, collateral allows for differentiation of
potentially dangerous, or occur very possible diagnoses. This should be followed
frequently, then a number of medications by video-PSG employing a full scalp
can be trialled. Clonazepam and the montage. Multiple studies may be necessary
benzodiazepine class of drugs are generally if events are infrequent and sometimes
first line, followed by tricyclic antidepressants. continuous video-EEG telemetry may be
Psychotherapy, progressive relaxation, necessary. Treatment regimens are variable
hypnosis and cognitive behavioural therapy and related to the type of seizure disorder
are often employed in long-term management encountered. Referral to a specialist sleep
with less drug-responsive cases, or those unit with experience in epileptology is
particularly associated with stress etc. Referral recommended to establish diagnosis and
to a specialist sleep unit is recommended in assist with management.
more difficult cases to establish diagnosis
and assist with management. Periodic leg movement disorder and
‘restless legs’ syndrome
Nocturnal seizures
Restless legs syndrome (RLS) is a
After stroke and Alzheimer’s disease, sensorimotor-related sleep disorder, highly
epilepsy is one of the most commonly prevalent but potentially under-recognised
occurring neurological conditions in throughout the world.
industrialised countries.
RLS is an unpleasant sensation in the legs,
Epilepsy is the term applied to a number of but can also affect the arms, occurring during
seizure disorders which are characterised by the day but usually worsening at night.
abnormal, uncontrolled electrical discharges
in the brain manifesting as motor, verbal or Diagnosis The essential diagnostic criteria
experiential phenomena, which are for RLS were established in 2002 by the
undesirable and often harmful. International RLS Study Group (IRLSSG)
and comprise the following: 1) an urge to
The importance of epilepsy in the context of move the legs, often accompanied by an
sleep medicine is the recognition that it is unpleasant sensation in the legs or other

body parts; 2) symptoms aggravated by rest; dorsiflexion of the ankle with occasional
3) symptoms alleviated by movement; and 4) flexions of the knee and hip. Periodic limb
symptoms worse in the evening or night with movements are scored only if they are part
an urge to move the legs, usually of a series of four or more consecutive
accompanied by an unpleasant sensation in movements lasting 0.5–5 s with an interval
the legs (other body parts may be involved, in of 4–90 s. A periodic limb movement index
addition to the legs). The differential of greater than 5 per hour is considered
diagnosis includes periodic limb movement abnormal but the significance outwith
disorder, positional discomfort at night, symptoms of RLS is debatable.
nocturnal leg cramps, arthritis, akathisia, and
peripheral neuropathy and anxiety disorders. RLS can be very difficult to treat,
augmentation of symptoms can occur as
Classification and epidemiology RLS is well as tachyphylaxis, requiring alteration of
classified into two main types: 1) primary drug regimens. A combination of
RLS, which usually occurs earlier in life with pharmacological treatments is often a useful
a peak incidence at age 20 yrs, having a strategy. Dopamine agonists are the
strong genetic component (40–60% of all treatment of choice. Benzodiazepines,
patients with RLS have a positive family anticonvulsants, dopaminergic agents,
history); 2) secondary RLS, which develops bupropion and folate and iron
later in life and is associated with a medical supplementation can also be effective.
disorder, such as diabetes mellitus and iron- Nonpharmacological methods such as
deficiency anaemia. The general population lifestyle changes are potentially useful
prevalence of RLS ranges from 1–15%. Most adjuncts, e.g. cessation of caffeine intake.
RLS studies, including the large genetic
studies, do not have PSG confirmation of
RLS (manifested by periodic limb movements) Further reading
and bias is inherent in changes in diagnostic
criteria over the years (Yeh et al., 2011). N Aurora RN, et al. (2010). Best practice
guide for the treatment of REM sleep
Pathophysiology There is strong evidence for behavior disorder (RBD). J Clin Sleep
a genetic component in primary RLS. Several Med; 6: 85–95.
large genome-wide association studies have N Bassetti C, et al. (2000). SPECT during
shown an increased frequency of various sleepwalking. Lancet; 356: 484–485.
susceptibility loci which, however, have not N Boeve BF. (2010). REM sleep behavior
been confirmed to be of functional disorder: updated review of the core
significance to date. Some evidence points features, the REM sleep behavior
disorder-neurodegenerative disease asso-
to dopaminergic mechanisms and potential
ciation, evolving concepts, controversies,
central nervous system iron deficiency. Risk
and future directions. Ann N Y Acad Sci;
factors for development of RLS include: 1184: 15–54.
pregnancy, low iron levels, poor overall N Derry CP, et al. (2009). NREM arousal
health, increased age, PD and end-stage parasomnias and their distinction from
renal disease. nocturnal frontal lobe epilepsy: a video
EEG analysis. Sleep; 32: 1637–1644.
Management Sleep studies are not always
N Hublin C, et al. (2003). Genetic aspects
necessary if the history is clear. Full iron
and genetic epidemiology of parasom-
studies should always be performed. nias. Sleep Med Rev; 7: 413–421.
Maintaining a ferritin level of .50 mg?L-1 N American Academy of Sleep Medicine.
may abate symptoms secondary to iron (2005). International Classification of
deficiency. Severity of symptoms can be Sleep Disorders. 2nd Edn. Westchester,
assessed using the IRLSSG rating scale (10- American Academy of Sleep Medicine.
point scale). If PSG is performed, patients N Kemlink D, et al. (2009). Replication of
are found to have an elevated periodic limb restless legs syndrome loci in three Euro-
movement index. Periodic limb movements pean populations. J Med Genet; 46: 315–318.
are rhythmic extensions of the big toe and

N Kunz D, et al. (2010). A two-part, double- N Oudiette D, et al. (2009). Dreamlike
blind, placebo-controlled trial of exogen- mentations during sleepwalking and sleep
ous melatonin in REM sleep behaviour terrors in adults. Sleep; 32: 1621–1627.
disorder. J Sleep Res; 19: 591–596. N Siclari F, et al. (2010). Violence in sleep.
N Mahowald MW, et al. (2007). Pathophy-
Brain; 133: 3494–3509.
siologic mechanisms in REM sleep beha-
vior disorder. Curr Neurol Neurosci Rep; 7: N Yeh P, et al. (2011). Restless legs
167–172. syndrome: a comprehensive overview on
N Manni R, et al. (2010). Comorbidity its epidemiology, risk factors, and treat-
between epilepsy and sleep disorders. ment. Sleep Breath; [Epub ahead of print
Epilepsy Res; 90: 171–177. doi: 10.1007/s11325-011-0606-x].

Hypersomnia
Renata L. Riha
Hypersomnias of central origin comprise a Narcolepsy can exist either with or without
number of entities which are listed in cataplexy, or as a consequence of a medical
table 1. The best studied, and in some condition (secondary narcolepsy) (table 3).
respects defined, primary hypersomnia is
narcolepsy with or without cataplexy. Cataplexy is virtually pathognomonic of the
Secondary causes for hypersomnia should disease, with all voluntary skeletal muscles
always be excluded prior to making a being affected. However, presentation can
diagnosis of primary hypersomnia, which range from only slight weakness of the arms,
includes narcolepsy with or without legs or facial muscles to severe episodes of
cataplexy, recurrent hypersomnia, Kleine– weakness. Most patients will be aware of
Levin syndrome and idiopathic symptom onset and can generally adopt a
hypersomnia. Psychiatric and organic safe posture at the onset of the attack,
disorders, including head injury, can also making injury rare. Other features of
lead to excessive daytime sleepiness. With narcolepsy to be aware of, in addition to
rare disorders, referral to a specialised sleep those listed in table 2, are an increased
clinic for confirmation of diagnosis and tendency of developing REM behaviour
management advice is always advisable. disorders (RBD): an association is seen in
7–36% of patients and is higher in patients
Narcolepsy with cataplexy (Nightingale et al., 2005).
Presenting features The term narcolepsy was Pathogenesis A canine model for narcolepsy
first used in 1880 by Dr Jean-Baptiste- was first described in 1973 and has been
Edouard Gélineau, to describe a patient with used in narcolepsy research subsequently.
sleep attacks, excessive daytime sleepiness In Doberman Pinschers and Labrador
and episodes of muscle weakness triggered Retrievers, the condition is autosomal
by emotions. Table 2 outlines the classical recessive with complete penetrance. This
symptoms of narcolepsy. observation led to the discovery of a
mutation in the gene coding for the
Narcolepsy has a prevalence of 25–50 per hypocretin-2 receptor, suggesting that
100,000 people with no sex preponderance. hypocretin may be involved in the disease
The age of onset is variable, from early pathogenesis (Lin et al., 1999).
childhood to mid-50s. Epidemiological
studies have shown two peaks of onset at Hypocretin Hypocretins (also known as
ages 15 and 36 yrs (Longstreth et al., 2007). orexins) were described only in 1998 (de
It is often unrecognised and many patients Lecea et al., 1998). Two forms of hypocretin
may be labelled with other neurological or are currently known to exist (hypocretin-1
psychiatric disorders before a diagnosis is and -2), produced by a specific set of
made, causing a delay in diagnosis of up to neurons in the lateral hypothalamus that
6 yrs from the onset of symptoms project to the olfactory bulb, cortex,
(Longstreth et al., 2007). thalamus, hypothalamus and parts of the

Table 1. Hypersomnias of central origin (ICSD II classification).
Primary hypersomnias Secondary hypersomnias
Narcolepsy with cataplexy Narcolepsy due to medical conditions e.g. head
injury
Narcolepsy without cataplexy Menstruation-related hypersomnia
Idiopathic hypersomnia with long sleep time Behaviourally-induced insufficient sleep
syndrome
Idiopathic hypersomnia without long sleep Hypersomnia due to medical condition, drug or
time substance
Recurrent hypersomnia Physiological (organic) hypersomnia, not
otherwise specified
Kleine–Levin syndrome (males
predominantly)
Hypersomnia not due to substance or known
physiological condition
brainstem. Projections in the brainstem, to with narcolepsy with cataplexy, but is only
the laterodorsal and pedunculopontine present in 40% with narcolepsy alone
tegmental nuclei, and pontine reticular (Mignot, 1998). The clinical relevance of
formations are considered important for these abnormalities is unclear, with variable
sleep regulation. Recent studies suggest associations between ethnic groups and
that hypocretin is important to maintain subtypes of narcolepsy. The evidence for an
vigilance, by exerting excitatory effects on autoimmune process is currently not
the monoaminergic and cholinergic systems definite, although case reports of narcolepsy
in the cortex and hypothalamus (Tsujino commencing after streptococcal infections
et al., 2009). An imbalance in both of these or vaccinations are highly suggestive.
systems may lead to narcolepsy. Both
animal and human studies have supported The pathogenesis of cataplexy remains
this hypothesis. Cerebrospinal fluid (CSF) unclear at the present time.
studies of patients with narcolepsy show low Diagnosis Although sleepiness is difficult to
or undetectable levels of hypocretin, and define objectively, a clear history of
post mortem studies have identified subjective sleepiness with an eyewitness
hypocretin-ligand deficiency in the where possible (for the cataplexy), will
narcoleptic brain (Peyron et al., 2000). In greatly assist with diagnosis.
addition, patients with narcolepsy
demonstrate reductions in their baseline A note of caution! Many cases have been
energy homeostasis with resulting obesity described of non-organic, or ‘‘pseudo’’
and type-II diabetes mellitus, both partly narcolepsy, often in association with
regulated by hypocretin (Nishino et al., drug-seeking behaviour. The International
2001). This suggests that the metabolic Classification of Sleep Disorders 2nd
changes are directly linked to the Edition (ICSD2) criteria suggest that
pathophysiology of the condition, rather narcolepsy with cataplexy ‘‘should, wherever
than being related to excessive sleepiness possible’’ be confirmed with PSG and
or inactivity. MSLTs. In the absence of cataplexy, a PSG
and MSLT are mandatory to confirm the
One important clinical marker for diagnosis of narcolepsy.
narcolepsy is the presence of altered human
leukocyte antigen (HLA) gene complexes. Recent guidelines (Littner et al., 2005;
For example, one specific marker (HLA Billiard et al., 2006) support the use of
DQB1*0602) is found in 90% of patients objective and subjective monitoring of sleep

Table 2. Diagnostic criteria for narcolepsy with cataplexy#.
Symptoms present for at least 3 months
Excessive daytime sleepiness
Repeated naps or lapses into sleep of short duration (,1 h) occurring almost daily
Refreshing sleep with recurrent sleepiness within 1–2 h
Sleep attacks in socially unacceptable situations
History of cataplexy
Sudden loss of muscle tone provoked by strong emotion
Short duration lasting seconds to minutes
Immediate and complete recovery
No impairment of consciousness or memory and no respiratory or ocular muscle involvement
Associated features (not always present)
Sleep paralysis
Hypnagogic hallucinations
Automatic behaviour
Nocturnal sleep disruption
Hypersomnia not explained by another sleep disorder, psychiatric disorder or medical illness
Investigations
PSG and MSLT results: mean sleep latency of f8 min with o2 SOREMPs following at least
6 h of sleep prior to the test
CSF hypocretin-1 levels f110 ng?L-1, or less than one-third reference range
SOREMPs: sleep onset in REM periods; CSF: cerebrospinal fluid. #: adapted from ICSD-2.
duration at least 1 week prior to in-lab Overnight PSG may demonstrate features
investigation (using sleep diary and consistent with narcolepsy, including short
actigraphy), followed by an overnight PSG REM latency, sleep fragmentation,
prior to daytime testing using the MSLT. increased stage 1 sleep and excessive slow-
Sleep deprivation and medications can wave sleep towards the end of the night.
adversely influence the outcome of the MSLT. Urinalysis for drugs commonly abused is
also helpful, as these drugs can also
Table 3. Common causes of secondary narcolepsy. influence the outcome of the MSLT and
overnight PSG.
Lesions affecting the hypothalamus
Head trauma On the MSLT, a sleep latency ,8 min with
two sleep onset in REM periods (SOREMPs)
Multiple sclerosis
(REM periods within 15 min of sleep onset)
Myotonic dystrophy is considered to be consistent with
Parkinson’s disease narcolepsy (fig. 1) (Billiard et al., 2006).
Prader–Willi syndrome However, recent studies have shown that
15% of cataplexy patients will not have
Paraneoplastic encephalitis
SOREMPs or shortened sleep latency on
Niemann–Pick type C disease MSLT (effectively a negative test) (Mignot
Sarcoidosis et al., 2002), while patients with OSA may
Coffin–Lowry syndrome present with MSLT data that is consistent
with narcolepsy (Aldrich et al., 1997).

REM
W
1
2
3
4
Nap 1 09:22:35 09:43:05
REM
W
1
2
3
4
Nap 2 11:18:05 11:38:35
REM
W
1
2
3
4
Nap 3 13:21:35 13:42:05
REM
W
1
2
3
4
Nap 4 15:19:35 15:40:05
Figure 1. MSLT showing four sleep onset REM periods with a multiple sleep latency of 0.8 min. Black:
REM sleep; green: N2 sleep; yellow: N1 sleep.
HLA DQB1*0602 analysis can also be Management Stimulants remain the

undertaken despite its low specificity cornerstone for treating the excessive
(Dauvilliers et al., 2007). CSF hypocretin daytime sleepiness of narcolepsy and are
levels can also be checked; low CSF summarised in table 4. Although there is
hypocretin levels (,110 pg?mL-1 or one-third little evidence supporting their use,
of the mean control value) are consistent antidepressants are used for the treatment
with narcolepsy. CSF hypocretin levels are of cataplexy. In recent trials, sodium oxybate
never this low in patients without narcolepsy has also been shown to improve cataplexy in
and cataplexy (Dauvilliers et al., 2007). some patients.
Cataplexy cannot at present be measured Importantly, all anti-narcolepsy medications,
objectively and the diagnosis is largely while improving the symptoms of sleepiness
based on eyewitness history. Unfortunately, do not necessarily return the patient to full
narcolepsy without cataplexy often does not and sustained alertness.
have hypocretin deficiency and this can
confuse the diagnosis (Dauvilliers et al., Scheduled naps to maintain wakefulness are
2003). Other causes of hypersomnia should often promulgated as a form of treatment,
be considered, including OSAS, idiopathic but reviews suggest that this has only
hypersomnia, recurrent hypersomnia, limited use in patients who remain sleepy
insufficient sleep syndrome and despite stimulants (Wise et al., 2007). If
hypersomnia associated with depression. tolerance develops, a drug holiday with

Table 4. Commonly prescribed treatment for narcolepsy and cataplexy.
Pharmacological compound Proposed mode of action
Stimulants
Amphetamine Increases monoamine release (dopamine,
noradrenaline, serotonin); blocks monoamine
re-uptake and monoamine oxidase at high
doses
Methylphenidate Blocks monoamine uptake at doses lower than
amphetamine
Modafinil Low binding affinity for dopamine receptor;
mode of action currently unknown
Other
Sodium oxybate (salt of GHB) Possibly acts via GABA-b or via specific GHB
receptors; decreases dopamine release
Anti-cataplectic medication Antidepressants
Venlafaxine Noradrenaline and serotonin selective re-
uptake inhibitor
Fluoxetine Selective serotonin re-uptake inhibitor (high
doses sometimes required)
Imipramine Monoaminergic uptake inhibitors, less selective
Clomipramine for noradrenaline, dopamine and serotonin;
anitcholinergic effects; active metabolites
Protryptiline
GABA: c-aminobutyric acid; GHB: c-hydroxybutyrate.
recommencement at a lower stimulant dose idiopathic hypersomnia over 40 yrs ago,

is effective. noting the features to be excessive daytime
somnolence unaccompanied by cataplexy
Safety and efficacy profiles should be (Roth, 1976). A characteristic of this disorder
considered in detail while prescribing all is ‘sleep drunkenness’ or difficulty achieving
drugs for narcolepsy and cataplexy and the full alertness during wakefulness despite
patient kept under review.
adequate sleep.
The issues of pregnancy, use of stimulants
The ICSD-2 classification distinguishes
in the context of comorbidities such as
between idiopathic hypersomnia with and
psychoses and hypertension, and risks
without long sleep time.
related to driving and certain forms of
employment, pose challenges which benefit Idiopathic hypersomnia with long sleep time
from specialised input. There is also an is characterised by complaints of excessive
increased incidence of psychological and sleepiness occurring daily for at least
psychiatric comorbidity in narcolepsy 3 months. Patients have prolonged sleep of
usually related to diagnostic delay, more than 10 h, which is subjectively and
hypersomnolence/cataplexy if severe and
objectively documented. Waking up at the
occasionally to medications used in
end of this period is difficult and naps are
its treatment.
not refreshing.
Idiopathic hypersomnia
There are no secondary causes to explain the
Bedrich Roth, a Professor of Neurology at hypersomnia, including psychiatric, lifestyle
Prague, was among the first to describe and medical conditions (Billiard, 2007).

Idiopathic hypersomnia without long sleep syndrome, and other hypersomnias
time likewise needs to be present for at least and neurological conditions. J Neurol
3 months on presentation, but the patient Neurosurg Psychiatry; 74: 1667–1673.
reports normal nocturnal sleep (.6 h but N Dauvilliers Y, et al. (2007). Narcolepsy
,10 h) objectively and subjectively with cataplexy. Lancet; 369: 499–511.
documented. There is generally no difficulty N de Lecea L, et al. (1998). The hypocretins:
in waking up in the morning (Billiard, 2007). hypothalamus-specific peptides with neu-
roexcitatory activity. Proc Natl Acad Sci
In both forms of idiopathic hypersomnia, USA; 95: 322–327.
nocturnal PSG is unremarkable for any other N American Academy of Sleep Medicine
sleep-related pathology. An MSLT (2005). International Classification of
performed after adequate PSG is considered Sleep Disorders. 2nd Edn. Westchester,
American Academy of Sleep Medicine.
diagnostic for the condition if the mean
N Lin L, et al. (1999). The sleep disorder
sleep latency is ,8 min and there are fewer
canine narcolepsy is caused by a muta-
than two SOREMPs (Billiard, 2007). tion in the hypocretin (orexin) receptor 2
gene. Cell; 98: 365–376.
The epidemiology of true idiopathic
N Littner MR, et al. (2005). Practice para-
hypersomnia is unknown; it presents
meters for clinical use of the multiple
generally at a younger age and it is sleep latency test and the maintenance of
considered to be rare. Many cohorts wakefulness test. Sleep; 28: 113–121.
published in the literature have not taken N Longstreth WT Jr, et al. (2007). The
into account all possible comorbidities, epidemi-
including psychiatric and organic, and some ology of narcolepsy. Sleep; 30: 13–26.
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circadian rhythm disturbances. cerebrospinal fluid hypocretin measure-
ment in the diagnosis of narcolepsy and
In contrast to narcolepsy, there are generally other hypersomnias. Arch Neurol; 59:
no laboratory abnormalities associated with 1553–1562.
idiopathic hypersomnia and there is N Mignot E. (1998). Genetic and familial
generally no family history. Recent studies aspects of narcolepsy. Neurology; 50:
have suggested a genetic predisposition Suppl. 1, S16–S22.
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stimulants, as for narcolepsy, but response narcolepsy with cataplexy on history
to medication is generally variable and not alone: challenging the International
Classification of Sleep Disorders (ICSD-
always satisfactory. Management has to be
2) criteria. Eur J Neurol; 18: 1017–1020.
tailored to the individual.
N Nevsimalova S. (2009). Narcolepsy in
childhood. Sleep Med Rev; 13: 169–180.
Further reading N Nightingale S, et al. (2005). The associa-
tion between narcolepsy and REM
N Aldrich MS, et al. (1997). Value of the behavior disorder (RBD). Sleep Med; 6:
multiple sleep latency test (MSLT) for 253–258.
the diagnosis of narcolepsy. Sleep; 20: N Nishino S, et al. (2000). Hypocretin
620–629. (orexin) deficiency in human narcolepsy.
N Billiard M, et al. (2006). EFNS guidelines Lancet; 355: 39–40.
on management of narcolepsy. Eur J N Nishino S, et al. (2001). Low cerebrosp-
Neurol; 13: 1035–1048. inal fluid hypocretin (Orexin) and altered
N Billiard M. (2007). Diagnosis of narco- energy homeostasis in human narco-
lepsy and idiopathic hypersomnia. An lepsy. Ann Neurol; 50: 381–388.
update based on the International classi- N Peyron C, et al. (2000). A mutation in a
fication of sleep disorders, 2nd edition. case of early onset narcolepsy and a
Sleep Med Rev; 11: 377–388. generalized absence of hypocretin pep-
N Dauvilliers Y, et al. (2003). CSF hypocretin- tides in human narcoleptic brains. Nat
1 levels in narcolepsy, Kleine-Levin Med; 6: 991–997.

N Roth B. (1976). Narcolepsy and hyper- N Wise MS, et al. (2007). Treatment of
somnia: review and classification of 642 narcolepsy and other hypersomnias of
personally observed cases. Schweiz Arch central origin. Sleep; 30: 1712–1727.
Neurol Neurochir Psych; 119: 31–41. N Xyrem International Study Group. (2005).
N Trakada G, et al. (2003). Family aspects A double-blind, placebo-controlled study
of idiopathic hypersomnia (polysympto- demonstrates sodium oxybate is effective
matic form). Sleep; 26: Suppl. A350. for the treatment of excessive daytime
N Tsujino N, et al. (2009). Orexin/ sleepiness in narcolepsy. J Clin Sleep Med;
Hypocretin: a neuropeptide at the inter- 1: 391–397.
face of sleep, energy homeostasis, and N Young TJ, et al. (2006). Hypersomnias of
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Circadian rhythm disorders
Renata L. Riha
Circadian rhythmicity has been (PER1, PER2 and PER3), the CLOCK gene
demonstrated in all human cells and and two cryptochrome genes (CRY1 and
regulates integral physiological processes CRY2). Deletion or mutation of these genes
such as core body temperature and leads to abnormalities in circadian rhythm
hormone secretion, including cortisol, when tested under constant conditions (Dijk
prolactin and growth hormone (Sack et al., et al., 2009, 2010; Viola et al. 2007; Wulff
2007a). There is significant interindividual et al., 2009). Several human families have
variation as a result of age, sex and been identified with specific abnormalities
morningness/eveningness preference. The in these genes affecting circadian
latter reflects an individual’s preferences for rhythmicity. However, there is currently no
timing activity and correlates with timing of evidence to support routine genetic testing
the individual’s circadian pacemaker. to establish the basis of these disorders in
Morning types, in contrast to evening types, general clinical practice (Sack et al., 2007a;
schedule sleep earlier and experience earlier Hofstra et al., 2008; Sack et al., 1992;
peaks in alertness and performance during Morgenthaler et al., 2007).
the ‘24-h period’ (Sack et al., 2007a; Hofstra
et al., 2008). Recent, exhaustive reviews and guidelines
have been published by the American
The differences between morningness and Association of Sleep Medicine (AASM) on
eveningness are partly the result of the use of actigraphy and other tools for
genotype. Several genes have been identified evaluating the various circadian rhythm
in animal studies affecting the expression of disorders (summarised in table 1)
autoregulatory translation–transcription (Morgenthaler et al., 2007).
feedback loops, including the Period genes
There is insufficient evidence currently to
recommend routine measurement of
Key points circadian rhythm utilising tools other than
actigraphy and sleep logs/diaries in the
N DSPS is typified by an exaggerated majority of disorders. However, dim light
‘night owl’ pattern of sleep and wake- melatonin onset (DLMO) and core body
fulness; ASPS is the opposite of DSPS. temperature have proven useful in
diagnosing and assessing free running
N FRD is common in blind individuals. circadian disorder (FRD), which affects up
N In irregular sleep/wake syndrome, to 50% of blind individuals (Sack et al.,
there is an absence of a well-defined 2007b; Skene et al., 2007).
sleep/wake cycle and there is no major
sleep period. Recommendations published on the therapy
of circadian disorders highlight the fact that
N Shift work disorder is common in 24-h there is still much to be learned about the
societies and can lead to significant intrinsic pathophysiology governing them
morbidity. endogenously, and the degree to which
exogenous factors determine their onset,

Table 1. Summary of evaluation tools and indications for their use in circadian rhythm disorders.
Evaluation tool Data collection method Factors masking signal Application
DLMO 1) Melatonin concentration Posture; exercise; sleep; Useful in FRD
in plasma or saliva sleep deprivation; caffeine;
2) 6-sulfatoxymelatonin in medications e.g. NSAIDs
urine and b-blockers; age?
3) Mid-sleep melatonin
(supplementary)
4) Must be collected in dim
light (50 lx)
CBT Thermometer Posture; physical activity; Useful in FRD
meals; ambient
temperature; sound;
humidity; bright light; age
Cortisol levels Cortisol concentration in Stress; light; ageing; high- Useful in FRD
serum and saliva protein meals; sleep
architecture
Questionnaires 1) MEQ MEQ assesses preferences Useful to assess
2) CTI of timing of activity, and morningness/
3) MCTQ does not assess work and eveningness but
weekend/holidays not routinely
separately; MCTQ collects recommended
information on actual for diagnosis
timing of daily sleep and
activities
Actigraphy Actimetry sensor worn on Can be taken off; less Indicated
nondominant wrist to reliable if sleep is routinely to
measure gross motor fragmented e.g. limb diagnose and
activity; increased movement movement disorders, assess response
during wakefulness and parasomnias, insomnia; to therapy in
reduced movement during restless legs syndrome DSPS, ASPS;
sleep optional use in
Must be worn continuously ISWS, FRD,
for o5 days SWD, JLD
Sleep log/ A variety of sleep diaries are Failure to complete diary Indicated
sleep diary available on daily basis in routinely to
accordance with actual assess presence
sleep/wake times of and response
to therapy in
ISWS, DSPS,
ASPS, FRD,
SWD, JLD
PSG Electrophysiological data First night effect; Indicated to
derived from EEG, EMG, insufficient sleep; technical exclude other
EOG, ECG, pulse oximetry, issues concurrent sleep
markers of respiratory effort disorders e.g.
sleep apnoea if
suspected on
clinical history
NSAID: nonsteroidal anti-inflammatory drug; CBT: core body temperature; MEQ: Morningness–Eveningness
Questionnaire; CTI: Circadian Type Inventory; MCTQ: Munich Chronotype Questionnaire; ISWS: irregular
sleep/wake syndrome; SWD: shift work disorder; JLD: jet lag disorder.

course and response to treatment (Sack A combination of techniques is generally
et al., 1992, 2007a). All circadian rhythm used to make the diagnosis, including
disturbances are at least partially, if not fully, actigraphy, PSG, sleep diaries and a history
amenable to planned sleep schedules, timed of the complaint (table 1). A number of
light exposure (except the unsighted) and different methods can be used to treat
timed melatonin administration (Sack et al., DSPS; these include bright light therapy,
1992, 2007a). changing bedtimes gradually
(chronotherapy), use of melatonin and
Sleep/wake rhythm disorders reinforcing behavioural changes. Specialist
supervision should be available at all times
Delayed sleep phase syndrome Delayed sleep
to assist with these treatments.
phase syndrome (DSPS) is typified by an
exaggerated ‘night owl’ pattern of sleep and Advanced sleep phase syndrome Advanced
wakefulness. Sleep onset and waking times sleep phase syndrome (ASPS) is the
are delayed by 3–6 h compared with opposite of DSPS. Sleep is normal but the
conventional sleep/wake times. The person sleep/wake schedule runs ,3 h earlier than
with DSPS is generally sleepy and ready to average. Irresistible sleepiness occurs in the
go to bed between 02:00 and 06:00 h and late afternoon and bedtime becomes early
generally gets up at 10:00–13:00 h. Sleep evening. Waking time is generally between
itself is normal. The sleep/wake pattern 02:00 and 05:00 h. The causes, diagnosis
must be present for o3 months for the and treatment of ASPS are similar to those
diagnosis to be made. Exclusion of of DSPS but targeted at different parts of the
depression and other medical and day and circadian rhythm. About 1% of
psychiatric conditions is important to the middle-aged adults have ASPS but it is
diagnosis. DSPS can occur in children and generally not considered such a socially
well into old age, being most common in incapacitating problem as DSPS (Hofstra
adolescents and young adults. About 7% of et al., 2008). People with ASPS often
young adults and adolescents are estimated gravitate towards jobs that suit their extreme
to have DSPS (Sack et al., 1992; early morning habits.
Morgenthaler et al., 2007). Presenting
Free-running circadian disorder FRD is
complaints are generally of sleep-onset
thought to result from a circadian
insomnia (delay in falling asleep into the pacemaker that has no stable phase
early hours of the morning) and severe relationship to the 24-h cycle (fig. 1). The
difficulty rousing in the morning at socially problem is rare in sighted people and,
appropriate times (e.g. for school and generally, will result from DSPS that has
employment). Sufferers may complain of ‘escaped’ any form of entrainment and is
daytime tiredness, which may lead to often behaviourally induced. This disorder is
impairment of school and job performance. common in the totally blind with some
Tiredness is greatest in the morning, with studies showing 50% of subjects having
increasing alertness during the day. free-running melatonin rhythms (Skene et al.,
Behaviourally induced DSPS is a subtype 2007). Investigation is as for other circadian
which is frequently seen, particularly in sleep disorders. Long-term melatonin
younger patients. administration is the treatment of choice in
the totally blind (Sack et al., 2007b) and may
A combination of factors most likely results
be supplemented by bright light therapy in
in DSPS. There are genetic factors, as
sighted individuals. Behavioural and
discussed above, associated with the
psychological factors predisposing to or
circadian clock genes that consitute a
maintaining FRD should be addressed and
hereditary component in some cases. Subtle
managed appropriately.
problems in the regulation of circadian
rhythm and with sleep recovery ability may Irregular sleep/wake syndrome Irregular
exist. Behaviour plays a strong role in sleep/wake syndrome is a rare disorder,
reinforcing DSPS. commonly occurring in association with

00:00 06:00 12:00 18:00 00:00 06:00 12:00 18:00 00:00
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Tue 18 Nov
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Fri 21 Nov
Sat 22 Nov
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Mon 24 Nov
Tue 25 Nov
Wed 26 Nov
Thu 27 Nov
Fri 28 Nov
Sat 29 Nov
Sun 30 Nov
Mon 1 Dec
Tue 2 Dec
Wed 3 Dec
Thu 4 Dec
Fri 5 Dec
Sat 6 Dec
Sun 7 Dec
Mon 8 Dec
Tue 9 Dec
Wed 10 Dec
Thu 11 Dec
Fri 12 Dec
Sat 13 Dec
Sun 14 Dec
Mon 15 Dec
Tue 16 Dec
Figure 1. Actigraphy showing FRD.
neurological dysfunction, Shift work and sleep

institutionalisation (e.g. for dementia),
schizoaffective disorders and psychomotor Sleep and other health problems arising
retardation. There is an absence of a well- from working schedules outside normal
defined sleep/wake cycle and there is no daylight hours can result in shift work
major sleep period. Patients generally disorder. Shift work problems result from
complain of insomnia or excessive the interaction of social/domestic factors,
sleepiness in association with irregular sleep circadian rhythm factors and sleep factors.
bouts/naps. The total sleep time over the 24- This disorder is common in every society
h period is generally appropriate to the where the service or production sector of the
person’s age and requirements. Diagnosis economy needs to be maintained 24 h?day-1.
and treatment are similar to those for other Although many individuals seem to cope
circadian rhythm disorders, using a with shift work, people most vulnerable to
combination of pharmacological, light- developing problems include: those aged
related and behavioural strategies. .50 yrs; those with a history of sleep
Outcomes are variable (Sack et al., 1992; disorders (e.g. sleep apnoea and
Morgenthaler et al., 2007). narcolepsy); those with epilepsy, diabetes or

heart disease; and those with psychiatric early awakening; disturbed sleep patterns;
illness, digestive problems, or a history of and impaired concentration and alertness
alcohol or substance misuse. Other factors during the day. Other symptoms include
impairing tolerance to shift work include a loss of appetite, inappropriate toilet times
heavy domestic work load, working two or and excessive urination at night (Sack et al.,
more jobs and ‘morning-type’ orientation 2007a).
(Sack et al., 1992; Morgenthaler et al., 2007).
Jet lag is worse when travelling eastwards,
Management Drawing up an appropriate as the day is shortened to ,24 h. Travelling
shift work roster is crucial to maintaining westwards has the opposite effect. It is
not only optimal performance but also in easier for most people to phase-delay, rather
minimising problems of coping with shifts. than attempt to sleep at an earlier time than
Types of shifts detrimental to well-being usual (this occurs when one travels east).
include: 12-h shifts that involve critical Travelling westwards generally leads to
monitoring tasks, heavy physical labour or quicker adaptation to local sleep times. The
exposure to harmful substances; more than severity of symptoms also depends on other
four 12-h shifts in a row; first shift starting
factors, including the number of time zones
earlier than 07:00 h; split shifts with too
crossed, the length of the flight and the
short breaks between shifts; complicated
ability of the circadian system to adapt to
schedules making planning ahead difficult;
changes. Approximately one-third of people
weekly rotations; more than five late night
who fly do not experience any significant
shifts in a row without a break; and
effects of jet lag.
backward rotating hours (Sack et al., 2007a;
Morgenthaler et al., 2007). Treatment Melatonin may, if taken
appropriately, assist with decreasing the
Impact on overall health Shift workers have
an increased risk of heart disease and symptoms of jet lag. The usual dose trialled
hypertension, and many have problems with is 5 mg. Melatonin can cause reduced
their digestive tracts. Disrupted family and alertness and induce sleepiness, the
social roles are also a side-effect. Permanent commonest side-effects being sleepiness,
shift workers have an increased risk of headache and nausea. Strategies for
affective disorders, particularly depression reducing jet lag have been extensively
and substance misuse/abuse. Their sleep is published (Sack et al., 2007a).
never entirely normal.
Further reading
Sedative and stimulant medication, applied
judiciously, can sometimes be useful to N Dijk DJ, et al. (2009). Light, sleep, and
regulate the sleep/wake pattern. ‘Night owls’ circadian rhythms: together again. PLoS
tend to do better than ‘morning larks’. After Biol; 7: e1000145.
middle-age, shift work becomes more N Dijk DJ, et al. (2010). PERIOD3, circadian
difficult to cope with due to changes in sleep phenotypes, and sleep homeostasis.
patterns with ageing. Those with serious Sleep Med Rev; 14: 151–160.
medical conditions should consider leaving N Hofstra WA, et al. (2008). How to assess
shift work (Sack et al., 2007a; Morgenthaler circadian rhythm in humans: a review of
et al., 2007). literature. Epilepsy Behav; 13: 438–444.
N Horne JA, et al. (1976). A self-assessment
Jet lag questionnaire to determine morning-
ness–eveningness in human circadian
The body clock adjusts slowly in response to systems. Int J Chronobiol; 4: 97–110.
abrupt changes in environmental time cues. N Morgenthaler TI, et al. (2007). Practice
No change is probably more abrupt than parameters for the clinical evaluation and
that of air travel across several time zones. treatment of circadian rhythm sleep dis-
Jet lag comprises a constellation of orders. An American Academy of Sleep
symptoms including: inappropriate daytime Medicine report. Sleep; 30: 1445–1459.
tiredness in the new time zone; insomnia;

N Sack RL, et al. (1992). Circadian rhythm Academy of Sleep Medicine review. Sleep;
abnormalities in totally blind people: 30: 1484–1501.
incidence and clinical significance. J Clin N Skene DJ, et al. (2007). Circadian rhythm
Endocrinol Metab; 75: 127–134. sleep disorders in the blind and their
N Sack RL, et al. (2007a). Circadian rhythm treatment with melatonin. Sleep Med; 8:
sleep disorders: part I, basic principles, 651–655.
shift work and jet lag disorders. An
American Academy of Sleep Medicine N Viola AU, et al. (2007). PER3 polymorph-
review. Sleep; 30: 1460–1483. ism predicts sleep structure and waking
N Sack RL, et al. (2007b). Circadian rhythm performance. Curr Biol; 17: 613–618.
sleep disorders: part II, advanced sleep N Wulff K, et al. (2009). Sleep and circadian
phase disorder, delayed sleep phase rhythm disturbances: multiple genes and
disorder, free-running disorder, and irre- multiple phenotypes. Curr Opin Genet
gular sleep-wake rhythm. An American Dev; 19: 237–246.

Psychiatric aspects of sleep
Chiara Baglioni and Dieter Riemann
Sleep difficulties are a pervasive problem for consistent with the definition of insomnia in
many patients suffering from psychiatric the Diagnostic and Statistical Manual of
conditions. This is especially true for Mental Disorders (DSM) IV (American
depression and anxiety disorders, but also Psychiatric Association, 2000) as difficulties
holds for schizophrenia, eating disorders, in initiating or maintaining sleep or
alcoholism and bipolar disorder. Sleep nonrestorative sleep accompanied by
difficulties can be present as objectively decreased daytime functioning lasting for at
measured alterations in sleep architecture, least 4 weeks. Historically, insomnia
as well as insomnia, hypersomnia, delayed symptoms have been conceptualised as a
sleep phase, reduced sleep need, consequence of psychopathology. However,
nightmares and nocturnal panic attacks both clinical and research evidence
(Harvey, 2011). The most frequently demonstrates that this is not the case.
encountered symptoms are, however, those Insomnia is now considered as an
independent diagnostic entity, which shares
underlying psychophysiological factors with
many psychiatric conditions and which
Key points might play an important role in the
causation and maintenance of
N Sleep difficulties consistent with the psychopathology.
symptoms of insomnia are a clinical
predictor of major depression and Sleep difficulties and depression
may play an important role in the
causation and maintenance of Impairment of sleep has been associated
psychopathology in general. with affective disorders, and especially
major depression. Up to 80% patients with
N Sleep is important for the maintenance depression have sleep complaints
of adaptive emotion regulation and consistent with insomnia. Moreover,
reactivity and alterations of the symptoms of insomnia often present before
emotional system have been found in the first onset of a depressive episode and
patients with insomnia compared with may persist into remission and recovery,
healthy controls. even after adequate treatment of
N The addition of psychological treatment depression. The close link between the two
for insomnia in the standardised conditions suggests that they are not
intervention protocols of many randomly associated. More than 40 studies
psychiatric conditions could improve have been published evaluating the question
the efficacy of these interventions. of whether insomnia is a predictor of the
development of depression (reviewed in
N Chronic insomnia occurs in ,10% of Riemann, 2009 and Baglioni et al., 2010a).
the adult population. Psychiatric A recent meta-analysis summarised
illness and SDB are the most quantitatively the results of the available
common comorbidities. longitudinal epidemiological studies
between 1980 and 2010 (Baglioni et al.,

2011), showing that non-depressed people latency, sleep efficiency, REM latency,
with insomnia have a two-fold increased risk lengths in minutes and in percentages of
of developing depression, compared with REM sleep and slow-wave sleep, REM
people with no sleep difficulties (fig. 1). density, REM activity and duration of the
Subgroup analysis indicates that the effect first REM period. The authors found that
of insomnia in predicting subsequent although sleep alterations were present in all
depression is similar in children, conditions, no impairment in any single
adolescents, working-age individuals and sleep variable had an absolute specificity for
the elderly. any particular psychiatric disorder.
Consistently, Harvey (e.g. Harvey et al., 2011)
Sleep difficulties and other psychiatric
advanced the hypothesis that sleep
disorders
disturbances could represent a
In 1992, Benca et al. conducted a meta- mechanistically transdiagnostic process –
analysis of studies that measured sleep in a that is, a contributing factor to the onset and
range of psychiatric disorders: affective maintenance of a range of disorders – in the
disorders, anxiety disorders, schizophrenia, context of psychiatric disorders by
borderline personality disorder, eating contributing to their development and
disorders, alcohol abuse, dementia, maintenance. Such a process can operate at
insomnia and narcolepsy. Data for the different levels: biological, psychological and
analysis were obtained from studies that emotional, social and contextual. Data
scored sleep EEGs through PSG following consistent with the transdiagnostic
standard criteria. Sleep variables considered hypothesis include: the reciprocal
included total sleep time, sleep onset relationship between insomnia and
Szklo-Coxe et al. 2010

Kim et al. 2009
Buysse et al. 2008
Cho et al. 2008
Jansson-Fröjmark et al. 2008
Roane et al. 2008
Morphy et al. 2007
Perlis et al. 2006
Hein et al. 2003
Roberts et al. 2002
Johnson et al. 2000
Mallon et al. 2000
Foley et al. 1999
Chang et al. 1997
Weissman et al. 1997
Breslau et al. 1996
Vollrath et al. 1989
Combined odds ratio
0.00 2.00 4.00 6.00

Odds ratio
FIGURE 1. Odds ratio of developing depression for people with insomnia versus those with no sleeping
difficulties. (Based on data from Baglioni et al., 2011.)

emotional regulation; genes known to be could mean that positive emotions have a
important in the generation and regulation protecting value for sleep, and specifically
of circadian rhythms that have been linked for the subjective perception of it. However,
to a range of psychiatric disorders; and the further investigation is needed.
interplay between sleep/circadian biology
and neurotransmitter systems known to be Psychological intervention for insomnia
important across a range of psychiatric comorbid with other psychiatric disorders
disorders, such as the dopamine and Cognitive behavioural therapy for insomnia
serotonin systems (see also Wulff et al., 2010). (CBT-I) is a multicomponent intervention
Sleep and emotions including behavioural, cognitive, and
educational components. Taylor et al.
In recent years, there has been increased (2007) published a pilot study evaluating
interest in the relationship between sleep the efficacy of CBT-I in a sample of 10
and emotions. Studies on sleep deprivation patients with both depression and insomnia.
have shown enhanced emotional The study showed that psychological
physiological responses to negative stimuli, treatment for insomnia was efficacious not
suggesting an important role of sleep for the only for sleep symptoms, but that it had an
maintenance of adaptive emotion regulation ameliorating effect on depressive
and reactivity (e.g. Yoo et al., 2007). With symptoms. Consistent with these results,
respect to primary insomnia, recent Manber et al. (2008) found that CBT-I in 30
aetiological theories suggest that people patients with symptoms of both insomnia
presenting with this disorder are and depression is efficacious and
characterised by heightened guarantees a better treatment outcome in
psychophysiological arousal, which could be this population than standard
physiological, cognitive and emotional antidepressive treatment alone. In a recent
(reviewed in Riemann et al., 2010). randomised controlled trial (Edinger et al.,
Alterations in the emotional system have 2009), 81 adults with chronic primary
been described by two patterns of subjective insomnia (n540) or comorbid insomnia
experience of emotions. The cognitive associated predominantly with mixed
model of insomnia (Harvey, 2002) describes psychiatric disorders (n541) were assigned
the heightened cognitive activity to either CBT-I or sleep hygiene education
experienced by people with insomnia as (SHE). CBT-I included strategies directed to:
excessively negatively toned. The a) educate patients about sleep regulation
psychobiological model of insomnia (Espie, processes (sleep education model); b)
2002) suggests that insomnia is correct patients’ misperceptions about sleep
characterised by strong positive and (cognitive module); c) associate the bed
negative emotions. Recent experimental with sleep and to reinforce a regular sleep/
data based on self-reported questionnaires wake schedule (stimulus control behavioural
suggest that people with insomnia module); and d) make the patients stay in
experience more negative emotions than bed only for the time she or he slept (sleep
good sleepers both in general and close to restriction behavioral module). SHE
sleep time (reviewed in Baglioni et al., included the sleep education model together
2010a). Very few studies have evaluated the with the delivery of a list of
physiological correlates of emotional recommendations, for example eliminating
processes in primary insomnia (e.g. Baglioni caffeine and alcohol in the evening or
et al., 2010b). Moreover, the relationship engaging in moderate exercise. CBT-I was
between positive emotions and sleep is still equally efficacious for primary and comorbid
not understood. Norlander et al. (2005; insomnia. These findings, although
described in Baglioni et al, 2010a) found preliminary, suggest that the addition of
that good sleep quality was associated with psychological treatment for insomnia in
intense positive emotions independently of standardised intervention protocols of many
the intensity of negative emotions. This psychiatric conditions could improve the

efficacy of these interventions. Moreover, N Edinger JD, et al. (2009). Cognitive
considering the longitudinal association behavioral therapy for patients with
between insomnia and depression and the primary insomnia or insomnia associated
transdiagnostic hypothesis, treating predominantly with mixed psychiatric
sleeping difficulties at an early stage could disorders: a randomized clinical trial.
interrupt the sequential process that Sleep; 32: 499–510.
gradually reduces the quality of life of people N Espie CA. (2002). Insomnia: conceptual
with chronic primary insomnia and ends in issues in the development, persistence,
and treatment of sleep disorders in
the development of symptoms of
adults. Annu Rev Psychol; 53: 215–243.
psychopathology. Therefore, there is
N Harvey AG, et al. (2011). Sleep distur-
increasing interest in developing new bance as transdiagnostic: consideration
treatment algorithms for the psychological of neurobiological mechanisms. Clin
treatment of insomnia, which are easy and Psychol Rev; 31: 225–235.
accessible for the general population. For N Harvey AG. (2002). A cognitive model of
instance, stepped-care models or internet insomnia. Behav Res Ther; 40: 869–893.
programs have been proposed and found to N Manber R, et al. (2008). Cognitive
be efficacious (reviewed in Morin et al., 2012). behavioral therapy for insomnia enhances
depression outcome in patients with
comorbid major depressive disorder and
insomnia. Sleep; 31: 489–495.
Further reading N Morin CM, et al. (2012). Chronic insom-
nia. Lancet; 379: 1129–1141.
N American Psychiatric Association. N Riemann D. (2009). Does effective man-
(2000). Diagnostic and Statistical agement of sleep disorders reduce
Manual of Mental Disorders. 4th Edn, depressive symptoms and the risk of
Text Revision. Arlington, American depression? Drugs; 69: 43–64.
Psychiatric Association. N Riemann D, et al. (2010). The hyperar-
N Baglioni C, et al. (2011). Insomnia as a ousal model of insomnia: a review of the
predictor of depression: a meta-analytic concept and its evidence. Sleep Med Rev;
evaluation of longitudinal epidemio- 14: 19–31.
logical studies. J Affect Disorders; 135: N Taylor DJ, et al. (2007). A pilot study of
10–19. cognitive-behavioral therapy of insomnia
N Baglioni C, et al. (2010b). Psychophy- in people with mild depression. Behav
siological reactivity to sleep-related emo- Ther; 38: 49–57.
tional stimuli in primary insomnia. Behav N Wulff K, et al. (2010). Sleep and circadian
Res Ther; 48: 467–475. rhythm disruption in psychiatric and
N Baglioni C, et al. (2010a). Sleep and neurodegenerative disease. Nat Rev
emotions: a focus on insomnia. Sleep Neurosci; 11: 589–599.
Med Rev; 14: 227–238. N Yoo SS, et al. (2007). The human
N Benca RM, et al. (1992). Sleep and emotional brain without sleep – a pre-
psychiatric disorders. A meta-analysis. frontal amygdala disconnect. Curr Biol; 17:
Arch Gen Psychiat; 49: 651–668. 877–878.

Sleep history
Silke Ryan and Walter T. McNicholas
Chronic disturbances in sleep and sleep/wake frequency, type and time of onsets of
patterns are very common, although symptoms. A potential relationship to
frequently under-reported by affected external factors, such as environmental,
subjects. In addition, medical and other social or medical influences, also needs to
healthcare professionals are generally less be understood and evaluated, and every
aware of sleep disorders and their history must include details on medication,
management than of conditions arising caffeine, alcohol and illicit drug use.
during wakefulness. The assessment of sleep
disorders requires an understanding of The first step in obtaining a history is to
normal sleep and how it may alter in differing assess the patient’s complaint or reason for
circumstances, and also with disorders that seeking attention, i.e. primary insomnia,
affect the nature of sleep. This knowledge excessive daytime sleepiness (EDS) or
needs to guide the patient interview, and a abnormal breathing behaviour or
thorough sleep and medical history is the first movements during sleep. Furthermore, the
history should establish when the problem
and most important step in the diagnosis and
began and whether there was any
management of sleep disorders.
relationship to an external factor.
A sleep history involves more than a
Detailed questionnaires have been
description of a patient’s sleep and is
developed to cover important questions that
actually a sleep/wake history with an
need to be asked and that can serve as a
evaluation of the entire 24-h period. This
road map for planning the direction of the
involves recording of alertness and
interview. It often includes a scale of
tiredness, occupation and leisure hours, in
alertness, such as the ESS. Completion of a
addition to details of rest and sleep.
sleep diary for 1–2 weeks may give
Particular attention should be paid to the
important indications of sleep habits, sleep
hygiene and daytime symptoms, and is
especially useful in the assessment of
insomnia or daytime sleepiness of unknown
Key points
cause. This typically includes the recording
of bedtime, time asleep, nocturnal
N A detailed longitudinal sleep history is awakenings, rising time, daytime naps and
the most critical part of the consumption of substances that may affect
assessment of subjects with sleep alertness.
disorders.
N A sleep history involves assessment of The patient often has little or no awareness
the whole 24-h sleep/wake pattern. of the problem and, therefore, it is highly
desirable to conduct an interview with the
N The elicitation of a collateral history is patient’s bed partner or caregiver or, in the
often crucial in the assessment of a case of a child, with the parent or teacher.
subject with a sleep disorder. The bed partner can provide vital
information regarding sleep behaviour,

abnormal movements or breathing Finally, events at sleep termination are
problems during sleep, and can also provide important in the overall evaluation. These
valuable independent input about events include the time of awakening, whether the
during wakefulness. awakening is spontaneous and how tired or
refreshed the patient feels. Early morning
While many components of the sleep history symptoms, such as headache, dry mouth
are common to all sleep complaints, some and sore throat, could point to obstructive
disorders require special questions, and the sleep apnoea.
physician should be constantly formulating
and testing hypotheses of diagnosis as the Specific nocturnal symptoms
history evolves. One must also bear in mind
Respiration Snoring is among the most
that there are often multiple causes of a
common nocturnal symptoms and,
sleep-related problem.
frequently, the primary reason for a patient
The most important aspects of the sleep and partner to seek medical attention. To
history are detailed below. help distinguish ‘simple’ snoring from
snoring as part of OSAS, one should
Details of the patient’s sleep ascertain the intensity, duration and
frequency of snoring, as well as the sleeping
It is important to establish the regularity of
position associated with snoring, in addition
the sleep/wake pattern, including preferred
to potential association with alcohol or
bed and rising time. Irregularity of this
sedative medication. The bed partner should
pattern, such as with varying work shifts, at
be carefully interviewed about frequency and
weekends or during holidays, should be
length of apnoeas as well as the position in
noted and, where relevant, compared to the
which they occur. Apnoeas may also be
premorbid sleep cycle. Particularly in the
associated with jerking movements,
case of insomnia, note should also be taken
suggesting an associated arousal, and the
of the sleep environment. Noise,
patient may report episodes of waking with a
temperature and brightness of the bedroom,
choking sensation in the throat. Nocturnal
and comfort of the bed can frequently
dyspnoea can be a symptom of various
influence sleep quality, and the patient may
diseases and further details, such as
be unaware of these links.
wheeze, association with apnoeas or body
The time of sleep onset should be recorded position when dyspnoea occurs, may help to
and if sleep latency is prolonged, potential narrow the differential diagnosis.
reasons should be sought with the patient.
Movements Abnormal movements during
Activities before bed and any behaviour
sleep could potentially point to periodic limb
while awake in bed, such as reading or
movement disorder, epileptic seizures or
watching television, should be described, as
various parasomnias. Any history of restless
these can affect sleep onset.
legs syndrome should be elucidated.
Furthermore, problems with sleep Information about behaviour during dreams,
maintenance need to be ascertained. These such as shouting, flailing the arms or kicking
include recording of the number of the legs, should be sought. If abnormal motor
awakenings with an attempt to determine behaviour is present, the time of events as
the causes of arousals, which could include well as the occurrence of any injuries to the
external factors, such as restless partners, patient or others should be noted.
noise, nightmares, or medical causes Specific daytime symptoms
including dyspnoea, leg jerking, nocturia or
anxiety. Multiple causes of pain or Excessive daytime sleepiness Sleepiness is a
discomfort can also arouse patients, very common complaint and is experienced
including arthritis, fibromyalgia, restless in a number of somatic, psychiatric and
legs or angina. The length of time before primary sleep disorders, but also occurs
returning to sleep and an estimation of total physiologically in the absence of sufficiently
time spent asleep should be evaluated. restorative sleep periods. EDS should be

Table 1. Important nocturnal and daytime symptoms and their possible implications.
Symptom Possible implications
Snoring ‘Simple’ snorer, UARS, OSA
Nocturnal gasping/choking OSA, asthma, gastro-oesophageal reflux, panic attacks
Early morning headaches OSA, CO2 retention, insomnia
EDS Extrinsic: sleep deprivation, shift work sleep disorder, drug-
related hypersomnia
Intrinsic: sleep-disordered breathing, narcolepsy, idiopathic
hypersomnia, RLS and PLMD, Circadian rhythm sleep disorder
Loss of strength with emotion Cataplexy
Pre-sleep leg discomfort RLS, PLMD
UARS: upper airway resistance syndrome; RLS: restless legs syndrome; PLMD: periodic limb movement
disorder.
distinguished from mental or physical Further reading

fatigue, which usually has an organic cause
N Chokroverty S. (2010). Overview of sleep &
or may be related to insomnia. EDS severity
sleep disorders. Ind J Med Res; 131: 126–140.
can be gauged by frequency of occurrence N Engleman HM, et al. (2004). Sleep. 4:
and the type of situation in which the patient Sleepiness, cognitive function, and quality
falls asleep. EDS is likely to be more severe if of life in obstructive sleep apnoea/hypop-
sleep occurs despite stimulating noea syndrome. Thorax; 59: 618–622.
circumstances, such as while talking, eating N Falloon K, et al. (2011). The assessment
or on exertion, and if it occurs frequently and and management of insomnia in primary
at any time during the day. Sleepiness while care. BMJ; 342: d2899.
driving should be characterised in terms of N Ferini-Strambi L. (2007). RLS-like symp-
the time and distance before lapses of toms: differential diagnosis by history
alertness occur, and whether motor vehicle and clinical assessment. Sleep Med; 8:
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N Johns MW. (1991). A new method for
Motor and sensory symptoms Abnormal measuring daytime sleepiness: the Ep-
movements during the daytime due to worth sleepiness scale. Sleep; 14: 540–545.
epilepsy or a primary movement disorder N Jones BE. (2000). Basic mechanisms of
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bilateral loss of muscle strength due to N Phillips B. (2004). Movement disorders:
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be noted that these manifestations could obstructive sleep apnoea/hypopnoea syn-
also occur as part of other conditions. drome. Thorax; 59: 347–352.
N Silber MH, et al. (2004). Assessing the
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daytime symptoms and their possible MH, et al, eds. Sleep Medicine in Clinical
implications is provided in table 1. Practice. London, Taylor & Francis; p. 31–42.

Differential diagnosis
Walter T. McNicholas
Hypersomnolence, also referred to as disorders associated with sleep

excessive daytime sleepiness (EDS), is fragmentation such as OSAS, use of
defined as the inability to stay awake and sedative medications, circadian rhythm
alert during the waking periods of the day, disturbances that result in a mismatch of
resulting in lapses into drowsiness or sleep. the sleep/wake pattern, and neuronal
Thus, EDS is a condition that is associated degeneration within the brain structures that
with an increased tendency to fall asleep modulate the sleep/wake rhythm, such as
during daytime activities where alertness is narcolepsy. The range of disorders
a normal feature. EDS is more likely to occur associated with EDS are summarised in
in boring monotonous situations that do not table 1. EDS is a central symptom
require active participation, such as associated with several sleep disorders,
watching television and reading a book, but including OSAS and narcolepsy, in addition
can also occur in potentially dangerous to neurological or other medical disorders
situations, such as while driving or such as Parkinson’s disease, hepatic failure
operating machinery. When very severe, EDS and hypothyroidism. The most common
may result in episodes of automatic cause of EDS is behavioural where an
behaviour, in which subjects have no individual persistently fails to obtain
memory of events that they have performed. sufficient sleep to maintain a normal level of
In children, EDS may present as restlessness, alertness and wakefulness, and this probably
inattention and hyperactivity. Chronic explains why some normal people record
hypersomnolence is arbitrarily defined as high sleepiness scores on subjective
being present for at least 3 months. sleepiness scales such as the ESS. The most
common medical cause of EDS is OSAS,
The causes of EDS vary widely, ranging from although not all OSAS patients report this
behavioural factors such as insufficient or symptom. The presence of EDS is a
fragmented night-time sleep, medical prerequisite for the diagnosis of some sleep
conditions such as narcolepsy but not of
others such as OSAS. In some disorders,
Key points chronic EDS may represent the principal and
most disabling complaint. It can also be the
N EDS is commonly the result of poor first to occur, such as in narcolepsy,
lifestyle habits associated with depression or Parkinson’s disease.
insufficient sleep time.
Chronic EDS may be ignored or
N Proper evaluation of EDS requires a
underestimated by affected patients simply
careful history, preferably with the
because it is a subjective feature which
partner present.
depends on the patient’s ability to
N Subjective sleepiness correlates poorly distinguish normal from abnormal
with objective tests of sleepiness such behaviour. Individuals may deny
as the MSLT and the MWT. experiencing EDS but report other related
symptoms such as tiredness, poor memory

Table 1. Causes of EDS/hypersomnolence. with narcolepsy and more recently in
Parkinson’s disease, particularly in those
OSAS patients taking dopaminergic replacement
Other sleep-related breathing disorders therapy. However, sleep attacks have also
Narcolepsy been described rarely in severe OSAS,
typically associated with severe
Behaviourally-induced insufficient sleep
hypersomnolence.
Depression
Idiopathic hypersomnia (with/without It is also necessary to differentiate EDS from
increased sleep duration) other forms of "fatigue". This is not always
easy as the terms "sleepiness" and "fatigue"
EDS due to a medical disorder: infections,
are often used interchangeably. However,
metabolic disturbances, endocrinopathies,
the definition of sleepiness as the
Parkinson’s disease, myotonic dystrophy
occurrence of actual dozing off makes it
Drug or substance induced possible to distinguish situations where the
Recurrent hypersomnia (e.g. Kleine–Levin patient feels like sitting or lying and doing
syndrome) nothing, from situations where the patient
Circadian rhythm disorders would like to do things but is just unable to
do so because he/she dozes off, especially
Shift work sleep disorder
when the situation is boring. Tiredness
Chronic fatigue syndrome without sleepiness is rarely a symptom of
OSAS, and is seen more in other conditions
such as chronic fatigue syndrome or
and concentration, in addition to lack of depression. However, females may be more
energy, weakness or fatigue. EDS may likely than males to report fatigue as a
present in different ways, which may provide symptom of OSAS. These considerations
insight into the underlying cause. One is a stress the need for specific questions during
state of sleepiness that is recognised by the the history taking: vague questions such as
patient, thus allowing him/her to fight "Are you sleepy during the day?" are likely to
against the symptom. Patients experience a be unreliable. Situational questions such as
constant pressure towards falling asleep and "Do you fall asleep reading or watching
also difficulty with remaining awake. They television, as a passenger in car, or while
tend to fall asleep and/or take frequent short attending meetings?’’ provide a more
naps at inappropriate times and/or settings, accurate picture of true sleepiness.
especially when situations are not Questions should be adapted to the
stimulating, such as watching television and patients’ usual activities, and should also
reading. In more severe cases, the sleepiness take into account the fact that patients
develops while driving, but affected patients engaged in active, outdoor, occupations are
can usually recognise the problem and pull less likely to report sleepiness than patients
over to rest and/or take a nap. with more passive, indoor, occupations.
The other presentation of EDS is much less The clinical evaluation of EDS may be
common and consists of sudden onset of difficult since subjective sleepiness scales
sleep episodes. These episodes are abrupt, may be unreliable, either because of the
brief and unexpected and have been patient’s lack of perception of the true extent
reported to occur during active situations of the problem, or alternatively, a desire to
such as driving, eating, talking, walking, or minimise the problem because of concern
while speaking on the telephone. It is about possible occupational consequences
unclear whether these episodes, often of EDS, such as driver licensing. Collateral
termed ‘‘sleep attacks’’, constitute a unique history from the spouse or another close
entity or they are merely an extreme relative may be helpful, and it is important
manifestation of hypersomnolence. They to distinguish EDS from other related
have been classically described in patients symptoms such as fatigue, lack of energy,

asthenia, poor concentration and tiredness. 4) use of medications that could alter sleep
Several objective tests of sleepiness are architecture, such as antidepressants, wake
available, most importantly the MSLT and promoting agents and benzodiazepines; and
MWT (see also ‘‘Assessment of daytime 5) stimulating or upsetting events between
sleepiness’’). nap opportunities.
The multiple sleep latency test While the MSLT is a detailed and complex
test, there is some debate as to whether
The MSLT is considered by most specialists sleep latency is a true measure of EDS.
to be the standard objective measure of EDS Precise normative ranges for mean sleep
and is the most widely used and extensively latency are not well defined and many
published. The MSLT is intended to factors may influence it, such as motivation,
measure physiological sleep tendency under age, external stimuli, medication, previous
standardised conditions in the absence of sleep quality and sleep time, medical
external alerting factors and is based on the disorders and psychological factors.
premise that the degree of sleepiness is Nonetheless, a mean sleep latency .10 min
reflected by the sleep latency. The test is is generally accepted as normal. The
typically performed during the day after diagnostic sensitivity of the MSLT for the
overnight PSG to evaluate the possible diagnosis of narcolepsy has been estimated
presence of a cause of EDS (e.g. OSAS), and at ,60%, while the diagnostic specificity
to document an adequate quantity and when two or more SOREM are present is
quality of sleep on the night preceding the ,95%. Mean sleep latency of ,3 min is
MSLT. The standard clinical MSLT consists typically seen in narcolepsy, and when
of four or five nap opportunities performed combined with the occurrence of one or
at 2-h intervals across a patient’s usual more SOREM provides a diagnostic
period of wakefulness during which accuracy close to 100%. The MSLT is not
standard PSG recordings are obtained to routinely indicated for the evaluation or
objectively identify sleep stage during the diagnosis of OSAS or assessment of
recordings. Strict guidelines should be response to treatment of OSAS. Mean sleep
followed regarding meals, ambient latency in OSAS is typically in the region of
environment and surrounding noise and 7 min, although it varies with the severity of
other relevant factors to ensure a consistent the disorder. However, the MSLT may be
and reproducible test. indicated in OSAS patients that continue to
Sleep onset is determined by the time from experience EDS despite correct treatment of
lights out to the first epoch of any stage of the underlying condition.
sleep in a 30-s epoch. Sleep onset is defined Maintenance of wakefulness test
as the first epoch containing more than 15 s
of cumulative sleep in a 30-s epoch. The The MWT is a variant of the MSLT in which,
patient is permitted to sleep for 15 min after rather than attempt to sleep, the patient is
the first epoch scored as sleep. This is to asked to remain awake as long as possible,
assess sleep continuity and the early and the test assesses ability to resist the
occurrence of REM sleep. REM sleep latency urge to fall asleep during soporific
is taken as the time from the first epoch of circumstances. Thus, MWT is not a
sleep to the beginning of the first epoch of diagnostic test for the degree of sleepiness
REM sleep. Sleep onset REM periods but rather a test of the ability to remain
(SOREM) are defined as episodes of at least awake. MWT can be used to assess the
15 s of REM sleep within a 30-s epoch. efficacy of a particular treatment once the
Conditions that may adversely affect the diagnosis has been reached previously, and
validity of the MSLT include: 1) insufficient is also used to assess the patient fitness to
sleep during nights prior to the test; 2) drive and to fly, or ability to return to work
performance of the MSLT at a time different and, obviously, to quantify the extent of EDS.
than the patient’s usual time of wakefulness; This is to assess an individual’s ability to
3) excessive noise or temperature extremes; remain awake when his or her ability to

remain awake constitutes a public or N Chellappa SL, et al. (2009). Chronobio-
personal safety issue. The MWT is subject to logy, excessive daytime sleepiness and
more motivational factors than the MSLT. depression: is there a link? Sleep Med; 10:
505–514.
Similar to MSLT, four nap opportunities are N Coelho FM, et al. (2011). Testing sleepi-
performed at 2-h intervals after an overnight ness and vigilance in the sleep laboratory.
PSG. The patient is asked to try to remain Curr Opin Pulm Med; 17: 406–411.
awake with the eyes open, but is not allowed N Dauvilliers Y. (2006). Differential diag-
to use extraordinary measures such as nosis in hypersomnia. Curr Neurol
walking, singing or talking. The latency to Neurosci Rep; 6: 156–162.
the first three consecutive 30-s epochs of N De Cock VC, et al. (2008). Sleep dis-
sleep (or to the first epoch of sleep as in the turbances in patients with parkinsonism.
Nat Clin Pract Neurol; 4: 254–266.
MSLT) is measured for each trial and the
N Engleman HM, et al. (2004). Sleep. 4:
mean sleep latency is calculated. The patient sleepiness, cognitive function, and quality
is awakened when sleep onset is scored. of life in obstructive sleep apnoea/hypop-
noea syndrome. Thorax; 59: 618–622.
A variant of the MWT is the OSLER test,
N Fong SY, et al. (2005). Comparing MSLT
where the subject is asked to press a switch and ESS in the measurement of excessive
in response to a repetitive flashing light daytime sleepiness in obstructive sleep
placed in front of the face, which flashes for apnoea syndrome. J Psychosom Res; 58:
one second in every three. Sleep onset is 55–60.
identified when the subject fails to respond N Kothare SV, et al. (2008). The clinical and
to seven successive light flashes. laboratory assessment of the sleepy child.
Semin Pediatr Neurol; 15: 61–69.
There is a poor correlation between MSLT and N Ohayon MM. (2008). From wakefulness
MWT, and also between MSLT/MWT and to excessive sleepiness: what we know
subjective scores of sleepiness such as the ESS. and still need to know. Sleep Med Rev; 12:
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specific, thus indicating that there is more than between excessive daytime sleepiness
a single component to EDS. and fatigue: toward improved detection
and treatment. J Psychosom Res; 54: 61–69.
N Sullivan SS, et al. (2008). Multiple sleep
Further reading latency test and maintenance of wakeful-
ness test. Chest; 134: 854–861.
N Ancoli-Israel S, et al. (2006). Insomnia N Thorpy MJ. (2005). Which clinical condi-
and daytime napping in older adults. tions are responsible for impaired alert-
J Clin Sleep Med; 2: 333–342. ness? Sleep Med; 6: Suppl. 1, S13–S20.
N Bodkin CL, et al. (2011). Office evaluation N Zeman A, et al. (2004). Narcolepsy and
of the "tired" or "sleepy" patient. Semin excessive daytime sleepiness. BMJ; 329:
Neurol; 31: 42–53. 724–728.

Questionnaires on sleep
Brian D. Kent and Walter T. McNicholas
OSAS is a highly prevalent but markedly for triage according to their

under-diagnosed condition. Valuable clinical symptomatology. These questionnaires can
information can be obtained by carrying out be broadly divided into three groups – those
a careful history and examination of assessing sleepiness, those assessing pre-
individuals suspected of having the test probability of OSAS and those
disorder. However, these are susceptible to assessing sleep quality.
reporter and observer bias, and may not
Questionnaires assessing sleepiness
produce objective, reproducible findings.
Furthermore, accurate risk stratification and Excessive daytime sleepiness (EDS) is one
clinical triage of patients referred to sleep of the hallmarks of OSAS. Sleepiness can be
services is highly desirable, as the current objectively measured by using in-laboratory
diagnostic capacity of sleep laboratories investigations, such as the MSLT and the
across the developed world is greatly MWT or modifications thereof. However,
exceeded by the number of subjects these investigations are highly resource
awaiting investigation. Consequently, efforts intensive, require expert interpretation and
have been made to standardise clinical are inconvenient for the patient.
history using questionnaires, potentially
allowing both for the identification of The Epworth Sleepiness Scale Probably the
subjects with a high likelihood of SDB and most widely used questionnaire in clinical
sleep medicine is the ESS, a simple and
practical tool designed to assess the
subject’s likelihood of falling asleep across a
Key Points
range of everyday activities (Johns, 1991).
Eight separate situations are addressed,
N The ESS is used to subjectively
with the patient asked to score their
quantify sleepiness across a range of
propensity for falling asleep in each situation
everyday situations, with a cumulative
from 0 to 3 (table 1), with 0 representing no
score of .10 suggesting EDS.
chance of dozing and 3 a high chance of
N The Berlin Questionnaire has high dozing. A total score of o10 across the eight
specificity for identifying subjects with questions is indicative of EDS and should
moderate–severe OSAS, but relatively prompt further investigation. Caution should
low sensitivity. be exercised in interpreting the ESS score,
however, as there are conflicting data on its
N The STOP and STOP-Bang
correlation with objective sleepiness
questionnaires have high sensitivity
measured by the MSLT (Sullivan et al., 2008;
for identifying subjects with sleep
disordered breathing, but relatively Punjabi et al., 2003) and its utility in the
low specificity. prediction of the presence or severity of
OSAS remains uncertain (Gottlieb et al.,
N Sleep quality can be subjectively 1999; Kapur et al., 2005). In particular, a
assessed by the PSQI. normal ESS score does not exclude the
presence of significant SDB.

Table 1. Situations assessed by the ESS. variant, while the absence of the typical
clinical phenotype does not exclude a
Sitting and reading diagnosis of SDB. This has led to the
Watching television development and attempted validation of a
Sitting inactive in a public place number of screening questionnaires for
OSAS. Perhaps the best studied of these are
As a passenger in a car for an hour without a
the Berlin Questionnaire, and STOP and
break
STOP-Bang questionnaires.
Lying down to rest in the afternoon when
circumstances permit The Berlin Questionnaire The Berlin
Sitting and talking to someone Questionnaire classifies subjects as low- or
high-risk for OSAS based on their responses
Sitting quietly after a lunch without alcohol in three clinical categories – snoring history,
In a car, while stopped for a few minutes in daytime sleepiness and history of
traffic hypertension or obesity (table 2) (Netzer
et al., 1999). To be considered at high risk
Each situation is scored from 0 to 3, with 0
representing no chance of dozing and 3 a high
for OSAS, patients need to respond
likelihood of dozing. The upper limit of normal positively in two of the categories assessed.
of the sum of the scores is generally considered The Berlin Questionnaire has been validated
to be 10. in primary care, sleep clinic and surgical
populations, and provides a high degree of
specificity for the diagnosis of moderate-to-
The Stanford Sleepiness Scale In contrast severe SDB, albeit with a relatively low
with the ESS, the Stanford Sleepiness Scale degree of sensitivity (Abrishami et al., 2010).
(SSS) measures current, rather than In a sentinel study assessing its use in a
everyday, sleepiness (Hoddes et al., 1973). primary care setting, Netzer et al. (1999)
Subjects choose one of seven statements reported a sensitivity of 54% and a
describing their level of sleepiness, ranging specificity of 97% for identifying subjects
from 1 (‘feeling active, vital, alert, or wide with a respiratory disturbance index (RDI) of
awake’) to 7 (‘no longer fighting sleep, sleep .15 events?h-1, with a positive predictive
onset soon, having dream-like thoughts’). value of 97%.
Selection of statements 4–7 at a time when
the subject should be feeling alert is The STOP questionnaire Developed in an
considered consistent with excess attempt to screen surgical patients for
sleepiness. The key advantage of the SSS is undiagnosed OSAS, the STOP questionnaire
its ability to be administered on several comprises four questions (Chung et al.,
occasions throughout the day and night, 2008). These address the presence or
allowing a dynamic picture of the subject’s absence of snoring, daytime tiredness,
symptomatology to be built up. Moreover, observed apnoeas during sleep and a history
as a research tool, it is well validated against of high blood pressure. Positive answers to
objective measures of sleepiness. Conversely, two or more of these questions categorises
it is unable to differentiate between the patient as at high risk for underlying
individuals who are sleepy due to simple OSAS. The sensitivities of STOP with AHIs
sleep deprivation and those who have an .5, 15 and 30 events?h-1 were 65.6%, 74.3%
underlying sleep disorder, thereby limiting its and 79.5% respectively in a validation cohort
utility in everyday clinical practice. of predominantly overweight and obese
surgical patients (Chung et al., 2008).
Screening questionnaires for OSAS However, this was at the cost of reduced
specificity compared with the Berlin
As discussed earlier, reliance on the clinical Questionnaire.
history and examination as a screening tool
for OSAS may lead to reporter and observer The STOP-Bang questionnaire A refinement
bias. In particular, patients may consider of the STOP questionnaire, incorporating
longstanding symptoms to be a normal additional questions on BMI, age, neck

Table 2. The Berlin Questionnaire.
Questions Answers Scoring
Category 1 Items 1, 4, 8, 10 Category 1
1) Do you snore? Yes (1), no or don’t Positive if total score o2
2) If yes, how loud is it? know (0) points
3) How often do you snore? Item 2 Category 2
4) Has your snoring ever bothered Slightly louder than Positive if total score o2
other people? breathing (0) points
5) Has anyone noticed you stop As loud as talking (0) Category 3
breathing during your sleep? Louder than talking (1) Positive if answer to item
Category 2 Can be heard in 10 is yes or if BMI
6) How often do you feel tired or adjacent room (1) .30 kg?m-2
fatigued after your sleep? Items 5, 6, 7, 9 High risk of OSAS: o2
7) During your waking time, do you Nearly every day (1) categories positive
feel tired, fatigued or not up to par? 3–4 times a week (1) Low risk of OSAS: ,2
8) Have you ever nodded off or fallen 1–2 times a week (0) categories positive
asleep while driving a vehicle? 1–2 times a month (0)
9) If yes, how often does this occur? Never (0)
Category 3
10) Do you have high blood pressure?
circumference and sex (table 3), has been Questionnaires assessing sleep quality
shown to improve its sensitivity significantly.
SDB is associated with poor subjective sleep
When applied to .4,000 community-based
quality. Longitudinal assessment of sleep
participants in the Sleep Heart Health Study,
quality may be performed in patients with OSAS
STOP-Bang had a sensitivity of 87% in the
to gauge symptomatic response to treatment.
identification of subjects with moderate–
The best studied instrument in this field is the
severe SDB (Silva et al., 2011). Moreover, it
Pittsburgh Sleep Quality Index (PSQI).
may also have a role in predicting severity of
underlying OSAS (Farney et al., 2011), Pittsburgh Sleep Quality Index The PSQI is a
thereby facilitating triage of patients self-administered questionnaire that
attending sleep clinics. measures sleep quality over a 1-month time
period. It consists of 19 questions on sleep
quality, symptoms and hygiene, which are
Table 3. The STOP-Bang questionnaire. combined into seven component scores,
1) Do you snore loudly? each rated 0–3, giving a global score of 0–21
2) Do you often feel tired, fatigued or sleepy
(Buysse et al., 1989). A score of o5 may be
during the daytime? suggestive of some form of underlying sleep
disorder, but PSQI scores do not correlate
3) Has anyone observed you stop breathing significantly with formally measured on PSG
while you sleep? sleep abnormalities (Buysse et al., 2008).
4) Do you have or are you being treated for Consequently, it has utility in assessing
high blood pressure? subjective quality of sleep, but is deficient as
5) BMI o35 kg?m-2? an objective measure of this.
6) Age o50 yrs?
7) Neck circumference o40 cm? Further reading
8) Male? N Abrishami A, et al. (2010). A systematic
review of screening questionnaires for
High risk of OSAS: answering yes to three or obstructive sleep apnea. Can J Anaesth;
more items; low risk of OSAS: answering yes to
57: 423–438.
fewer than three items.

N Buysse DJ, et al. (2008). Relationships N Hoddes E, et al. (1973). Quantification of
between the Pittsburgh Sleep Quality sleepiness: a new approach. Psychophysio-
Index (PSQI), Epworth Sleepiness Scale logy; 10: 431–436.
(ESS), and clinical/polysomnographic N Johns MW. (1991). A new method for mea-
measures in a community sample. J Clin suring daytime sleepiness: the Epworth
Sleep Med; 4: 563–571. sleepiness scale. Sleep; 14: 540–545.
N Buysse DJ, et al. (1989). The Pittsburgh N Kapur VK, et al. (2005). Sleepiness in
Sleep Quality Index: a new instrument for patients with moderate to severe sleep-
psychiatric practice and research. disordered breathing. Sleep; 28: 472–477.
Psychiatry Res; 28: 193–213. N Netzer NC, et al. (1999). Using the Berlin
N Chung F, et al. (2008). STOP question- Questionnaire to identify patients at risk
naire: a tool to screen patients for for the sleep apnea syndrome. Ann Intern
obstructive sleep apnea. Anesthesiology; Med; 131: 485–491.
108: 812–821. N Punjabi NM, et al. (2003). Predictors of
N Farney RJ, et al. (2011). The STOP-Bang objective sleep tendency in the general
equivalent model and prediction of sever- population. Sleep; 26: 678–683.
ity of obstructive sleep apnea: relation to N Silva GE, et al. (2011). Identification of
polysomnographic measurements of the patients with sleep disordered breathing:
apnea/hypopnea index. J Clin Sleep Med; comparing the four-variable screening tool,
7: 459B–465B. STOP, STOP-Bang, and Epworth Sleepi-
N Gottlieb DJ, et al. (1999). Relation of ness Scales. J Clin Sleep Med; 7: 467–472.
sleepiness to respiratory disturbance N Sullivan SS, et al. (2008). Multiple sleep
index: the Sleep Heart Health Study. latency test and maintenance of wakeful-
Am J Respir Crit Care Med; 159: 502–507. ness test. Chest; 134: 854–861.

Predisposing factors
Maria R. Bonsignore
In the clinical assessment of patients with et al., 2010). However, the clinical
suspected SDB, anatomical and functional significance of asymptomatic OSA in elderly
predisposing factors should be carefully subjects is unclear (Launois et al., 2007).
assessed. In addition, several diseases may
Sex Men are more susceptible to SDB than
increase the risk of developing SDB through
women, but the sex difference becomes
various mechanisms. Table 1 summarises
attenuated in old age (Lindberg et al., 2010),
predisposing conditions that should alert
suggesting that hormonal factors may play
the physician and suggest SDB as a possible
some role. Women are relatively resistant to
diagnosis.
upper airway collapse during sleep (Lin et al.,
General predisposing factors 2008; Kirkness et al., 2008). Central
apnoeas are also less frequent in women
Age OSA occurs at all ages and its than in men due to differences in ventilatory
prevalence increases with ageing (Lindberg control (lower apnoea threshold and
ventilatory overshoot after apnoeas in
women) (Lin et al., 2008).
Key points
Race Although data are scarce, Asians and
N Several conditions predispose to African-Americans appear to be at higher
development of SDB. risk of developing OSA than Caucasians
(Villaneuva et al., 2005), a finding at least
N Anatomical and functional factors are partly explained by differences in craniofacial
central to the pathogenesis of upper structures (Lee et al., 2010).
airway obstruction, alone or in
association with other pathological Anatomical abnormalities
conditions.
Several conditions can decrease the
N Obesity is the risk factor most dimensions and patency of the upper airway
frequently found in OSA patients, by affecting bony structures or soft tissues
sometimes associated with endocrine of the face and neck. Clinically, in any
disorders. patient with suspected SDB, it is advisable
N Other diseases also predispose to to record the Mallampati score, a simple
SDB and should be carefully way to evaluate the patency of
investigated in the clinical assessment oropharyngeal airways (Nuckton et al.,
of patients with suspected OSA. 2006). Craniofacial structure and upper
airway morphology are genetically
N Chronic HF predisposes to Cheyne– determined and explain racial differences in
Stokes breathing during sleep, prevalence of OSA. Increased fat deposition
through complex mechanisms in the neck is a common finding in OSA
involving central and peripheral patients (Schwab et al., 2003), and neck
control of breathing, but is often circumference correlates with OSA severity.
associated also with OSA. The following conditions predispose to
development of OSA.

Table 1. Predisposing factors to be considered in the diagnosis of SDB.
General Ageing
Males
Asian or African-American race
Anatomical abnormalities Nasal obstruction
Micrognathia
Hyoid bone displacement
Hypertrophy of uvula, soft palate and tonsils
Macroglossia
Upper airway shape and length
Functional factors Factors affecting upper airway collapsibility
(drugs and alcohol)
Airway inflammation
Instability of respiratory drive
Associated diseases Obesity
Congenital syndromes (Pierre Robin, Down,
etc.)
Endocrine disorders
Heart failure
Stroke
Chronic kidney disease (CKD)
Gastro-oesophageal reflux disease
Nasal obstruction This can be associated Hypertrophy of uvula, soft palate and tonsils A
with deviation of the nasal septum or ‘‘crowded’’ oropharynx can be found in OSA
hypertrophy of turbinates. Classically, it is patients, in part secondary to fat deposition
considered a predisposing factor for upper in the neck associated with obesity and in
airway collapse through increased nasal part resulting from snoring-associated
resistance and development of markedly vibrations and inflammation of soft tissues
negative pressure during inspiration. (Gaudette et al., 2010).
According to a recent meta-analysis nasal
obstruction increased the risk of snoring but Macroglossia In both adults and children, an
not of OSA (Kohler et al., 2007). enlarged tongue is a predisposing factor of
SDB. In adults, macroglossia is a feature of
Micrognathia A small retropositioned acromegaly, but is also common in obese
mandible, such as in patients with Pierre patients; in paediatric patients, macroglossia
Robin syndrome, reduces the can be found in Down’s syndrome,
retropharyngeal area considerably (Gaudette mucopolysaccharidosis type VI and other
et al., 2010). genetic diseases (Gaudette et al., 2010).
Hyoid bone displacement The hyoid bone is Upper airway shape and length Profound
an anchoring site for pharyngeal muscles. alterations in the shape of upper airways
Its downward displacement alters the have been documented in OSA patients, in
position of the tongue, favouring upper particular an elliptical shape of the airway
airway collapse (Gaudette et al., 2010). with increased anteroposterior dimension

and lateral narrowing (Schwab et al., 2003; mechanical stimuli. The opposite occurs
Gaudette et al., 2010). Increased upper with arousal (i.e. a shift from sleep to
airway length also predisposes to collapse wakefulness). These state changes are
(Malhotra et al., 2002). Such alterations are responsible for the apnoeas which may
not easily appreciable clinically, and require physiologically occur in normal subjects
imaging studies. while falling asleep, but may also contribute
to the cyclic occurrence of respiratory events
Functional factors in patients with SDB (Gaudette et al., 2010;
Increased upper airway collapsibility OSA is McKay et al., 2010).
characterised by increased collapsibility of
There are two pathophysiological
the oropharynx, which lacks rigid support
mechanisms involved in instability of the
structures. The Starling resistor is the
respiratory drive, the apnoeic threshold and
classical model to study collapsible tubes, an increased loop gain (Gaudette et al.,
and the critical closing pressure (Pcrit) is 2010; McKay et al., 2010). Briefly, the
defined as the pressure inside the airway at apnoeic threshold defines the level of PaCO2
which collapse occurs (Gaudette et al., 2010; (usually 1–2 mmHg below the eupneic
McKay et al., 2010). Pcrit is affected by waking level) at which ventilation stops
several factors, such as age, sleep stage, during NREM sleep. If arousal from sleep is
position, presence of obesity, oedema of the associated with hyperventilation,
airways and reflexes activated by negative hypocapnia ensues and apnoea develops
pressure. Upper airway dilator muscles when sleep is re-established.
actively counteract airway collapse
(Gaudette et al., 2010; McKay et al., 2010). The loop gain is a complex mechanism
Drugs such as benzodiazepines defining the response of the respiratory
(Guilleminault, 1990) or alcohol (Peppard centre to a change in CO2. The larger this
et al., 2007) negatively affect respiratory response, the higher the instability in
drive and upper airway collapsibility, and respiratory drive. The reader is referred to
worsen SDB. During clinical assessment Gaudette et al. (2010) and McKay et al.
patients with suspected SDB should be (2010) for a comprehensive description of
asked specific questions regarding the use this topic. See also the articles on CSA in
of such substances. chapter 2 of this book. Gaudette et al. (2010)
summarises the role of an unstable
Airway inflammation Inflammation respiratory drive in the pathogenesis of
contributes to upper airway alterations in sleep apnoea. Such a mechanism is central
OSA patients and is caused by mechanical to explain central apnoeas, but can also be
trauma associated with snoring or apnoeas, important in OSA. Clinical markers of an
and oxidative stress associated with hypoxia- unstable respiratory drive are scarce; some
reoxygenation. Factors that can worsen the patients may report difficulty in maintaining
inflammatory milieu in OSA patients include sleep due to frequent awakenings with sense
smoking, allergy or systemic inflammation of suffocation due to apnoeas. Arterial blood
(see Gaudette et al., 2010 for more details). gases during wakefulness can show a
Such factors should also be actively tendency towards hypocapnia. Occurrence
investigated in the clinical assessment of of central or mixed apnoeas during a
patients with SDB. nocturnal recording is also suggestive of an
Instability of respiratory drive The complex unstable respiratory drive.
response to obstructive apnoeas during Associated diseases
sleep is associated with sleep
fragmentation, as the arousal is necessary to Several diseases which increase the risk of
re-establish airway patency. The shift from developing SDB have been recognised.
wakefulness to sleep is associated with Some congenital syndromes predispose to
reduced respiratory drive, i.e. the response SDB due to craniofacial or upper airway
of the respiratory centre to chemical and alterations (Pierre Robin and Down’s

syndrome, among others). They are usually syndrome. Therefore, patients who have
of paediatric pertinence, but can occasionally previously had a stroke should be carefully
be seen in adults referred for sleep studies. investigated for sleep disorders.
Obesity is by far the most frequent disease Chronic kidney disease may predispose to
predisposing to OSA, especially in subjects OSA through the mechanisms of volume
showing central fat distribution (Gaudette overload and nocturnal shift of fluid from
et al., 2010). Obesity explains, at least in peripheral tissues (Mavanur et al., 2010).
part, the increased frequency of SDB found
in many other diseases, such as Down’s The role of gastro-oesophageal reflux
syndrome or hypothyroidism. The close disease (GERD) in OSA is debatable.
relationship between obesity and OSA is Improvement of OSA was shown in subjects
confirmed by the changes in OSA severity with documented pathological proximal pH-
associated with weight changes. metry after proton pump inhibitor
treatment, but no randomised controlled
Endocrine disorders can be associated with trial is available on this topic (Karkos et al.,
SDB (Attal et al., 2010). Approximately 10% 2009). Given the high prevalence of both
of obese patients with suspected OSA show OSA and GERD, it is advisable to enquire
subclinical hypothyroidism. Acromegaly about GERD symptoms in patients with
modifies upper airway structure by affecting suspected OSA.
both soft tissues and bones, and about two-
thirds of acromegalic patients show OSA.
Further reading
Diabetes is often associated with both
central and obstructive events during sleep N Attal P, et al. (2010). Endocrine aspects of
(Rasche et al., 2010). The polycystic ovary obstructive sleep apnea. J Clin Endocrinol
syndrome also carries a high risk for OSA Metab; 95: 483–495.
(Nitsche et al., 2010). N Gaudette E, et al. (2010). Pathophysio-
logy of OSA. Eur Respir Monogr; 50: 31–50.
Chronic HF predisposes to central apnoeas, N Guilleminault C. (1990). Benzodiaze-
and especially to Cheyne–Stokes breathing pines, breathing, and sleep. Am J Med;
(McKay et al., 20110; Naughton et al., 2010). 88: 25S–28S.
OSA is also frequent and should be N Karkos PD, et al. (2009). Reflux and
suspected in overweight/obese patients with sleeping disorders: a systematic review.
chronic HF with a clinical history of snoring J Laryngol Otol; 123: 372–374.
(Naughton et al., 2010). Identification of N Kirkness JP, et al. (2008). Contribution of
these patients is important, since untreated male sex, age, and obesity to mechanical
OSA increases cardiovascular risk. instability of the upper airway during
sleep. J Appl Physiol; 104: 1618–1624.
Stroke is often associated with SDB (Ramar N Kohler M, et al. (2007). The role of the
et al., 2010). According to epidemiological nose in the pathogenesis of obstructive
studies, OSA often precedes stroke and sleep apnoea and snoring. Eur Respir J;
could be a risk factor. Many patients show 30: 1208–1215.
N Launois SH, et al. (2007). Sleep apnea in
severe OSA after a stroke, but CPAP
the elderly: a specific entity? Sleep Med
treatment is problematic in these patients
Rev; 11: 87–97.
and often not accepted. Central apnoeas N Lee RW, et al. (2010). Differences in cranio-
and CSR have been shown to occur quite facial structures and obesity in Caucasian
commonly in the acute phase of stroke, but and Chinese patients with obstructive sleep
spontaneously resolve with time and rarely apnea. Sleep; 33: 1075–1080.
need treatment, unless concomitant chronic N Lin CM, et al. (2008). Gender differences
HF is found. It should be noted that stroke in obstructive sleep apnea and treatment
can be associated with several other sleep implications. Sleep Med Rev; 12: 481–496.
disorders, such as insomnia, hypersomnia, N Lindberg E. (2010). Epidemiology of OSA.
circadian rhythm disturbances and periodic Eur Respir Monogr; 50: 51–68.
leg movements during sleep or restless leg

N Malhotra A, et al. (2002). The male independent predictor of obstructive
predisposition to pharyngeal collapse: sleep apnea. Sleep; 29: 903–908.
importance of airway length. Am J Respir N Peppard PE, et al. (2007). Association of
Crit Care Med; 166: 1388–1395. alcohol consumption and sleep disor-
N Mavanur M, et al. (2010). Sleep disordered breathing in men and women.
dered breathing in patients with chronic J Clin Sleep Med; 3: 265–270.
kidney disease. Indian J Med Res; 131: N Ramar K, et al. (2010). The relationship
277–284. between sleep disorders and stroke.
N McKay LC, et al. (2010). Physiology and Postgrad Med; 122: 145–153.
neural control of breathing during sleep. N Rasche K, et al. (2010). Obstructive sleep
Eur Respir Monogr; 50: 1–16. apnea and type 2 diabetes. Eur J Med Res;
N Naughton MT, et al. (2010). Sleep apnoea 15: Suppl. 2, 152–156.
in chronic heart failure. Eur Respir N Schwab RJ, et al. (2003). Identification of
Monogr; 50: 396–420. upper airway anatomic risk factors for
N Nitsche K, et al. (2010). Obstructive sleep obstructive sleep apnea with volumetric
apnea and metabolic dysfunction in magnetic resonance imaging. Am J Respir
polycystic ovary syndrome. Best Pract Crit Care Med; 168: 522–530.
Res Clin Endocrinol Metab; 24: 717–730. N Villaneuva AT, et al. (2005). Ethnicity and
N Nuckton TJ, et al. (2006). Physical obstructive sleep apnoea. Sleep Med Rev;
examination: Mallampati score as an 9: 419–436.

Diagnostic algorithms
Josep M. Montserrat, Ferrán Barbé and Juan Fernando Masa
The gold standard for the diagnosis of bands and oximetry (respiratory
OSAH is attended PSG, but this is time- polygraphy). Different national
consuming and expensive. The prevalence, recommendations also endorse this
morbidity and mortality of OSAH, as well as strategy, including the excellent French
the increasing awareness of the problem in guidelines (Société de Pneumologie de
both the medical community and the Langue Française, 2010). Nowadays,
general population, have increased the however, some other important aspects
demand for consultations and diagnostic must be taken into account, as the whole
studies in recent years. There is, therefore, a diagnostic management picture is about to
growing interest in alternative diagnostic change in several important ways and, in
methods and approaches. The American fact, some changes can already be noted.
Academy of Sleep Medicine (AASM) The most significant of these are the
recommends home diagnosis with portable involvement of different fields or levels of
monitoring devices in patients with a high medicine, the search for strategies that
pre-test probability of moderate-to-severe guarantee cost-effectiveness, the
OSAH but no significant comorbidities development of telemedicine (Masa et al.,
(Collop et al., 2007). A negative result 2011a, b) and, finally, the current re-
should lead to a PSG. Of the four systems examination of the real role of the diagnostic
for OSAH evaluation available (level 1: sleep procedure for level 4 (one or two respiratory
laboratory PSG; level 2: unattended PSG; variables) (Thornton et al., 2012). Before
level 3: respiratory polygraphy; level 4: one or moving onto a description of the different
two respiratory variables), the AASM’s strategies applied to diagnostic
minimum recommendation proposed the management, a few points need to be
use of a type 3 portable monitoring device considered.
that includes airflow, thoracoabdominal
1. At present, the typical population in
need of OSAH evaluation is quite
Key Points different from that of a few years ago
(table 1). This change in the population
N There has been a shift from laboratory affects diagnosis strategies because
PSG to home portable monitoring in some patients are more difficult to
patients with a high pre-test probability diagnose and, therefore, full PSG is
of OSAS. mandatory in a significant number of
cases.
N Two groups of patients need to be
2. Most patients, at least in some
evaluated: i) those with symptoms;
countries, are controlled by the sleep
and ii) those with risk factors for OSAS.
clinic of a fully equipped reference
N A network approach is likely to be the hospital (Hernández et al., 2007), which
best care model for managing the means that only a minority are
growing sleep medicine caseload. controlled in primary medicine (fig. 1a).
It is important to consider this aspect

Table 1. ‘‘Typical’’ and actual characteristics of people who need OSAH evaluation.
‘‘Typical’’ patients Actual patients
‘‘Pickwickian syndrome’’ Elderly patients, children
Obesity Pregnancy
Heavy snoring Fibromyalgia
Pauses in breathing UPPP
Systemic hypertension Maxillomandibular surgery
Bariatric surgery
Cardiovascular patients
Nonclinic population
Mild-to-moderate symptoms
Neurological and psychiatric diseases
Myopathies and metabolic diseases
UPPP: uvulopalatopharyngoplasty.
because when a disease is prevalent, all All three of these points needed to be taken
medical levels must be involved and into consideration in our approach to the
equipped with the appropriate diagnostic management of OSAH patients.
technology to screen or diagnose
patients, or at least severe ones. Regardless of the strategy chosen for OSAH
diagnosis (as discussed later), figure 2 shows
3. Finally, as a consequence of points 1 a summary of the various aspects and steps
and 2, and the prevalence of the that must always be followed in every case. As
disease, a network system is needed for can be seen at the top of figure 2, two groups
the management of these patients of patients need to be evaluated.
(fig. 1b), because a network optimises
the use of knowledge emerging from 1. Those patients with symptoms (we plan
interactivity. In other words, the whole to treat the symptoms).
network is more than the sum of its 2. Those patients with risk factors (we
individual parts. plan to treat the risk factors) for OSA,
a) At present Future b)
Reference hospital
Nonreference hospitals
Specialists
Family medicine Network Non-network

Optimal conditions Nonoptimal conditions
Nurses Cost-effective Not cost-effective
Figure 1. a) Left: the current situation. Most patients are managed by the reference hospital. Right: the
most reasonable follow-up approach when a disease is common. All the medical levels should be involved
and when sleep apnoea is mild, family medicine should be implicated. b) Intercommunication between
the different levels is the optimal way of working. As mentioned in the text, a network optimises the use of
knowledge emerging from interactivity. Orange: reference hospitals; light blue: nonreference hospitals;
dark blue: family physicians; red: other medical levels.

Patients at high risk Patients that need Symptoms
Hypertension (resistant) to be evaluated Snoring
Obesity (BMI >35 kg·m-2), Witnessed apnoeas
especially in professional drivers Nocturia
Before bariatric surgery Daytime somnolence or fatigue
Pulmonary hypertension Unrefreshing sleep
Metabolic disturbances and
arrhythmias (AF)
Stroke and cardiac failure
Myopathies
Some respiratory disease
with hypercapnia
Differential diagnosis OSAH Intensity of the symptoms

Sleep hygiene clinical assessment Somnolence that clearly
Sleep restriction disturbs social or work life
Narcolepsy Somnolence while driving
RLS Severe episodes of choking
Insomnia Compressive history and
Depression examination
Drugs that induce somnolence Broad ENT examination
Different neurological disease Spirometry in smokers
Basic blood test with
glycosylated Hb
Check for reflux
Sleep study
Clear sleep apnoea symptoms without Symptoms with known comorbidity or

known comorbidity suspicion of nonrespiratory sleep disorders
If discordance between
RP PSG
symptoms and RP
Figure 2. The three steps that should always be followed when sleep apnoea is suspected: detection
(patients to be evaluated); clinical assessment for the differential diagnosis and assessment of the clinical
severity of the disease; and, finally, the sleep study, which should be undertaken on the basis of a pre-test
possibility of sleep apnoea and the presence or otherwise of known comorbidity. AF: atrial fibrillation; RLS:
restless legs syndrome; Hb: haemoglobin; RP: respiratory polygraphy.
despite the absence of classical (Barbé et al. 2010). In contrast, the role
symptoms. In this case, some of CPAP treatment in all spectrums of
uncertainty exists over aspects of the patients with asymptomatic OSA and
treatment. Of course, these patients metabolic syndrome is not clear at
need to be evaluated, but the effects of present (Sharma et al., 2011; Lam et al.,
treatment with CPAP have not been fully 2012). In these cases, more long-term
demonstrated in every part of the interventional trials are still needed
situation presented in figure 2. In (Lam et al., 2012).
patients with refractory hypertension, it
is clear that they can be asymptomatic Therefore, the key point in deciding whether
and that treatment of OSA with CPAP a sleep study is performed is the history of
significantly improves blood pressure symptoms obtained by the physician. This

Table 2. Basic entities in OSAH.
Daytime somnolence Bad sleep hygiene or insufficient sleep
Shift work
Sleep apnoea
Depression
Narcolepsy
Narcolepsy Cataplexy: sudden and transient episode of loss of muscle tone
triggered by emotions
Restless legs syndrome Need to move the legs to stop uncomfortable leg sensations
that improve with moving
Disturbs sleep and can induce insomnia and somnolence
Depression Lack of interest and pleasure in daily activities, insomnia or
excessive sleeping, lack of energy or inability to concentrate
Negative thoughts of death or even suicide
Insomnia Difficulty initiating (20 min) or maintaining sleep with the
perception of poor-quality sleep
Can produce tiredness or somnolence during the day or be a
symptom of depression
Somnolence induced by drugs Antianxiety drugs, some antidepressants or antihistamines or
narcotics
Others such as pramipexole
Neurological diseases Infections, tumours, Steiner myopathy, stroke etc.
Other sleep disorders
REM behaviour disorders Singular behaviours during sleep, usually violent
In some cases, will result in injury to the bed partner
In some cases, precedes brain degenerative diseases
(Parkinson’s)
Classical parasomnias Somnambulism, nocturnal terrors, nightmares and the basic
chronobiological entities
will also determine the type of test chosen are the major OSAH symptoms but they are
and the urgency of its application. In the sometimes confusing as they can have
case of high-risk patients with no major different causes, which must also be well
symptoms or no symptoms at all, a sleep understood. The most important of these
test is mandatory in patients with alternatives are insufficient sleep time and
noncontrolled hypertension or heart disease depression. Moreover, the severity of the
with an ejection fraction ,40%, or in those symptoms must be checked. As regards
who are truncally obese professional drivers. somnolence, in addition to the classic
questionnaires, which of course must be
The next step is the clinical assessment of used, two simple questions need to be
OSAH, as shown in figure 2. First of all, a asked: whether sleepiness induces
good differential diagnosis should be drowsiness that hinders work or social life
reached. Table 2 shows the basic entities (especially in the morning) and whether the
that any professional working with OSAH patient experiences somnolence while
needs to know: differential diagnosis, how to driving. Choking episodes during the night
diagnose, management and the basic can also be very stressful. On the basis of all
features of treatment, as well as differential these data, the appropriate type of sleep
diagnosis taking into account other causes study can be chosen along the lines shown
of somnolence and daytime fatigue; these in figure 2. This procedure is advocated by

a)
High pre-test
RP
probability
SAHS suspicion Sleep unit
Reference hospital
Low pre-test
Some hospitals perform full PSG in all patients Full PSG
probability
b)
Special patients (known diseases, insomnia,
depression, or suspicion of neurological entities)
Sleep unit
Reference hospital
Sleep unit Difficult Multidisciplinary team
Nonference hospital patients
SAHS suspicion Fully equipped
RP
Family physicians
or other specialist Can diagnose and manage a
significant number of patients
Family physicians or other specialist

c) Simplified devices
Sleep unit
Nonreference hospital
SAHS suspicion RP
Family physicians or
Sleep unit
other specialist
Reference hospital
Multidisciplinary team
Fully equipped
Figure 3. A summary of the various diagnostic strategies on offer. Although this will depend on the
characteristics of each centre or country, (b) is probably the most well-balanced. Reference and
nonreference hospitals are involved in two types of sleep test. a) is the most classical approach. It is only
performed in reference centres and sometimes all patients are studied via a full PSG. Finally, c) represents
what could happen in the future when a family physician or nonhospital specialist may use simple
technology to play an important role in screening and even diagnosis. In the latter case, in particular, this
will occur when sleep medicine has become well understood and incorporated into the daily routine of non-
hospital physicians. RP: respiratory polygraphy.
several sleep societies, including the Spanish management model. Some groups use only
Sleep Network (Lloberes et al., 2011). full PSG for OSAH diagnosis, although a
number of centres use respiratory
Moving more specifically onto the different polygraphy when patients show a high
diagnosis strategies on offer, figure 3 possibility of having OSAH but do not
summarises the various possibilities, present any notable comorbidity. All these
illustrating the maxim that when a disease is procedures, however, are performed in
common, almost all medical levels must be reference hospitals and, therefore, as can be
involved. This means a networking seen in table 1, these centres are
approach, in which each patient is managed overcrowded. Figure 3b shows what would
at the appropriate medical level, such as a perhaps be the most adequate approach to
reference or nonreference hospital or a diagnosis management nowadays, with
family physician. All these levels probably nonreference hospitals handling a
need to be involved, especially during follow- significant number of patients, always in
up, but also in the diagnosis strategy. accordance with the guidelines of figure 2.
Figure 3a shows the classic diagnosis When full PSG is needed, patients should be

sent to a reference hospital. Finally, figure 3c N Collop NA, et al. (2007). Clinical guide-
shows what could, and ideally will, happen lines for the use of unattended portable
in the near future if we want to reach all our monitors in the diagnosis of obstructive
patients. Even family physicians could sleep apnea in adult patients. Portable
diagnose very typical patients, probably with Monitoring Task Force of the American
the use of simplified devices. One important Academy of Sleep Medicine. J Clin Sleep
factor, as mentioned above, and as pointed Med; 3: 737–747.
out recently by Masa et al. (2001a, b), is N Dempsey JA, et al. (2010). Pathophysiology
of sleep apnea. Physiol Rev; 90: 47–112.
cost-effectiveness. The study of Masa et al.
N Durán J, et al. (2001). Obstructive sleep
(2001a, b) focused on patients with apnea–hypopnea and related clinical fea-
suspected OSAH due to the presence of tures in a population-based sample of
snoring, observed apnoeas, sleepiness (ESS subjects aged 30 to 70 yr. Am J Respir Crit
score .10) or unrefreshing sleep, while Care Med; 163: 685–689.
excluding patients with other suspected N Hernández L, et al. (2007). Management
sleep disorders or severe and unstable heart of sleep apnea: concordance between
disease, or those who were unable to set up nonreference and reference centers. Chest;
respiratory polygraphy by themselves. The 132: 1853–1857.
authors’ main conclusions were that a home N Lam JC, et al. (2012). Obesity, obstructive
respiratory polygraph connected to a sleep apnoea and metabolic syndrome.
hospital via a telemetric procedure can Respirology; 17: 223–236.
exclude and confirm the diagnosis of OSAH N Lloberes P, et al. (2011). Diagnosis and
treatment of sleep apnea–hypopnea syn-
and that home respiratory polygraphy has
drome. Spanish Society of Pulmonology
the same diagnostic efficacy as PSG, at half
and Thoracic Surgery. Arch Bronconeumol;
the cost (or even less). Therefore, a 47: 143–156.
satisfactory cost-efficiency could be attained N Marin JM, et al. (2005). Long-term
by following this strategy. cardiovascular outcomes in men with
obstructive sleep apnoea-hypopnoea with
Lastly, another important question is how to or without treatment with continuous
approach the level 4 procedure (one or two positive airway pressure: an observational
respiratory variables) in OSAH diagnosis. study. Lancet; 365: 1046–1053.
Once sleep medicine is more widely N Masa JF, et al. (2011a). Therapeutic
understood, however, all the procedures decision-making for sleep apnea and
mentioned above will be complementary, hypopnea syndrome using home respira-
because networking is cost-effective and tory polygraphy: a large multicentric
essential, as it is the only way to reach most study. Am J Respir Crit Care Med; 184:
patients. Accreditation in sleep medicine 964–971.
represents a huge advance. Medical N Masa JF, et al. (2011b). Effectiveness of
preparation and knowledge that will allow a home respiratory polygraphy for the
good clinical evaluation to be made is the diagnosis of sleep apnoea and hypop-
noea syndrome. Thorax; 66: 567–573.
best sleep test of all.
N Montserrat JM, et al. (2001). Effective-
ness of CPAP treatment in daytime
function in sleep apnea syndrome: a
randomized controlled study with an
Further reading optimized placebo. Am J Respir Crit Care
Med; 164: 608–613.
N Barbé F, et al. (2010). Long-term effect of N Sharma SK, et al. (2011). CPAP for the
continuous positive airway pressure in metabolic syndrome in patients with
hypertensive patients with sleep apnea. obstructive sleep apnea. N Engl J Med;
Am J Respir Crit Care Med; 181: 718–726. 365: 2277–2286.

N Societe de Pneumologie de Langue N Terán-Santos J, et al. (1999). The associa-
Francaise. (2010). Recommandation pour tion between sleep apnea and the risk of
la pratique Clinique. Syndrome d’apnées traffic accidents. Cooperative Group Burgos-
hypopnées obstructive du sommeil de Santander. N Engl J Med; 340: 847–851.
l’adulte. [Recommendations for clinical N Thornton AT, et al. (2012). AASM criteria
practice. Obstructive sleep apnea hypop- for scoring respiratory events: interaction
nea syndrome in adults]. Rev Mal Respir; between apnea sensor and hypopnea
27: 806–833. definition. Sleep; 35: 425–432.

Quality of life
Maria R. Bonsignore
Quality of life is defined as ‘the overall state medical field, analysis is usually restricted to
of well-being that individuals experience as health-related quality of life (HRQoL), i.e.
assessed by subjective and objective the aspects more strictly correlated with the
measures of functioning, health and health status of patients with regard to the
satisfaction with the important dimensions effects of their disease. The instruments for
of their lives’ (Reimer et al., 2003). HRQoL assessment are usually in the form
Assessment of quality of life in patients with of questionnaires developed according to
SDB or other sleep-related pathological the most common complaints associated
conditions is an important issue, since it with poor health in different domains of life
allows us to appreciate the real effects of the (Reimer et al., 2003; Weaver, 2001).
disease on several domains of patients’ lives
(Reimer et al., 2003; Weaver, 2001). Evaluating HRQoL helps to understand the
effects of a given disease on patients
Quality of life includes many complex items, compared with healthy individuals from the
such as the level of satisfaction related to general population, but is even more
housing conditions or current job. In the important in evaluating the effects of
treatment. An effective treatment for a
certain disease should not only normalise or
Key points improve a chosen disease indicator but also
cause tangible improvement in the daily life
N HRQoL measures the impact of a of patients, since the latter is the real reason
disease on several domains of life of that leads patients to seek medical care.
the patients and is an important Hence, large randomised clinical studies
outcome in the evaluation of commonly include evaluation of HRQoL
treatment. among their outcomes, since a positive
effect of treatment on HRQoL is of utmost
N HRQoL can be measured by generic importance for patients and for assessment
and disease-specific instruments, of cost/benefit ratios of healthcare.
which are generally in the form of
questionnaires. Both types have been There are several questionnaires available
used in patients with OSAS or other for evaluation of HRQoL, but the main
sleep disorders. distinction is between ‘generic’ and ‘disease-
N OSAS significantly affects HRQoL and specific’ instruments. The former are useful
CPAP treatment causes improvement to assess HRQoL in heterogeneous
in several domains. populations and compare the effects of
different disease states; however, they can
N The effects of OSAS on HRQoL are be relatively insensitive to the effects of a
limited in elderly patients, in whom specific disease or its treatment. Conversely,
HRQoL appears more linked to disease-specific questionnaires have been
occurrence of comorbidities than developed based on complaints reported by
to SDB. affected patients and provide valuable, in-
depth information on the effects of the

disease on different HRQoL domains Despite their limited sensitivity in the
(Reimer et al., 2003; Weaver, 2001). Several assessment of sleep complaints, such
such instruments have been developed for questionnaires have been used to measure
OSA, as well as restless legs syndrome, HRQoL in the general population and
narcolepsy and insomnia. In 2001, the analyse the effects of OSAS and other sleep
World Health Organization developed the disorders. In the Sleep Heart Health Study
International Classification of Functioning, (SHHS), mild-to-moderate SDB was
Disability and Health (ICF) and an ‘ICF Core associated with decreased vitality, whereas
Set for Sleep Disorders’ is currently under severe SDB was associated with low HRQoL
study in order to identify the best existing assessed by SF-36, with overall scores
instruments or develop new ones according similar to those associated with other
to a standardised method to be used at chronic disease states (Baldwin et al., 2001).
large in the context of a common More recent data from the SHHS suggest
biopsychosocial framework (Gradinger et al., that sleepiness, difficulty in maintaining
2011). Due to the large number of generic sleep (DIMS) and low HRQoL are found
and specific instruments available and especially in patients with SDB occurring in
space limitations, this chapter will NREM sleep, while REM-predominant
summarise available evidence for HRQoL in events seem not to exert detrimental effects
patients with OSAS. The interested reader is on HRQoL (Chami et al., 2010).
referred to the review by Gradinger et al.
(2011) for further information regarding 115 In clinical series of OSAS patients, the
questionnaires used to evaluate HRQoL in subscales ‘physical functioning’, ‘general
patients with OSAS or other sleep disorders. health’ and ‘role limitation due to physical
problems’ of SF-36 were shown to correlate
Generic instruments for HRQoL with measures of sleep fragmentation
assessment (Goncalves et al., 2004). However, PSG
measures of OSAS severity correlated weakly
The most commonly used generic with self-reported measures obtained by the
instrument for assessment of HRQoL is the SF-36 (Goncalves et al., 2004; Weaver et al.,
Medical Outcomes Study 36-item short-form 2004). Finally, in elderly patients, HRQoL was
health survey (SF-36) (Ware et al., 1992). It is unaffected by OSAS and its reduction was
a self-administered questionnaire covering best explained by occurrence of comorbidities
eight dimensions of health (physical (Martinez-Garcia et al., 2009).
functioning, role limitation due to physical
problems, role limitation due to emotional As for the effects of CPAP treatment,
problems, social functioning, mental health, Bennett et al. (1999) were the first to
energy/vitality, body pain and general health demonstrate a positive effect of CPAP on SF-
perception). The SF-36 does not include 36. More recently, a meta-analysis
questions on sleep, but is widely used and documented improvements in treated versus
validated in different languages. In Europe, untreated OSAS patients in physical
the Nottingham Health Profile (NHP) is also function, body pain, energy vitality and the
popular, has the advantage of being easily physical component summary of SF-36 and
administered and includes sleep in NHP part 2 (Jing et al., 2008).
assessment (Hunt et al., 1980). Disease-specific instruments for HRQoL in
One major problem with generic HRQoL sleep disorders
instruments is that they are insensitive in Disease-specific instruments have been
detecting subtle differences, especially in developed in the last two decades to
subjects with very good or very poor HRQoL address the problem of HRQoL in patients
(so-called ‘ceiling’ and ‘floor’ effects). Their with sleep disorders (Reimer et al., 2003;
widespread use, however, has produced a Weaver, 2001).
large amount of data in the last few decades,
which represent solid background 1. The Functional Outcome of Sleep
information on many disease states. Questionnaire (FOSQ) is a 30-item self-

administered instrument (Weaver et al., symptoms, but also emotional and social
1997). It provides information on disturbances. The physician should be aware
difficulties encountered by patients in of the concept and utility of HRQoL
performing selected tasks and roles assessment in daily practice and be able to
because of excessive daytime employ validated instruments to objectively
sleepiness (EDS). Domains explored document HRQoL before and after
are: activity level, vigilance, intimacy treatment. Some data also indicate that bed
and sexual relationships, general partners of OSAS patients improve their
productivity, and social outcome. The quality of life when CPAP treatment is
FOSQ has two major advantages, the started, suggesting that the HRQoL
first being the possibility of a ‘did not implications of OSAS treatment extend to
engage’ answer for activities not family members of the patients. Finally,
performed by the patient for reasons assessment of new treatments must include
other than sleepiness. The second HRQoL evaluation, as only treatments with
advantage is that it explores the positive impact on HRQoL are really of
intimacy/sexual domain, which is often benefit for the patients.
disregarded by other questionnaires.
The FOSQ performs well in the
assessment of treatment-induced Further reading
changes and a short 10-item version
has been recently introduced (Chasens N Baldwin CM, et al. (2001). The association
et al., 2009). of sleep-disordered breathing and sleep
2. The Calgary Sleep Apnea Quality of Life symptoms with quality of life in the Sleep
Index (SAQLI) is a 45-item Heart Health Study. Sleep; 24: 96–105.
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domains: daily functioning, social obstructive sleep apnea: relationship with
interactions, emotional functioning, sleep fragmentation and daytine sleepi-
symptoms and treatment-related ness, and effects of continuous positive
airway pressure treatment. Am J Respir
symptoms (Flemmons et al., 2002). It
Crit Care Med; 159: 1884–1890.
is administered by a trained inteviewer;
N Chami HA, et al. (2010). Sleepiness,
3. The Quebec Sleep Questionnaire quality of life, and sleep maintenance in
(QSQ) is a 32-item, self-administered REM versus non-REM sleep-disordered
questionnaire, similar to the SAQLI breathing. Am J Respir Crit Care Med;
(Lacasse et al., 2004). 181: 997–1002.
N Chasens ER, et al. (2009). Development
In general, at least for research purposes,
of the FOSQ-10: a short version of the
different instruments are used at the same
functional outcomes of sleep question-
time, such as the combination of a generic naire. Sleep; 32: 915–919.
with a disease-specific questionnaire, in N Flemmons WW, et al. (2002). Measure-
order to encompass multiple aspects of ment properties of The Calgary Sleep
HRQoL, often with the addition of the ESS Apnea Quality of Life Index. Am J Respir
and the Beck Depression Inventory (BDI). Crit Care Med; 165: 159–164.
Depression is a common finding in patients N Goncalves MA, et al. (2004). Obstructive
with sleep disorders and may independently sleep apnea syndrome, sleepiness, and
contribute to worsening HRQoL (Harris et quality of life. Chest; 125: 2091–2096.
al., 2009). N Harris M, et al. (2009). Obstructive sleep
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currently under development (Gradinger et approach to perceived health status: a
al., 2011), it is important to carefully and validation study. J Epidemiol Community
sympathetically listen to patients’ Health; 34: 281–286.
complaints regarding not only physical

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of continuous positive airway pressure in tion. Med Care; 30: 473–483.
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syndrome: a meta-analysis. Lung; 186: graphy vs self-reported measures in
131–144. patients with sleep apnea. Arch
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questionnaire specific to obstructive measure functional status outcomes for
sleep apnea. Thorax; 59: 494–449. disorders of excessive sleepiness. Sleep;
N Martinez-Garcia MA, et al. (2009). 20: 835–843.
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on quality of life in the elderly. Sleep Med; ment in sleep medicine practice and
10: 104–111. research. Part 1: assessment of symp-
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Surgical and anaesthesia risk
assessment
Maria R. Bonsignore
OSA patients may encounter problems

when undergoing general anaesthesia and
Key points
surgical procedures (Vasu et al., 2012).
Retrospective studies in surgical patients
N The high prevalence of unrecognised
have reported increased respiratory
OSA in the general population and
complications in patients with a pre-
the increased OSA-associated
operative oxygen desaturation index (ODI)
perioperative risk have alerted
.5 events?h-1 (Hwang et al., 2008) or a high
anaesthesiologists to the need to
incidence of perioperative complications,
detect patients at high risk of OSA.
especially occurrence of periods of oxygen
N Short clinical questionnaires are desaturation, in OSA compared with non-
useful in identifying patients at high OSA patients (Liao et al., 2009). In a very
risk of OSA, and several protocols large retrospective study, Memtsoudis et al.
have been developed for their (2011) reported a high incidence of
perioperative management. perioperative pulmonary complications in
OSA patients undergoing orthopaedic or
N OSA patients may undergo
general surgical procedures, including
problems at intubation (difficult
aspiration pneumonia, acute respiratory
airways) or extubation (slow or
distress syndrome (ARDS) and intubation/
insufficient recovery of upper airway
mechanical ventilation.
muscle tone); the most frequently
encountered problem is the The common association of OSA with
development of hypoxaemia in both obesity makes its prevalence especially high
immediate and delayed post- in patients undergoing bariatric surgery.
surgical periods. Such surgical procedures are increasingly
N Use of opioids for analgesia may common due to the rising prevalence of
precipitate hypoventilation and/or morbid obesity. Screening of these patients
central apnoeas and should be by cardiorespiratory monitoring or
avoided. Day surgery procedures simplified devices is nowadays standard
should also be avoided in patients practice before surgery, and OSA is usually
at risk. detected and treated pre-operatively.
Anaesthesiologists are aware of OSA in this
N Patients with known OSA treated population and can adopt preventive
with CPAP do not show increased strategies to control perioperative risk.
risk and should continue CPAP use
in the perioperative period. The real problem is that OSA is largely
underdiagnosed in the general population,
N Post-operative use of fixed or
and screening procedures cannot be
automatic CPAP in high-risk patients
extensively applied to all patients
not previously identified and treated
undergoing surgery. Therefore,
for OSA is not recommended.
anaesthesiologists need simple and reliable
tools to recognise patients at risk and

prevent OSA-related perioperative position is obtained by elevating the
complications. This is especially important if head, upper body and shoulders above
the burden of OSA comorbidities is the chest, in order to improve laryngo-
considered. A recent prospective scopic view (Neligan et al., 2009).
observational study estimated that about 24% 2. Difficult mask ventilation (DMV) under
of patients undergoing elective non-upper general anaesthesia was recently found
airway surgery are at high risk of OSA, and the to predict OSA in a prospective pilot
large majority of them are undiagnosed at the study (Plunkett et al., 2011).
time of surgical evaluation. 3. General anaesthesia causes marked
hypotonia of upper airway muscles,
For these reasons, practice guidelines on thereby increasing the risk of
perioperative management of OSA patients perioperative complications. OSA
were published by a Task Force of the patients are prone to develop upper
American Society of Anesthesiologists (ASA) airway problems at relatively mild
in 2006. Recent updates and algorithms to levels of anaesthesia, which can be
be used in the perioperative period were further worsened by depression of
published in 2010 (Seet et al. 2010; respiratory drive with low
Adesanya et al., 2010). responsiveness to chemical stimuli. All
these factors concur in increasing the
Questionnaires for clinical screening can
risk of oxygen desaturations after
facilitate pre-operative identification of OSA
extubation in the immediate post-
patients (table 1 (see also the
operative period, and in the following
‘‘Questionnaires on sleep’’ section of this
days, when a rebound in REM sleep
book)). The ASA checklist is different from
occurs post-surgery.
the others, as it considers the patient profile
4. Use of opioid medications for
but also the need for light or deep
analgesia may favour occurrence of
anaesthesia according to the planned
hypoventilation and hypercapnia or
surgery. The Berlin questionnaire and the
central apnoeas post-operatively, and
STOP-Bang score are excellent in identifying
should be limited in high-risk patients,
patients with an AHI .30 events?h-1, but are
with preference for short-action drugs.
less useful in mild disease. The STOP-Bang
score is increasingly popular, since it is The management strategy for patients at
based on four simple questions related to high risk of OSA, in view of surgical
Snoring, Tiredness, Observed apnoea, and procedure, is not yet evidence-based. The
blood Pressure, to which BMI, Age, Neck current attitude is to reserve special care to
circumference, and male sex information is patients identified as high-risk patients or
added by the clinician; all questions have patients with known OSA. In these high-risk
yes/no answers. Other questionnaires are patients without a previous diagnosis of
also used (table 1). The reader is referred to OSA, it has been suggested to delay elective
a recent meta-analysis for a comprehensive surgery in order to perform diagnostic
review of clinical screening instruments in studies and start CPAP treatment pre-
surgical patients (Ramachandran et al., 2009). operatively. Patients on CPAP with a good
compliance to treatment have been reported
The most common problems encountered to show a limited risk compared with OSA
in OSA patients are: patients not previously diagnosed or
showing a low compliance to CPAP
1. Intubation could be difficult due to treatment. These findings are possibly
upper airway anatomy or excess fat explained by the positive effects of CPAP on
deposits in the neck and occipital upper airway oedema and stability.
region. A prospective study in obese
subjects undergoing bariatric surgery Precautions should be implemented in the
reported no intubation problems when perioperative management of OSA patients.
a ramp position was used during the During surgery, monitoring of blood
intubation manoeuvre. The ramp pressure and arterial blood gases may be

Table 1. Clinical screening tools for OSA in surgical patients.
Validated Self-administered Reference
Berlin questionnaire Yes Yes Chung et al., 2008a
ASA checklist Yes No Gross et al. 2006; Chung et al., 2008a
STOP-Bang Yes Yes Chung et al., 2008b
SACS Yes No Flemons et al., 1994
PSAP score Yes No Ramachandran et al., 2010
SACS: Sleep apnoea clinical score; PSAP: perioperative sleep apnoea prediction.
indicated in high-risk patients. Extubation and adopt preventive strategies to limit

should be performed in the semi-recumbent perioperative risk. The most frequently
position to improve airway patency, reported complication in OSA patients is
preferentially when the patient is awake and post-operative hypoxaemia, but difficult
muscle tone is fully re-established. airway control or excessive loss of upper
Immediately after surgery, respiration and airway muscle tone can also occur.
oxygen saturation should be closely Measures to increase safety include: pre-
monitored for a sufficient time, in order to operative screening for OSA in high-risk
detect respiratory complications. patients and delay of surgery in order to
Occurrence of recurrent respiratory events start CPAP pre-operatively; use of short-
in the immediate post-operative period has acting anaesthetic drugs and extubation
been recognised to be associated with an when the patient is awake, and avoidance of
increased risk of oxygen desaturation in the opioids for post-operative analgesia.
subsequent period, warranting further Observation for an extended time post-
monitoring during the post-surgical period operatively is useful to detect patients who
in the hospital ward. For these reasons, day- need prolonged monitoring after surgery.
surgery procedures are not recommended in
high-risk patients, especially because
evidence-based information is not yet Further reading
available on its safety. N Adesanya AO, et al. (2010). Perioperative
management of obstructive sleep apnea.
Similarly, the use of CPAP is recommended
Chest; 138: 1489–1498.
post-operatively in patients already on
N Chung F, et al. (2008a). Validation of the
treatment, but evidence regarding the
Berlin Questionnaire and American
opportunity to use CPAP in surgical patients Society of Anesthesiologists checklist as
who had not been previously identified as screening tools for obstructive sleep
OSA patients is poor. It is worth noting that apnea in surgical patients. Anesthesio-
use of opioids for pain control may favour logy; 108: 822–830.
occurrence of central events, which are not N Chung F, et al. (2008b). STOP question-
effectively prevented by CPAP. A similar naire. A tool to screen patients for
reasoning can be applied to the use of obstructive sleep apnea. Anesthesiology;
automatic CPAP devices in the post- 108: 812–821.
operative setting, which is not currently N Chung F, et al. (2008c). Patients with
recommended. difficult intubation may need referral to
sleep clinics. Anesth Analg; 107: 915–920.
In summary, increased awareness of the N Finkel KJ, et al. (2009). Prevalence of undi-
perioperative complications associated with agnosed obstructive sleep apnea among
previously unrecognised OSA has prompted adult surgical patients in an academic
anaesthesiologists to routinely use standard medical center. Sleep Med; 10: 753–758.
questionnaires to detect high-risk patients

N Flemons WW, et al. (1994). Likelihood N Neligan PJ, et al. (2009). Obstructive
ratios for a sleep apnea clinical prediction sleep apnea is not a risk factors for
rule. Am J Respir Crit Care Med; 150: difficult intubation in morbidly obese
1279–1285. patients. Anesth Analg; 109: 1182–1186.
N Gross JB, et al. (2006). Practice guide- N Plunkett AR, et al. (2011). Does difficult
lines for the perioperative management mask ventilation predict obstructive sleep
of patients with obstructive sleep apnea: apnea? A prospective pilot study to identify
a report by the American Society of the prevalence of OSA in patients with
Anesthesiologists Task Force on Peri- difficult mask ventilation under general
operative Management of patients with anesthesia. J Clin Sleep Med; 7: 473–477.
obstructive sleep apnea. Anesthesiology; N Ramachandran SK, et al. (2009). A meta-
104: 1081–1093. analysis of clinical screening tests for
N Hwang D, et al. (2008). Association of obstructive sleep apnea. Anesthesiology;
sleep-disordered breathing with post- 110: 928–939.
operative complications. Chest; 133: N Ramachandran SK, et al. (2010).
1128–1134. Derivation and validation of a simple
N Kapur V, et al. (2002). Underdiagnosis of perioperative sleep apnea prediction
sleep apnea syndrome in U.S. commu- score. Anesth Analg; 110: 1007–1015.
nities. Sleep Breath; 6: 49–54. N Seet E, et al. (2010). Management of
N Liao P, et al. (2009). Postoperative sleep apnea in adults – functional algo-
complications in patients with obstruc- rithms for the perioperative period:
tive sleep apnea: a retrospective matched Continuing Professional Development.
cohort study. Can J Anesthesiol; 56: 819–828. Can J Anesth; 57: 849–864.
N Memtsoudis S, et al. (2011). Perioperative N Vasu TS, et al. (2012). Obstructive sleep
pulmonary outcomes in patients with apnea syndrome and perioperative com-
sleep apnea after noncardiac surgery. plications: a systematic review of the
Anesth Analg; 112: 113–121. literature. J Clin Sleep Med; 8: 199–207.

Comorbidity assessment
Maria R. Bonsignore
Comorbidities are frequent in OSA patients OSA (Smith et al., 2002). Such
and contribute to increased health costs in comorbidities include: hypertension,
the five years preceding the diagnosis of congestive HF, cardiac arrhythmias,
coronary artery and peripheral arterial
disease, COPD and depression. The high
prevalence of cardiovascular comorbidities
Key points highlights the potential role of OSA in
accelerating establishment and progression
N Assessment of comorbidities should of atherosclerotic lesions (Drager et al.,
be part of the diagnostic workup of 2011; Grote et al., 2010). Moreover, the
patients with OSA. common association of OSA with obesity
N Since untreated OSA is associated increases the risk of type II diabetes,
with increased cardiovascular dyslipidaemia and metabolic syndrome.
morbidity and mortality, special care Since OSA may independently contribute to
should be given to assess the pathogenesis of metabolic disorders
hypertension, cardiac hypertrophy and (Bonsignore et al., 2012), a modern clinical
other cardiovascular diseases, such as approach to OSA patients should aim at
coronary or vascular problems. assessing and correcting major comorbidities
that might contribute to the increased
N Assessment of COPD in smokers is cardiovascular morbidity and mortality in
advisable, since co-existence of OSA severe untreated OSA (Marin et al., 2005).
and COPD (overlap syndrome)
worsens respiratory function. Systemic hypertension
N Depression is common and often Although about 50% of OSA patients are
overlooked in OSA patients and may known to be hypertensive at diagnosis, as
improve with OSA treatment. shown by several studies in both clinical
N Metabolic abnormalities represent an series and the general population
important clinical topic. Assessment (Bonsignore et al., 2010), assessment of
of the metabolic syndrome by clinical blood pressure profile during sleep and
criteria is simple and inexpensive, wakefulness should be routinely obtained in
and allows risk stratification in the the diagnostic workup of all patients. It has
clinical setting. been convincingly shown that masked
hypertension, i.e. normal office blood
N There are no formal guidelines on the pressure but increased 24-h blood pressure
assessment of comorbidities in OSA level, is frequent in untreated OSA patients.
patients, and information in this Baguet and coworkers obtained ambulatory
section should be considered blood pressure monitoring (ABPM) for 24 h
suggestive, not mandatory, and based in 111 OSA patients, and found that normal
on current knowledge and medical blood pressure, masked hypertension, and
common sense. office hypertension each accounted for
about one-third of cases, whereas ‘‘white

Table 1. Diagnosis of the metabolic syndrome according to NCEP-ATP III criteria.
Elevated waist circumference In Caucasian men: .94 cm, women .88 cm
Elevated triglycerides o150 mg?dL-1, or treatment
Reduced HDL-cholesterol f40 mg?dL-1 in men, f50 mg?dL-1 in women, or
treatment
Elevated blood pressure Systolic o130 mmHg and/or diastolic o85 mmHg
Elevated fasting glucose o100 mg?dL-1, or treatment
A clinical diagnosis of the metabolic syndrome is based on occurrence of at least three of the criteria listed in
the table. Modified from Alberti et al., 2009 with pemission from the publisher.
coat’’ hypertension, i.e. high office blood patients is not evidence-based or currently
pressure with normal 24-h blood pressure recommended by any guideline.
level, was rarely observed (Baguet et al.,
2008). Therefore, ABPM should be obtained A dose–response effect between OSA
in OSA patients with normal office blood severity, in particular the degree of nocturnal
pressure in order to detect unknown hypoxaemia, and degree of left ventricular
hypertrophy, has been found in studies in
hypertension. ABPM should also be
OSA patients free from clinically evident
obtained in known hypertensives
cardiovascular abnormalities (Baguet et al.,
undergoing treatment, to check whether
2009). OSA appeared to be associated with
blood pressure is adequately controlled by
cardiac remodelling and altered diastolic
treatment. OSA is frequently associated with
function, and to exert an additive effect to
resistant hypertension, defined as lack of
that of increased blood pressure in patients
normalisation of blood pressure despite use
with both OSA and hypertension (Drager
of three or more anti-hypertensive
et al., 2007).
medications. Finally, because poorly
controlled blood pressure is associated with Most of the studies on the effects of CPAP
increased organ damage (left ventricular on cardiac abnormalities found significant
hypertrophy, vascular dysfunction, renal improvement of cardiac function, especially
damage), detecting abnormal blood diastolic, after OSA treatment (Noda et al.,
pressure values should prompt the 1995; Shivalkar et al., 2006). A recent long-
physician to extend assessment, and to term follow-up study documented a
monitor return towards the normal range of progressive improvement in cardiac
cardiovascular variables after initiation of remodelling in OSA patients on CPAP
CPAP treatment. treatment for a year and good compliance to
treatment, i.e. nightly use .4.5 h (Colish
Cardiac structure and function et al., 2012). These results are in line with
those obtained by a randomised controlled
Several studies have assessed the role of
study in patients with an average nightly use
OSA in causing cardiac hypertrophy with
of CPAP .6 h (Arias et al., 2005). However,
variable results, possibly explained by the
unchanged systolic and diastolic functions
concomitant effects of hypertension and
were found in patients with poor compliance
obesity. Interestingly, echocardiographic
to CPAP treatment (Akar Bayram et al., 2009).
studies suggest that cardiac hypertrophy
In patients with HF and OSA, there is evidence
involves not only the left but also the right that CPAP treatment improves left ventricular
ventricle (Baguet et al., 2008; Hanly et al., ejection fraction (Kasai et al., 2011).
1992), indirectly suggesting a role of OSA in
pulmonary hypertension. Therefore, Periodic assessment with ECG and
echocardiography appears clinically useful echocardiography might also be indicated in
and informative, although its use in OSA OSA patients with atrial fibrillation who fail

to maintain sinus rhythm after catheter but a clear cause–effect relationship
ablation (Ng et al., 2011). Weaker evidence between these two conditions has not been
suggests that CPAP treatment may also shown yet, possibly because of the
protect against recurrence of atrial multifactorial pathogenesis of both diseases
fibrillation in these patients. (see Ejaz et al., 2011 for review). Depression
has been evaluated by several tools in
Coronary artery disease and peripheral different studies; its prevalence is generally
arterial disease higher (up to five-fold) in OSA patients
Clinical history should focus on previous or compared with the general population. Poor
current symptoms of coronary artery disease sleep quality and sleepiness may play a role,
(CAD) or peripheral arterial disease (PAD) as may nocturnal hypoxaemia and cognitive
and their treatment, since patients with OSA dysfunction. The effects of CPAP treatment
and atherosclerotic disease may significantly on depression are also unclear. Use of self-
benefit from OSA treatment. There is clinical administered questionnaires to assess
and experimental evidence that intermittent depression and anxiety is advisable in
hypoxia and inflammation worsen vascular patients with OSA, together with careful
function and accelerate progression of enquiry on the use of antidepressant drugs
atherosclerosis. Obesity, however, is or benzodiazepines, since such drugs may
associated with multiple metabolic exert detrimental effects on upper airway
abnormalities that worsen the circulating muscle tone during sleep.
lipid profile, and intermittent hypoxia could Obesity and metabolic disorders
contribute to worsening of insulin resistance
and plasma lipids (Bonsignore et al., 2012). Central (or visceral) obesity is the most
Although definite clinical evidence is still frequent comorbidity associated with OSA
missing, recognising patients potentially at and its evaluation should be part of the
high risk for cardiovascular complications is routine management of OSA patients
a major task of the clinicians dealing with (Bonsignore et al., 2012; Lam et al., 2010).
OSA patients. Care should be taken to BMI, neck circumference and waist-to-hip
insure optimal treatment of such conditions. ratio should be routinely measured in OSA
patients during clinical assessment, and
Chronic obstructive pulmonary disease history should include questions about
Since COPD and OSA are known to diabetes or other endocrinological disorders
synergistically worsen respiratory function (i.e. thyroid disease, polycystic ovary
(‘‘overlap syndrome’’), smoking habits syndrome, etc.) associated with increased
should be carefully investigated and fat deposition.
spirometry and lung volume measurements Because OSA patients often show disturbed
should be obtained in patients suspected of glucose metabolism, fasting blood glucose
having both diseases. Both OSA and COPD and insulin should be routinely measured,
involve inflammatory activation, but little is and the homeostasis model assessment
known about the mechanisms at play when (HOMA) index calculated as a measure of
they co-exist in the same patient insulin resistance. Patients without known
(McNicholas, 2009). Some studies suggest diabetes should undergo an oral glucose
that pulmonary hypertension is more severe tolerance test, and glycosylated
in the overlap syndrome. Nocturnal oxygen haemoglobin should be measured in all
saturation should be monitored during patients since it appears as a sensitive index
follow-up, as these patients may require of abnormal glucose metabolism in OSA.
supplemental oxygen during sleep besides Similarly, plasma lipids (total cholesterol,
CPAP to maintain oxygen saturation .90%. triglycerides and high density lipoprotein
Depression (HDL)-cholesterol) are simple routine
measurements to be included in the
The frequent association between OSA and assessment of OSA patients. Finally,
depression has been known for a long time, because of the frequent occurrence of

Table 2. Assessment of comorbidities.
Comorbid condition Tests When to do them
Systemic hypertension Office blood pressure, ABPM Diagnosis (follow-up)
Cardiac hypertrophy, Echocardiography, ECG Diagnosis (follow-up)
atrial fibrillation
Atherosclerosis (coronary or ECG, Doppler Diagnosis (follow-up)
peripheral arterial disease)
COPD Spirometry, lung volume Diagnosis (follow-up)
measurements, arterial blood gases
Depression Questionnaires Diagnosis (follow-up)
Obesity BMI, neck circumference, waist-to-hip Diagnosis (follow-up)
ratio, plasma lipids, hepatic enzymes,
liver ultrasound
Diabetes Fasting blood glucose, insulin, Diagnosis (follow-up)
HOMA index, oral glucose tolerance
test, glycosylated haemoglobin
(HbA1c)
Metabolic syndrome NCEP-ATP III Diagnosis (follow-up)
hepatic steatosis, liver function should also of metabolic changes independently linked
be investigated by ultrasound and to OSA. It is also worth underlining that
measurement of hepatic enzymes, although most randomised controlled studies on the
the latter are not sensitive for the diagnosis effects of CPAP on metabolism were short-
of non-alcoholic fatty liver disease (NAFLD). term, and changes may require a longer time
to become evident. In addition, the
The metabolic syndrome, according to the
characteristics of the patients (i.e. the
simple clinical criteria National Cholesterol
percentage of diabetic or obese subjects in
Education Program (NCEP)-Adult Treatment
the different studies) probably contribute to
Panel III (ATP III) (table 1), should be
assessed in all patients as a surrogate variability of results.
marker of cardiovascular and metabolic risk,
Summary
since most studies to date have
documented progressive metabolic Assessment of comorbidities is increasingly
worsening with OSA severity (Bonsignore important in the management of OSA
et al., 2012; Lam et al., 2010). patients. The evaluation of these subjects
The role of CPAP treatment in reversing should aim at correcting not only SDB, but
metabolic abnormalities is unclear also the potential sources of increased risk,
(Bonsignore et al., 2012; Lam et al., 2010). especially in young patients. Table 2
Most studies to date have failed to show suggests a possible chart to use in the
improvement in insulin resistance or diagnostic workup and during follow-up; in
metabolic variables after short-term OSA the absence of clinical guidelines, repetition
treatment. It is possible that glycosylated of tests during follow-up should be limited
haemoglobin is a more sensitive marker for to patients with initial abnormal values (in
metabolic improvement after CPAP, but parentheses in the table) in order to limit
more studies are necessary to obtain further costs. A full assessment of OSA patients at
evidence on this point. It is likely that weight diagnosis is crucial to define the best
loss during CPAP treatment or compliance therapeutic options for OSA, and motivate
to CPAP may modulate metabolic variables the patient to lose weight or adhere to
in OSA patients, complicating the analysis CPAP treatment.

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continuous positive airway pressure ther- N Ejaz SM, et al. (2011). Obstructive sleep
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Eur J Echocard; 10: 376–382. sis and cardiovascular events. Eur Respir
N Alberti KG, et al. (2009). Harmonizing Monogr; 50: 174–188.
the metabolic syndrome: a joint interim N Hanly P, et al. (1992). Ventricular function
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Federation Task Force on Epidemiology sleep apnea. Chest; 102: 100–105.
and Prevention; National Heart, Lung, and N Kasai T, et al. (2011). Obstructive sleep
Blood Institute; American Heart Associa- apnea and heart failure: pathophysiologic
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N Arias MA, et al. (2005). Obstructive sleep Monogr; 50: 189–215.
apnea syndrome affects left ventricular N Marin JM, et al. (2005). Long-term
diastolic function. Effects of nasal con- cardiovascular outcomes in men with
tinuous positive airway pressure in men. obstructive sleep apnoea-hypopnoea with
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N Baguet JP, et al. (2008). Masked hyper- positive airway pressure: an observational
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Polysomnography
Renata L. Riha
The term ‘polysomnography’ (PSG) was first Sleep EEG

introduced by Holland et al. in 1974. It
comprises the recording, analysis and The recording of electrical potentials
interpretation of multiple, simultaneous generated by the cortex and deep structures,
physiological parameters that are used in especially the thalamus, is the primary
the diagnosis of sleep disorders. PSG is purpose of the EEG. The relative potential
essential to the understanding of normal difference between two recording electrodes
and abnormal sleep. forms the basis of the trace. One electrode
is negative compared with the other. Note
In 1968, Rechtschaffen and Kales convened that negative charges are upwardly
a panel of experts to agree on a standardised deflecting. The left-sided channels on the
manual for recording and scoring the sleep head are odd-numbered and the right
EEG. This manual then became the ‘‘gold channels even-numbered. The 10–20
standard’’ for scoring the sleep EEG until it international electrode placement developed
was superseded in 2007 by the American for the monitoring of EEG signals in the
Academy of Sleep Medicine (AASM) manual investigation of epilepsy is the standard
for the scoring of sleep and associated montage from which sleep montage is
events. This manual updates the ‘R&K’, derived. The R&K sleep montage initially
incorporating biological principles as well as used the following placements (fig. 1).
published evidence on interpretation of the
various signals used in PSG. N C4–A1
N C3–A2
The polysomnogram is a summary output of N EOG on the left eye referenced to A1
electrophysiological signals integrating sleep N EOG on the right eye referenced to A1
signals, respiratory signals, cardiovascular N EMG mentalis
signals and movement. The recording of
sleep states requires acquisition of three main The AASM (2007) electrode placement is as
measures: the EEG, EOG and EMG. follows (fig. 2).
Respiration is monitored by oronasal flow as N F4–M1 (best for d waves)

well as respiratory effort, movement and N C4–M1 (best for capturing spindles)
snoring. The effects of respiration are also N O2–M1 (best for capturing a rhythm)
monitored using oximetry and sometimes
carbon dioxide monitoring, usually Additional electrode placement includes F3–
transcutaneously. The ECG monitors heart M2, C2–M2 and O1–M2. The general rule is
rate and rhythm. Movement is recorded to read from the left cortical channels with
using EMG on the tibialis muscles and the the other side as a back-up.
body position sensor. These are the The EOG
minimum requirements for a simple PSG.
More elaborate montages are used, The EOG records the corneoretinal potential
particularly in the investigation of difference. Note that it is not a recording of
parasomnias and nocturnal seizure disorders. the movement of eye muscles.

Front Vertex
E1
E2 Left eye–A1
A1 Right eye–A1
A2
EMG
C4 C3 C4-A1 Left Right

side side
A2 A1
Back
Figure 1. Placement of electrodes for sleep staging Figure 2. AASM (2007) electrode placement.
according to R&K (1968).
of thoracic and abdominal compartments
The electrodes at the outer canthus of the (two-compartment model of thoracic cage)
right eye (ROC) are offset by 1 cm above the using two bands: one placed around the
horizontal plane and, likewise, the LOC at thorax and one around the abdomen. In
the outer canthus of the left eye is offset by each coil, there is an inductive band whose
1 cm below the horizontal plane. The ROC is electromagnetic properties depend on the
usually referenced to A1 and the LOC is area enclosed by the band. This allows for
generally referenced to A2. Additional assessment of the magnitude of a
electrodes can be placed; for instance, when hypopnoea or apnoea. However, the major
the patient is undergoing multiple sleep practical problem arises from positioning of
latency testing, when the capture of REM the bands on the body. Thoracoabdominal
sleep is particularly important. bands can be used to semiquantitatively
assess the magnitude of the inspiratory
The EMG effort in upper airway obstruction, and
analysis is undertaken of the amplitude of
Up to three EMG electrodes can be placed swing movements of thoracic and
on the face to allow for an alternative abdominal compartments, and comparison
electrode should one malfunction. The tone of synchrony between both movements. The
of the mentalis and submentalis muscles is measurement is semiquantitative. Other
monitored, and is essential to the diagnosis technology used to measure
of REM sleep. An electrode can sometimes thoracoabdominal movement includes
be placed over the masseter muscle to strain gauges, piezoelectric transducers and
record bruxism. pneumatic bands. Oesophageal monitoring
Sensors and associated monitoring
Table 1. Example of an instruction series prior to
A variety of electrodes can be used to record
commencing the PSG recording.
the EEG, EOG and EMG. For the EEG, types
that can be used include gold-cup, silver-cup 1) With eyes open, look straight ahead for
and disposable electrodes. Collodion-soaked 30 s
gauze has been one method used 2) With eyes closed, look straight ahead for
extensively in the past to attach electrodes 30 s
to the scalp. 3) Holding head still, look to the left and
right; up and down
When applying sensors, the aim is to keep
impedances ,5 kV. The ECG is acquired using 4) Holding your head still, slowly blink your
electrodes placed in standard configuration. eyes five times
5) Grit your teeth; clench your jaw
Measurement of rib cage and abdominal
movements can be undertaken using a 6) Inhale and exhale
variety of techniques. Inductive 7) Hold your breath for 10 s
plethysmography is one such technique and 8) Flex your right foot; flex your left foot
examines the change in cross-sectional area

Table 2. Wake stage (stage W).
Recording Characteristics
EOG Voluntary control, rapid eye movements or none, blinks, slow rolling eye
movements when drowsy
EEG Eyes open: low voltage, mixed frequency; eyes closed: rhythmic a, prominent
in occipital, attenuates with attention
a waves 8–13 Hz, seen mostly in occipital channels, mainly associated with
wakefulness, also associated with microarousals, 10–20% of patients will not
have a detectable a rhythm on EEG
EMG High tonic activity; voluntary movement
Table 3. Stage N1 sleep (stage 1 sleep).

EOG Slow rolling eye movements
EEG Low voltage, mixed frequency; may be h rhythm 2–7 Hz, up to 50–75 mV
range; vertex sharp waves (200 mV)
h waves 4–7 Hz; low voltage, mixed frequency backgrounds; often appear as sharp
vertex waves; mostly associated with stage 1
EMG Tonic activity, slight decrease compared with waking
Table 4. Stage N2 sleep (stage 2 sleep).

EOG Slow rolling eye movement occasionally near sleep onset
EEG Low voltage, mixed frequency
Sleep spindles Bursts of 12–14 Hz activity, o0.5 s long, no amplitude requirement, mostly
associated with stage 2
K complexes Sharp negative wave followed by positive component, o0.5 s long, no
amplitude requirement, mostly associated with stage 2, maximal over frontal
derivations
EMG Tonic activity, low level
is quite invasive and is not used routinely in to the temperature changes in flow at the
the assessment of sleep disordered airway (room air temperature during
breathing on a clinical level. inspiration and at 37uC at expiration). The
signal is semiquantitative, has a poor
Various techniques have also been developed dynamic response and there is a nonlinear
in order to assess flow. For a very long time, relationship between electrical signal and
thermistors and thermocouples were used airflow dependent on exact position at the
almost exclusively in measuring flow. They airway opening. These devices cannot
comprise small sensors whose electrical accurately quantify magnitude of flow but they
characteristics (resistance and voltage) can detect apnoeas. In many respects, they
depend on their temperature. The device is have been superseded by nasal prongs, which
placed close to the airway opening and flow is record pressure at the nostrils. The
detected by measuring the variation in the equipment comprises conventional prongs
electrical properties of the sensor as exposed connected to a pressure transducer. Airflow

Table 5. Stage N3 sleep (stages 3 and 4).
EOG None, reflects EEG
EEG d rhythm .20% of epoch, high amplitude waves (.75 mV), low frequency
(f2 Hz), prominent in frontal regions, sleep spindles may persist but not
necessary for scoring
d waves ,4 Hz, .75 Hz in amplitude, must be ,2 Hz to qualify for N3, mostly
associated with N3
EMG Tonic activity, low level
Table 6. Stage R sleep (REM sleep).

EOG Phasic REMs
EEG Low voltage, mixed frequency, sawtooth waves, h activity, slow a activity
Sawtooth 2–6 Hz serrated bursts of activity, maximal centrally and precede REMs
waves
EMG Tonic suppression, phasic twitches
Phasic muscle Bursts of EMG activity lasting ,0.25 ms, detected on chin EMG, anterior
activity tibialis, EOG–EEG leads
EOG
EOG
EOG
EOG
EEG
EEG α waves
EEG EEG δ waves
EMG EMG
Figure 3. Wake stage (stage W). Note a-waves Figure 5. Stage N3 sleep (stages 3 and 4). Note
on EEG. slow, high-amplitude d-waves.
EOG
EOG
EOG REMs
EOG
EEG
EEG
EEG Sawtooth waves
EEG Spindle K complex
EMG Phasic twitch
EMG
Figure 6. Stage R sleep (REM sleep). REMs: rapid

Figure 4. Stage N2 sleep (stage 2 sleep). eye movements.

LOC–Mix R
256 µV
ROC–Mix L
256 µV
Mix L–Cz
256 µV
Mix R–Cz
256 µV
Cz–Pz
128 µV
Pz–Cz
128 µV
EMG1–EMG2
64 µV
ECG1–ECG2
2.05 µV
Figure 7. A 30-s page from a PSG showing an arousal from N2 sleep.
turbulence at the nostrils induces pressure oximeter makes are alike and the oximeter is
that is directly related to the magnitude of the subject of continual technological
flow. There is an excellent dynamic response. evolution. Interestingly, no minimum
The relationship between pressure and flow is technical specification or standardisation of
nonlinear and may result in overestimation of signal processing is available internationally
flow magnitude. Unfortunately, the or nationally for oximeters. The minimum
drawbacks are lack of detection of mouth standard criteria set by AASM are a sample
breathing, poor signal with a blocked nose rate of 25 Hz with averaging of three values.
and increased resistance with prongs of A resolution of 0.1% is desirable but not
inadequate size. However, they are vastly specified. Oximetry is discussed in greater
superior to thermistors and thermocouples detail later.
and are recommended for detecting airflow in
modern montages. Measurement techniques
Pulse oximetry is used in monitoring Sensitivity, filter settings and amplifications

evidence of desaturation. However, no two need to be checked carefully prior to
Table 7. Definitions of respiratory events.

Event Definition
Obstructive The complete cessation of flow for o10 s with continued respiratory effort
apnoea throughout the apnoea
Hypopnoea Minimum 30–50% reduction in thoracoabdominal movement for o10 s
(definitions vary and may include 3–4% desaturations with or without
arousals)
Central event The complete cessation of respiratory movement and flow for 15 s (some
authors use 10 s)
Mixed apnoea The complete cessation of flow for o10 s with respiratory effort initially
absent, but returning midway through the apnoea

ECG
2.5 mV
EMG
31.3 µV
EOG(L)
250 µV
EOG(R)
250 µV
EEG
250 µV
100
SpO2
50
THOR RES
×1
ABDO RES
×1
Nasal
airflow
×1
Airflow
×1
EMGdia-
phragm
62.5 µV
SOUND
×1
LEG(L)
20 mV
LEG(R)
20 mV
POSITION F
B
L
R
Figure 8. 5-min page of PSG showing obstructive respiratory events (ObA) accompanied by desaturations
and arousals. THOR RES: thoracic respiratory band; ABDO RES: abdominal respiratory band; F: front;
B: back; L: left side; R: right side.
ECG
2.5 mV
EMG
15.6 µV
EOG(R)
250 µV
EOG(L)
250 µV
EEG
250 µV
100
Ptc,CO2
mmHg 50
100
SpO2
50
THOR RES
×1
ABDO RES
×1
Nasal
pressure
×1
Airflow
×1
EMGdia-
phragm
31.3 µV
SOUND
×1
LEG(L)
20 mV
LEG(R) F
20 mV B
POSITIONRL
Figure 9. 5-min page of PSG showing hypopnoeas (Hyp) accompanied by desaturations on the oxygen
saturation trace. THOR RES: thoracic respiratory band; ABDO RES: abdominal respiratory band; F: front;

ECG
2.5 mV
EMG
15.6 µV
EOG(R)
250 µV
EOG(L)
250 µV
EEG
250 µV
100
SpO2
50
THOR RES
×1
ABDO RES
×1
Nasal
pressure
×1
Airflow
×1
EMGdia-
phragm
62.5 µV
SOUND
×1
LEG(L)
20 mV
LEG(R)
20 mV F
POSITIONBL
R
Figure 10. 10-min page of PSG showing central apnoeas showing a Cheyne–Stokes respiratory pattern.
THOR RES: thoracic respiratory band; ABDO RES: abdominal respiratory band; F: front;
recording the PSG (see Spriggs, 2008). The designated according to the AASM (2007)
recording speed of the EEG is generally scoring manual and the R&K (1968)
10 mm?s-1 with epochs of sleep historically equivalent in brackets. Please consult the
scored as 30 s of sleep per page. After the AASM and R&K manuals as detailed and
electrode and monitor applications are exhaustive guides on scoring sleep and
complete, physiological calibrations to assess associated events.
proper electrode functioning are imperative. A
number of instruction series are available that EEG arousals
should be performed prior to the start of every An arousal appears in the EEG as a brief
PSG (table 1). This testing ensures that interruption of sleep continuity. The current
electrodes are placed appropriately and also AASM definition is an abrupt shift in EEG
allows for baseline data to be collected for frequency, for instance from h to a or
comparison during sleep scoring. .16 Hz. An arousal should be o3 s
Scoring the sleep EEG duration and should be preceded by o10 s
of stable sleep. In stage R, the EMG will be
Each sleep stage is assigned a 30-s epoch. elevated with respect to the arousal.
Each epoch is assigned a single state or Arousals in non-REM sleep do not require a
sleep stage. The sleep stage that comprises rise in EMG tone to be scored as such. EEG
the greater part of the epoch is assigned. arousals are scored in any stage of sleep
Events can be described within or across except wakefulness using the central and
epochs. The sleep stages are shown in occipital EEG. Arousals cannot be scored on
table 2–6 and figures 3–6 with the stage changes in submental EMG alone.

Scoring respiratory events Scoring movement in sleep
While sleep staging has been standardised Movements in sleep encompass a large
since 1968 and again more recently in 2007, variety of phenomena, including periodic
an international attempt to standardise limb movements, excessive fragmentary
respiratory events recorded during sleep and myoclonus, bruxism, rhythmic rocking
other movement disorders was only movement disorder and REM sleep
published in 1999 and again in 2007. behaviour disorder.
Table 7 details the definitions and types of
Please consult the AASM (2007) manual as
sleep related respiratory events commonly
detailed and exhaustive guide on scoring
recorded. Figures 8–10 represent the most
sleep associated movements.
commonly scored respiratory events.
Evaluating the ECG
Please consult the AASM (2007) manual as
a detailed and exhaustive guide on scoring In general, during PSG, a single modified
respiratory and associated events. ECG lead II is used with torso placement,
but this can be modified as necessary
The severity of sleep apnoea is classified depending on the type of study being
using the AHI, which comprises the total undertaken. Sinus tachycardia in sleep is
number of apnoeas and hypopnoeas scored defined as .90 beats?min-1 for adults and
during sleep divided by the total sleep time bradycardia as ,40 beats?min-1.
(in hours) as recorded using the EEG. Sleep
apnoea severity is classified as mild if the Please use Hampton (2008) as a detailed and
AHI is 5–15 events?h-1, moderate if the AHI exhaustive summary of normal and abnormal
is .15 but ,30 events?h-1 and severe if the ECG traces, and the AASM (2007) manual
AHI is .30 events?h-1. However, the AHI as an exhaustive guide on cardiac rules
must be interpreted in the context of actual during sleep.
sleep efficiency (the less sleep time, the Interpretation of PSG
smaller the denominator, with artificial
elevation of the AHI) and in the context of PSG is used in the diagnosis of sleep
age and sex. The older individual may have disorders, including obstructive sleep
greater number of events with no adverse apnoea/hypopnoea syndrome, narcolepsy,
impact on health at all. periodic limb movement disorders and
Table 8. Normative data for sleep stages across the lifespan

Age
20–29 yrs 30–39 yrs 40–49 yrs 50–59 yrs .60 yrs
TST min 374.9 375.8 370.2 366.6 348.8
Sleep efficiency % 94.4 94.4 90.2 90.4 85.8
Sleep latency min 6.3 10.0 8.4 6.1 8.2
Awakenings n 6.3 4.7 8.4 9.7 12.3
Stage R % TIB 22.2 23.1 20.4 20.9 16.4
Stage N1 % TIB 3.0 2.5 4.3 4.7 4.0
Stage N2 % TIB 50.5 52.8 54.6 56.7 57.6
Stage N3 % TIB 18.8 16.1 10.9 8.1 7.7
Sleep efficiency is defined as (TST6100)/TIB. Sleep latency is defined as the time to initial sleep onset from
TIB. TST: total sleep time; TIB: time in bed. Modified from Hirshkowitz (2004).

parasomnias. It is also important for the PSG, the general method is to first look at
exclusion of sleep disorders and can be the hypnogram and comment on sleep
useful in patients who have sleep state architecture, cycling of stages, paucity of
misperception. PSG is also an essential sleep stages and fragmentation of sleep.
research tool, providing information on the Table 8 gives an indication of the
duration and amount of sleep, the pattern of distribution of sleep stages across the
sleep, the quality of sleep, and any abnormal lifespan. The second stage of interpreting
behaviour during sleep. the PSG is to assess whether there are any
abnormalities in the respiratory, ECG and
Once the PSG has been scored, the movement traces, coupled with any
consolidated output is formatted in a abnormalities in oximetry or transcutaneous
standardised fashion and should depict carbon dioxide monitoring, if relevant. Body
both the hypnogram (summary of sleep position during sleep can affect the degree
stages), and the summary scoring and of sleep disordered breathing recorded and
recording of events, oxygen saturations, should be commented on if relevant (e.g.
body positions, etc. fig. 12 shows severe sleep apnoea). More
detailed examination of the raw data, e.g.
Figure 11 depicts a normal PSG and with extended montage or with video, is
figure 12 a PSG of someone with severe advisable in the case of parasomnias and
OSA. When interpreting and reporting the suspected seizures.
Time 22:36:13 5:36:13

h 0 1 2 3 4 5 6 7
Epoch 1 121 241 361 481 601 721 841
REM
MOV AWK
1
2
3
4
Arousals
F
Body Position BL
R
100
SpO2 %
50
Central apnoea +5
Obstructive apnoea +5
Mixed apnoea +5
Hypopnoea +5
Unsure +5
Sound +5
Leg movements +10
PLMs +10
120
Heart rate
beats·min-1
20
Figure 11. PSG report in a person without a sleep disorder, demonstrating normal sleep architecture, sleep
progression and sleep cycling. PLM: periodic limb movement.

23.00 00.00 01.00 02.00 03.00
Time
h 0 1 2 3 4 5
1 121 241 361 481 601
Epoch 22:28:31 03:28:31
Hypnogram
R
W
1
2
3
4
Body Position
F
BL
R
100
SpO2 %
55
Central apnoea +5
Obstructive apnoea +5
Mixed apnoea +5
Hypopnoea +5
Unsure +5
PLMs +10
Snoring +5
Figure 12. PSG report consistent with severe sleep apnoea. The hypnogram shows an absence of short-wave
sleep (SWS), poor sleep cycling and sleep fragmentation. There is severe arterial oxygen desaturation
associated with repetitive obstructive events. PLMs: periodic limb movements.
Pulse transit time in estimating the severity of sleep

disordered breathing.
Pulse transit time (PTT) is based on
measuring the time required for the arterial Further reading
pulse wave to travel between two points in N American Academy of Sleep Medicine.
the arterial tree: from the moment when the (1999). Sleep-related breathing disorders
pulse leaves the aortic valve (R wave on in adults: recommendations for syn-
ECG) to time when it reaches the vessels in drome definition and measurement tech-
the finger as identified by pulse oximetry. All niques in clinical research. The Report of
that is required to undertake PTT an American Academy of Sleep Medicine
measurements is a pulse oximeter, ECG Task Force. Sleep; 22: 667–689.
leads and a computation unit. Pulse wave N American Academy of Sleep Medicine.
speed depends on the vessel stiffness and The AASM Manual for the Scoring of
stiffness is in turn determined by blood Sleep and Associated Events: Rules,
pressure. During airway obstruction, Terminology and Technical Specifica-
increased swings in the intrathoracic tions. 1st Edn. Westchester, American
Academy of Sleep Medicine, 2007.
pressure modulate blood pressure and
N Böhning N, et al. (2010). Comparability of
induce parallel changes in PTT. Individual
pulse oximeters used in sleep medicine
PTT values do not correlate with absolute for the screening of OSA. Physiol Meas; 31:
values of pleural pressure; however, 875–888.
oscillations estimate swings of pleural N Grigg-Damberger MM. (2009). The
pressure that occur during the obstructive AASM scoring manual: a critical apprai-
breaths with high sensitivity and specificity. sal. Curr Opin Pulm Med; 15: 540–549.
PTT can thereby be used with some success

N Hampton JR. The ECG Made Easy. 7th impact on the apnea hypopnea index.
Edn. Edinburgh, Churchill Livingstone Sleep; 32: 150–157.
Elsevier, 2008. N Silber MH, et al. (2007). The visual
N Hirshkowitz M. (2004). Normal human scoring of sleep in adults. J Clin Sleep
sleep: an overview. Med Clin North Am; Med; 3: 121–131.
88: 551–565. N Sleep disorders Atlas Task Force of the
N Moser D, et al. (2009). Sleep classifica- American Sleep Disorders Association.
tion according to AASM and Rechts- (1992). EEG arousals: scoring rules and
chaffen & Kales: effects on sleep scoring
examples: a preliminary report from the
parameters. Sleep; 32: 139–149.
Sleep disorders Atlas Task Force of the
N Rechtschaffen A, et al. A Manual of
Standardised Terminology, Techniques, American Sleep Disorders Association.
and Scoring System for Sleep Stages of Sleep; 15: 173–184.
Human Subjects. Bethesda, National N Spriggs W. (2008). Essentials of polysom-
Institute of Neurological Disease and nography. Burlington, Jones & Bartlett.
Blindness, 1968. N The Atlas Task Force. (1993). Recording
N Ruehland WR, et al. (2009). The new and scoring leg movements. Sleep; 16:
AASM criteria for scoring hypopneas: 748–759.

Assessment of daytime
sleepiness
Renata L. Riha
Assessment of daytime sleepiness somnolence and daytime sleepiness. The

central premise of the MSLT is that the
The causes of excessive daytime sleepier a subject is, the more quickly they
somnolence (EDS) are many and varied and will fall asleep. The test is carried out under
not all will be attributable to sleep disorders. standardised laboratory conditions. The
However, there are a few very specific sleep initial guidelines for conducting this test
disorders that can be diagnosed with the aid (originally designed for confirming a
of daytime tests of sleepiness, such as diagnosis of narcolepsy) were developed
narcolepsy and idiopathic hypersomnolence. and published in 1986 (Carskadon et al.,
Conversely, it is often useful to assess 1986) with the most recent review of the
response to treatment, irrespective of the guidelines in 2005 (Littner et al., 2005).
type of disorder, using a test for ability to Table 1 summarises the instruction series
maintain wakefulness. for conducting an MSLT and the changes
Multiple sleep latency testing between the two sets of guidelines with time.
MSLT is designed to objectively assess The patient wears a standard EEG montage
sleepiness and is used for the assessment and is asked to lie down and sleep in a
and diagnosis of disorders of excessive darkened room on four to five separate
occasions. Each nap opportunity is 20 min
long and 2 h apart over the course of the
Key points day. Sleep is recorded and the time taken to
fall asleep is averaged over the number of
N The Multiple Sleep Latency Test naps taken.
(MSLT) is used to objectively test Figures 1 and 2 show a PSG performed the
propensity to sleepiness in disorders night before daytime testing of sleepiness
of daytime somnolence. using the MSLT in a narcoleptic patient.
N The Maintenance of Wakefulness Test
Potential drawbacks of the MSLT include
(MWT) measures ability to stay
awake for a defined period in a individual clinical interpretation of
standardised environment. instructions which may lead to variation in
the conducting and reporting of the test.
N The OSLER Wake Test is a This has major implications for diagnosis,
behavioural version of the MWT in disease classification and treatment (see
which subjects respond to a timed Carskadon et al., 1986 for more detail).
light stimulus.
Maintenance of wakefulness test
N Although they are useful
diagnostically, no test of sleepiness The MWT works on the opposite premise of
can reliably predict sleepiness and the MSLT, in that it measures the ability to
performance in real-life situations stay awake for a defined period of time in a
with certainty. standardised stimulus-free environment.
The ability to maintain wakefulness should

Table 1. Guidelines for the MSLT#.
General considerations
1-2 weeks of sleep diaries preceding MSLT
1 night PSG on habitual schedule
Consideration of drug schedule
Withdrawal of drugs that influence sleep latency
Withdrawal of drugs that influence REM sleep
Urinary drug screen
Loose comfortable street clothing
A minimum of four tests at 2-h intervals beginning 1.5–3 h after wake-up
Quiet, dark, temperature-controlled room
No alcohol or caffeine
Montage
Standard montage
C3–A2 or C4–A1
Right and left horizontal (or oblique) EOG
Mental/submental electromyogram
Strongly recommended
O1–A2 or O2–A1
A vertical EOG
ECG
Optional (respiratory indicators)
Respiratory flow
Respiratory sounds
Patient series
30 min – smoking should be ceased
15 min – vigorous exercise should be ceased
10 min – remove shoes and loosen restrictive clothing
5 min – hooked up in bed
30 s – ask patient to lie quietly, close their eyes and try and fall asleep
Calibration series
Impedances
Calibration
Stanford Sleepiness Scale
Study time schedule
20 min if no sleep
NREM sleep 15 min after sleep onset
REM sleep 15 min after sleep onset
Sleep onset
1st epoch of any stage of sleep"
Interpreting MSLT
,5 min pathological daytime sleepiness
10–20 min normal ranges
5–10 min diagnostic grey area
#
: adapted from Carskadon et al. (1986) and Littner et al. (2005); ": in 1986 guidelines: three consecutive
epochs of stage 1 sleep or one epoch of any other sleep stage.

be assessed in the context of the clinical press a button in response to a stimulus
history. A number of protocols for that is presented on a screen at random
undertaking the MWT are available, but the intervals over a given time period. One of
recommended one uses the 40-min protocol the simplest tests to this effect is the
over four periods during the day. In contrast OSLER test.
to the MSLT, onset of sleep is defined as
three continuous epochs of stage 1 sleep or The original OSLER test is the simplest test
one epoch of any other stage of sleep. It is to assess daytime sleepiness and is a
unusual to see REM sleep on this test. For a behavioural version of the MWT. The subject
detailed and exhaustive discussion of this sits in a darkened room; a small LED is lit
for 1 s in every three, and the subject is
test please consult Littner et al. (2005).
required to respond each time. Software
controls the LED, stores the response and
Non-EEG-based tests of vigilance alerts the technician when the subject fails
to respond. Consecutive misses mean sleep
There are a number of computer-based (Bennett et al., 1997). Figure 3 shows the
assessments of sustained visual attention results of an OSLER test for a sleep subject.
which measure the reaction time taken to These tests are practical and well-validated
Time 12 am 1 am 2 am 3 am 4 am 5 am 6 am 7 am
Hrs 0 1 2 3 4 5 6 7 8
Epoch 1 121 241 361 481 601 721 841 961
23:00.11 07:00.11
REM
W
Hypnogram 1
2
3
4
100
Sp,O2
70
F
Body position P L
R
CnA +5
CbA +5
Mx.A +5
Hyp +5
Unscored
PLM +10
Snorng +5
Figure 1. PSG for a narcoleptic patient; note the early onset REM-sleep and excessive sleep fragmentation.

REM
W
1
2
Nap 1 3
4 09:25:04 09:45:04
REM
W
1
Nap 2 2
3
4 11:25:04 11:45:04
REM
W
1
Nap 3 2
3
4 13:25:04 13:45:04
REM
W
1
Nap 4 2
3
4 15:20:34 15:40:34
Figure 2. MSLT in narcolepsy showing a sleep latency of ,8 min and four sleep-onset REM periods
pathognomonic for the condition.
Misses Run 1, start 10:00:00

7
6
4
2
0
Misses
7 Run 2, start 12:00:00
6
4
2
0
Misses
7 Run 3, start 14:00:00
6
4
2
0
Misses
7 Run 4, start 16:00:00
6
4
2
0
00:10:00
00:40:00
00:15:00
00:35:00
00:05:00
00:20:00
00:30:00
00:00:00
00:25:00
Interval 00:40:00 Time min
Figure 3. OSLER test showing a mean sleep latency of 21 min. The subject fell asleep on three of four runs.

as alternatives to more complex testing, Further reading
but are insufficiently standardised regarding
N Bennett LS, et al. (1997). A behavioural
normative population data. None of the
test to assess daytime sleepiness in obstruc-
tests discussed in this section can be used
tive sleep apnoea. J Sleep Res; 6: 142–145.
unequivocally to predict sleepiness in N Carskadon MA, et al. (1986). Guidelines
real-life situations. for the multiple sleep latency test
(MSLT): a standard measure of sleepi-
ness. Sleep; 9: 519–524.
N Littner MR, et al. (2005). Practice para-
meters for clinical use of the multiple
sleep latency test and the maintenance of
wakefulness test. Sleep; 28: 113–121.

Cardiorespiratory monitoring
during sleep
Maria R. Bonsignore and Juan Fernando Masa
Full nocturnal PSG in the sleep laboratory is since: 1) the signals recorded are not
the gold standard for diagnosis of sleep calibrated and scoring is based on
disorders, including OSA. However, full PSG recognition of qualitative patterns; 2)
is not free from limitations (Kuna, 2010), scoring of sleep and respiratory events show
some problematic points, even after the
revision of criteria by the American Academy
Key points of Sleep Medicine (AASM) (2005); 3) the
results of PSG correlate poorly with clinical
N Ambulatory management of OSA symptoms of OSA and measures of
patients has been shown to be as cardiovascular risk; and, consequently, 4)
effective as traditional, laboratory- there is no evidence-based threshold for AHI
based management in symptomatic or other variables to be used in comparative
patients with severe OSA free studies between different diagnostic or
from comorbidities. therapeutic management strategies (Kuna,
2010). In addition, the in-hospital PSG is not
N Portable monitoring devices should carried out under ‘normal’ sleep conditions,
include respiratory signals with the with subsequent alterations in sleep quality
same sensors as those recommended and/or frequency of apnoeic events. Full PSG
for PSG; however, devices based on entails a high cost in both equipment and
different technology (i.e. PAT) have personnel, and its limited availability with
been found to reliably identify OSA. respect to the increasing demand for sleep
N Limited monitoring (1–3 signals) is tests causes long waiting lists.
not recommended by current A full PSG is also indicated for CPAP
guidelines; however, according to titration, further increasing the time between
recent data, identification of OSA is diagnosis of OSA and institution of
possible by using nasal pressure and/ treatment. These problems have led to the
or oximetry signals. acceptance of ‘split-night’ studies (Epstein
N Actigraphy has been suggested as a et al., 2009), in which the first part of the
possible tool to better define sleep PSG is used for diagnosis and the second
time, but is not recommended by part to titrate CPAP in patients with severe
current guidelines and more studies OSA (AHI .20–40 events?h-1). Such
are necessary to ascertain its efficacy procedures are reasonably accurate
in ambulatory management of OSA. (Khawaja et al., 2010).
N Monitoring of PtcCO2 provides useful Alternative ambulatory methods have been
information in patients with developed for more efficient use of
hypoventilation during sleep. healthcare resources. For diagnosis of OSA,
Technological advancement have several devices are currently available to be
made measurement of PtcCO2 easier worn at home by patients during sleep.
and more reliable than in the past. Sleep monitoring devices are classified
according to completeness of the signals

recorded and presence of a technician In the USA, the use of portable devices for
overnight (table 1). Type 1 monitoring is the diagnosis of OSA is less widespread (Collop
complete PSG recording in the sleep et al., 2007; Ahmed et al., 2007). The AASM
laboratory monitored by a technician, while recommends that portable type 3
type 2–4 monitoring devices provide cardiorespiratory monitoring for the
unattended recordings from full PSG (type diagnosis of OSA be used only in patients
2), to four- to eight-channel (type 3) or one- with a high clinical probability of OSA and
to three-channel (type 4) recordings. without comorbidities (Collop et al., 2007).
Similar recommendations were recently
Type 3 cardiorespiratory monitoring during issued by the Canadian Thoracic Society
sleep is increasingly used in the diagnosis of (Canadian Sleep Society et al., 2010;
OSA. Underdiagnosis of OSA in the general Fleetham et al., 2011). Recent data
population and the rising prevalence of indicating that clinical results are not
obesity worldwide have increased the inferior to those of classic OSA
number of patients referred to sleep centres management in the sleep laboratory might
for suspected sleep apnoea. In addition, the change such restrictive use in the future (see
continuing search for cost-effective later). Several problems remain to be
diagnostic and therapeutic approaches addressed by future research studies before
makes type 3 portable devices very attractive use of respiratory polygraphy can be
to deal with a very large number of extended to additional groups of patients,
suspected OSA patients. such as subjects with comorbidities (Ayappa
et al., 2004).
A recent survey among physicians working
in academic sleep centres in 22 European As for type 4 devices, recording of airflow by
countries revealed that type 3 a nasal cannula, alone or in combination
cardiorespiratory polygraphy was used in with pulse oximetry, is a possible screening
.70% of them at home or in the sleep tool in patients with high clinical probability
laboratory. Type 4 devices were found to be of OSA (Ayappa et al., 2004; Grover et al.,
used for diagnosis of OSA in five countries. 2008). The nasal pressure signal and
Cardiorespiratory polygraphy was also used analysis of the flow limitation pattern allow
in a third of the centres to check reliable confirmation or exclusion of the
effectiveness of treatment (i.e. in patients occurrence of OSA in patients with high
undergoing domiciliary CPAP titration by an clinical probability of obstructive events
automatic device) (Fietze et al., 2011). (Ayappa et al., 2004). More recently, nasal
Table 1. Sleep monitoring devices (Collop et al., 2007.).

Type Characteristics Pros Cons
1 Full in-laboratory High diagnostic yield High cost, long waiting lists
overnight PSG#, attended
2 Full ambulatory overnight Feasible, can be used for Possible loss of signals, up to
PSG#, unattended in-hospital studies 20% of recordings inadequate,
more studies needed
3 4–8-channel" polygraphy Respiratory polygraphy Lack of standardisation and
used in many centres variability of signals recorded
4 1–3-channel recording Used as inexpensive Not recommended by AASM
(pulse oximetry plus 1–2 screening tests for severe
other channels) OSA or in obese patients
#
: EEG, EMG and EOG channels, plus cardiorespiratory and body position monitoring channels, etc.; ":
usually cardiorespiratory monitoring and position channels as in type 1–2 devices.

pressure recordings for three nights at home N Portable monitors can be used to assess
were found to be accurate diagnostic tools the effects of OSA treatment.
in patients with a high clinical probability for N The minimum of signals to be recorded
OSA (Rofail et al., 2010a). Such devices are by portable monitoring devices include
promising, since they are simple, airflow, respiratory effort and blood
inexpensive and well tolerated by patients. oxygenation. Sensors should be the same
However, further validation is needed in as those used in in-laboratory PSG.
order to optimise the choice of patients in N The equipment should be applied by
whom they provide clinically useful results. experienced personnel, and raw data
should be displayed and manually edited
Validation studies of portable by the reader; a sleep-certified physician
cardiorespiratory monitoring devices carry should revise the results.
some relevant problems. As recently N Negative or technically inadequate results
underlined by Kuna (2010), the diagnostic in patients with a high clinical probability
yield of a type 3 portable device can vary of OSA should prompt in-laboratory PSG.
according to the setting where it is used, i.e.
in a sleep laboratory or home setting. Sleep Commercially available type 3
apnoea assessment using a portable device cardiorespiratory monitoring devices can
in the laboratory was closer to results of PSG include different signals. Pulse oximetry and
than those obtained in a patient’s home respiratory signals (respiratory effort
(Kuna, 2010). This finding may, in part, be monitored by inductive plethysmography,
secondary to the resolution of problems by airflow and snoring) should be present, as
an experienced technician in the sleep recommended by the AASM guidelines
laboratory setting compared with the home (Collop et al., 2007; Redline et al., 2007).
setting. Another relevant factor, however, is Other signals that can be included in
represented by the night-to-night variability portable monitoring devices are heart rate or
in SDB, which further complicates the cardiovascular changes associated with
assessment of reproducibility of results respiratory events (Penzel et al., 2010). An
when different devices/settings are compared. example of the latter technology is pulse
arterial tonometry (PAT), which has been
Polygraphy scoring: settings, trends and used to diagnose sleep apnoea in
pitfalls combination with pulse rate, oximetry and
Figures 1 and 2 show typical examples of actigraphy, with promising results (Pittman
eight-channel respiratory polygraphic et al., 2004). The PAT signal undergoes
recordings. Home monitoring with type 3 attenuation when sympathetic-mediated
monitoring devices for the diagnosis of OSA vasoconstriction occurs at the end of
should be performed according to current apnoeas and such signals are used to
AASM guidelines (Epstein et al., 2009; recognise respiratory events. The PAT signal
Collop et al., 2007), which state the following: has recently been analysed to derive
information on sleep stages and found to
N Use of portable monitoring for the show a moderate agreement with standard
diagnosis of OSA should be limited to PSG; interestingly, OSA severity did not
patients with a high clinical pre-test affect the results (Hedner et al., 2011).
probability of moderate-to-severe OSA Current research is also investigating the
and free from significant comorbidities. possibility of diagnosing OSA by deriving
N Patients with suspected sleep disorders respiratory events from electrocardiographic
other than OSA should undergo full PSG, recordings obtained during sleep
since validation studies of portable (Babaeizadeh et al., 2011); such techniques,
monitoring in these disorders are lacking. however, involve complex algorithms and
N Use of portable monitoring for diagnosis need validation in large clinical populations.
of OSA may be appropriate in patients
who cannot undergo full PSG because of A major problem in assessing the validity of
immobility, safety or critical illness. commercially available devices for the

01:00 02:00 03:00 04:00 05:00 06:00 07:00 08:00
Button
Supine
Left
Prone
Right
Upright
Moving
high
Activity low
Desat
SpO2 % 100
80
140
Pulse 100 120
beats·min-1 80
60
Snore
high
Snore
low
90
Obstructive s 60
30
90
Central s 60
30
90
Mixed s 60
30
Figure 1. Respiratory polygraphy. Summary graphics regarding total recording time in a patient with OSA.
From top to bottom: body position, activity (moving and continuous signal), oxygen saturation (events
and continuous signal), pulse (lower and higher values of heart rate), snoring (events and continuous
signal), and obstructive, central and mixed events with their duration in seconds (s). Desat.: desaturation.
diagnosis of OSA is that they vary in the type objective of an effective management
and number of sensors. Moreover, lack of strategy, such studies assessed whether the
standardisation makes it difficult to results of both procedures were comparable.
compare results obtained with different These studies, summarised in table 2,
devices or analyse results of different indicate that ambulatory management is not
studies by meta-analyses. inferior to the traditional diagnostic pathway
used for OSA diagnosis and treatment
Portable monitoring devices have been used (Mulgrew et al., 2007; Berry et al., 2008;
in ambulatory OSA management protocols, Antic et al., 2009; Kuna et al., 2011b; Masa
including CPAP titration. In these studies, et al., 2011a). Interestingly, both inclusion
traditional in-laboratory management, based criteria and diagnostic methods varied
on full diagnostic PSG and manual CPAP among the studies (table 2). Masa et al.
titration during PSG, has been compared to (2011a) enrolled patients with moderate
an ambulatory protocol, using portable clinical OSA severity and found that portable
monitoring devices and automatic positive monitoring showed better diagnostic cost-
airway pressure (APAP) ventilators at home effectiveness than PSG. In addition, they
to establish the pressure level needed by the also tested the feasibility and results of a
individual patient. Some recent randomised telemedicine application, concluding that it
controlled trials tested whether clinical bore similar overall costs to the ambulatory
outcomes were comparable between management, since the costs of informatics
patients studied by type 3 portable were compensated for by the costs
monitoring or in-laboratory PSG-based sustained by the patients to travel to and
management. Since CPAP titration and from the laboratory (fig. 3) (Masa et al.,
follow-up after CPAP initiation are the final 2011b). Future studies can be expected to

7:12:40 7:12:50 7:13:00 7:13:10 7:13:20 7:13:30 7:13:40 7:13:50 7:14:00 7:14:10 7:14:20 7:14:30 7:14:40 7:14:50 7:15:00 7:15:10 7:15:20
Nasal PDG (5.46 mbar/cm)
Obstructive (45.50 s) Obstructive (35.00 s)

Nasal flow
Thorax
Abdomen (1.12 mV/cm)
Desaturation (50.60 s) [11] Desaturation (50.60 s) [11]

SpO2 (70–100%)
Pulse (50–125 bpm)
Snore pressure (0–262 mbar/cm) Snore
Position (0–379 cm)
Figure 2. 3-min respiratory polygraphic recording in a patient with OSA. Note the obstructive apnoeas,
consequent desaturations and their durations in seconds (s). Signals include, from top to bottom: nasal
pressure (cannula), nasal flow (cannula), thoracic movement (inductive band), abdominal movement
(inductive band), oxygen saturation (pulse oximeter), heart rate (pulse oximeter), snoring (nasal cannula)
and body position (sensor).
further focus on the diagnostic yield and been estimated to occur in 17% of cases
costs associated with widespread use of (Collop et al., 2007). The results of Pietzsch
information technology applied to et al. (2011) have been critically reviewed by
ambulatory management of OSA patients. Ayas et al. (2011), with special emphasis on
the multiple assumptions to be considered
The recent Canadian Thoracic Society 2011 in modelling studies, especially since
guideline update reviewed evidence-based evidence-based data derived from
data regarding outcomes of portable randomised controlled studies are not
monitoring and PSG-based management of available. This is an area of major interest
OSA patients. Although the AHI values that is in a state of continuous evolution,
obtained by portable monitoring devices and more studies can be expected to
and PSG were different, no difference was address and refine cost analysis of
found between the two management ambulatory systems for diagnosis of SDB in
strategies for: residual sleep apnoea, the near future.
sleepiness and quality of life; CPAP
adherence; CPAP pressure; patient Interpretation of cardiorespiratory
satisfaction; or neurocognitive function polygraphy
(Fleetham et al., 2011).
There are some problems in the
Despite these promising results, Pietzsch interpretation of cardiorespiratory
et al. (2011) reported that ambulatory polygraphy (Kuna, 2010; Collop et al., 2007;
management was not advantageous Ahmed et al., 2007; Kuna et al., 2011b),
compared with in-laboratory PSG. This which need to be known by the physician
finding was due to the need to repeat using portable devices instead of in-
recordings whenever ambulatory tracings laboratory full PSG. These problems concern
were technically unsatisfactory or resulted scoring of apnoeas and hypopneas and the
negative in patients with high clinical assessment of OSA severity.
probability of OSA, requiring further
assessment. False negative tests in patients N The exact duration of sleep and the AHI,
with high pre-test probability for OSA have i.e. the number of events divided by sleep

Table 2. Ambulatory management of OSA: effects on functional outcomes/therapeutic decision-making.
Ref. Study Patients Outcome Arms Results
Mulgrew et al., RCT, single 68 patients AHI on CPAP, Parallel design: No difference at
2007 centre with high ESS, SAQLI home oximetry/ 3 months in AHI on
clinical score, CPAP APAP (n533); CPAP, ESS, SAQLI
probability of adherence at hospital PSG/CPAP score; CPAP adherence
moderate-to- 3 months (n535) better in the ambulatory
severe OSA managed group
Berry et al., RCT, Veterans 88 patients CPAP Parallel design: Similar CPAP adherence
2008 Affairs Medical with EDS and adherence, home 4-channel at 6 weeks, mean
Center high clinical ESS, FOSQ at monitoring#/APAP nightly use; decrease in
probability of 6 weeks (n545); hospital ESS, FOSQ; CPAP
OSA PSG/CPAP (n543) satisfaction in both
groups
Antic et al., RCT, 3 195 patients ESS, CPAP Parallel design: Similar CPAP adherence
2009 academic sleep with suspected adherence at home oximetry/ at 3 months, mean
centres, moderate-to- 3 months APAP (n5100); nightly use; decrease in
Australia severe OSA hospital PSG/CPAP ESS; lower cost (the
(n595) home programme was
led by nurses)
Kuna et al., RCT, 2 223 FOSQ and Parallel design: Home management not
2011b Veterans consecutive CPAP home RP/APAP clinically inferior to the
Affairs Medical patients with adherence at (n5113); hospital laboratory management
Centers suspected OSA 3 months PSG/CPAP of OSA
(n5110)
Masa et al., Multicentre 348 patients Therapeutic Cross-over design: RP performed well in
2011a RCT, Spanish with decision on home RP/hospital severe OSA (AHI
Sleep Network intermediate- CPAP PSG o30 events?h-1), less
to-high prescription well in moderate OSA
probability of (AHI 15–30 events?h-1)
OSA
RCT: randomised controlled trial; RP: respiratory polygraphy. #: Watch-PATTM 100 (Itamar Medical Inc.,
Norwood, MA, USA).
time, cannot be assessed without o10 s associated with a 4% oxygen

recording of the signals used for sleep desaturation. The alternative definition of
scoring (EEG, EOG and EMG). When hypopnea is a 50% decrease in chest wall
portable monitoring devices are used to movement or airflow associated with a
diagnose OSA, the frequency of 3% oxygen desaturation and/or detection
respiratory events is reported as the of an EEG arousal (Redline et al., 2007).
respiratory disturbance index (RDI), i.e. While hypopneas of the first type can be
the number of events divided by detected by cardiorespiratory monitoring,
recording time. This leads to a systematic those of the second type cannot, due to
underestimation of OSA severity based the lack of the sleep signals (EEG, EOG
on the frequency of respiratory events and EMG), leading to further
compared with the results obtained by underestimation of the number of events.
full PSG (fig. 4). The AASM guidelines do not mention use
N The AASM Practice Parameters guideline of a nasal cannula and careful
indicates two possible ways to score assessment of the flow limitation pattern,
hypopneas (AASM, 2005). The first which may provide an accurate estimate
requires a 30% decrease in airflow for of obstructive events (Kuna et al., 2011).

800 devices that average the signal over 3–4 s
700 (AASM, 2005; Epstein et al., 2009; Collop
et al., 2007).
600
Cost in 2009 €
500 Pulse oximetry has limited diagnostic yield

500 when used as the only signal recorded
300 during sleep, for the following reasons:
200
N Occurrence of oxygen desaturations does
100 not provide any information on the type
0 of the associated event (central or
PSG Nontelemetric Telemetric obstructive apnoeas or hypopneas).
HRP HRP
N In patients with high oxygen saturation
during wakefulness, respiratory events
Figure 3. Cost per patient in a cohort of 348 might be insufficient to cause significant
subjects (Masa et al., 2011). PSG was performed drops in oxygen saturation, due to their
in hospital and respiratory polygraphy at home position on the flat portion of the oxygen
with two cost approaches: patients obtained the dissociation curve (i.e. nonobese sleep
respiratory polygraphy device at the hospital, went apnoea patients).
home and returned the following morning N The reliability of the pulse oximeter signal
(nontelemetric); or the devices were moved by a depends on adequate perfusion of the
transport company from home to home with site where the arterial oxygen saturation
telemetric transmission of data files from home to (SpO2) measurement is obtained. Low
hospital (telemetric). The costs of home perfusion states (as in critically ill
respiratory polygraphy (HRP) were adjusted for
patients) are often associated with poor
the same diagnostic efficacy as PSG. Note that
readings and abnormally low SpO2 values.
nontelemetric and telemetric HRP had similar
costs, which were approximately half of the costs N The results of oximetry vary when comparing
of PSG. Data are presented as mean¡SD. different devices (Zafar et al., 2005).
Therefore, pulse oximetry alone is not

N A third problem regards the type of signal recommended by any guideline on the
to detect airflow to be used in diagnosis of SDB. Recent reports, however,
cardiorespiratory monitoring. For optimal have provided new algorithms for analysis of
detection of changes in airflow, the AASM SpO2, alone or coupled with other signals,
guideline (2005) recommends use of two which could considerably improve the
sensors, i.e. the nasal pressure signal and
diagnostic yield of oximetry. In addition,
the thermistor oronasal flow signal. Nasal
some studies suggest that the number of
pressure is more sensitive for detection
3% oxygen desaturation events (ODI3%)
of the typical pattern of progressive
obtained by pulse oximetry recordings for
inspiratory flow limitation, while the
three nights may be used to diagnose OSA
signal derived by thermal sensor can
with acceptable accuracy, with a diagnostic
detect respiratory events occurring during
yield similar to nasal pressure recordings
oral breathing. Therefore, some
(Rofail et al., 2010b).
differences in diagnostic yield between
different devices may depend on the type Pulse oximetry is commonly used in patients
of airflow signal used, and the physician on home NIV to check effectiveness of
should be aware of this possibility. treatment. Unfortunately, it is not specific,
Oximetry since fast or slow oxygen desaturations may
occur for several reasons (Janssens et al.,
Pulse oximetry is commonly recorded during 2011). Therefore, it should only be
the night in patients with suspected OSA in considered as a screening tool to identify
the context of full PSG or cardiorespiratory patients who need more sophisticated
polygraphy. The AASM recommends using reassessment (Janssens et al., 2011).

39 actigraphy can be used instead of PSG to
show improved sleep efficiency and reduced
38
fragmentation in OSA patients treated with
37 CPAP (Otake et al., 2011). New models to
Events·h-1
36 analyse actigraphy data may provide clinically

useful algorithms (Wang et al., 2011).
35
34 A recently developed device with some
similarity to actigraphy is a noncontact
33 biomotion sensor allowing detection of body
32 and respiratory movements during sleep;
PSG AHI RP RDI RP AHI initial results appear promising (De Chazal
et al., 2011).
Nocturnal capnography
Figure 4. In PSG, the number of apnoeic episodes
is divided by the total sleep time (TST) to obtain Transcutaneous carbon dioxide tension
the AHI. In respiratory polygraphy (RP), the (PtcCO2) has been used for the last 30 years
number of apnoeic episodes is divided by the to noninvasively and continuously monitor
recording time, which is normally greater than the ventilation in children and adults in different
TST, to obtain the RDI. Accordingly, in a cohort of clinical contexts, including sleep. Recent
348 patients where PSG and RP were performed technological advancements have made the
simultaneously in hospital, the PSG AHI was
sensors smaller and more reliable compared
4 events?h-1 higher than the RP RDI. However, if
with the first commercially available models
the number of RP apnoeic events is divided by the
TST obtained from PSG, the resultant index (RP
(Eberhard, 2007). Carbon dioxide diffuses
AHI) is close to the PSG AHI. This calculation through the skin and this process is
emphasises that the habitual underestimation of RP enhanced by warming the skin to 42–45uC;
RDI is mainly attributable to the use of recording time most devices measure PtcCO2 by measuring
instead of sleep time, as in the PSG. changes in pH (or optical absorption in the
near-infrared light, as recently proposed).
Technology advancements have provided
Actigraphy sensors with faster responses and less need
for calibration or membrane change, making
Actigraphy records body movements using
it possible to record PtcCO2 for longer
accelerometers and is largely used in
periods of time with minimum discomfort to
epidemiological studies to measure sleep
the patient and no need to change the
duration and analyse circadian sleep
application site after 4 h, as in the older
disorders. Actigraphy has been proposed as
models (Kelly et al., 2011). PtcCO2
an additional signal to be recorded during
measurements have been used in neonatal
home sleep monitoring in order to solve the and paediatric settings since their
problem of the lack of an objectively introduction, but have recently gained
measured sleep period. This could allow a application in adults, especially in operating
more precise evaluation of RDI, since the rooms and intensive care settings, in sleep
number of events recorded could be divided laboratories and for home monitoring of
by the actual sleep duration instead of by the NIV. Both PtcCO2 and SpO2 can be recorded
entire recording time. The 2007 AASM by the most recently developed devices.
practice guideline did not find evidence for
sufficient accuracy of actigraphy devices for PtcCO2 values show excellent correlation with
such purposes (Collop et al., 2007). PaCO2 values obtained by arterial blood gas
Actigraphy together with PAT and oximetry (ABG) sampling with an acceptable delay (a
recordings provided acceptable results for few minutes) of the transcutaneous
ambulatory diagnosis of OSA using a compared with the direct measurement
commercially available device (Ayas et al., (Janssens et al., 2011), although large
2003). Some recent studies suggest that deviations (.10 mmHg) have been

reported in patients on NIV with initial PaCO2 pointed out that AASM guidelines do provide
.60 mmHg (Kelly et al., 2011). Some indications for use of PtcCO2 monitoring for
studies have shown that a drift occurs in the diagnosis and treatment of SDB.
PtcCO2 signal over time, and suggested
obtaining ABG samples at the beginning In summary, monitoring of PtcCO2 should be
and end of the recording in order to correct considered a useful adjunct to diagnostic
the results; future devices may automatically and therapeutic management of acute and
adjust for such drift. However, most chronic hypoventilation conditions. New
clinicians agree that the major advantage of devices for use in adults are easy to use and
PtcCO2 monitoring is the possibility of reliable. Conversely, measurement of end-
assessing the trend of carbon dioxide values tidal carbon dioxide is less practical and not
over time, besides estimating absolute currently recommended for use in the sleep
PaCO2 values. laboratory or at home (Janssens et al., 2011).
A clinically important application of PtcCO2

monitoring is the detection of Further reading
hypoventilation in patients with OHS or N Ahmed M, et al. (2007). Portable moni-
amyotrophic lateral sclerosis (ALS), tors in the diagnosis of obstructive sleep
especially during sleep. PtcCO2 monitoring apnea. Chest; 132: 1672–1677.
eliminates the need to obtain ABG samples N American Academy of Sleep Medicine.
before and after sleep and avoids false (2005). International Classification of
negative results due to rapid normalisation Sleep Disorders. 2nd Edn. Westchester,
of ventilation after awakening. American Academy of Sleep Medicine.
N Antic NA, et al. (2009). A randomized
PtcCO2 can be used to monitor the effects of controlled trial of nurse-led care for
NIV in acute settings, thus limiting the symptomatic moderate-severe obstruc-
number of ABG samples to be drawn to tive sleep apnea. Am J Respir Crit Care
assess the effectiveness of NIV (Storre et al., Med; 179: 501–508.
2007). In the home setting, it can yield very N Ayappa I, et al. (2004). Comparison of
useful information to check the effectiveness limited monitoring using a nasal-cannula
of NIV and help resolve problems (Janssens flow signal to full polysomnography in
et al., 2007). Although SpO2 and PtcCO2 sleep-disordered breathing. Sleep; 27:
monitoring do not provide information on 1171–1179.
the cause of the disturbances during NIV N Ayas NT, et al. (2003). Assessment of a
(i.e. leaks, insufficient pressure, upper airway wrist-worn device in the detection of
obstruction, etc.), their use has been suggested obstructive sleep apnea. Sleep Med; 4:
435–442.
in order to identify patients who need further
N Ayas NT, et al. (2011). The demise of
assessment to optimise ventilation during
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Treatment of obstructive
sleep apnoea
Johan Verbraecken, Arie Oksenberg, Marie Marklund and An Boudewyns
Therapeutic strategies for patients with episodes of apnoea or hypopnoea. The final
OSAS may be categorised into three general goal is to establish a stable oxygen curve
groups: behavioural, medical and surgical. and ventilatory pattern, abolish snoring,
Treatment decisions should be based on the eliminate sleep fragmentation due to upper
effect of OSAS on daytime symptoms, airway (UA) collapse and enhance alertness
cardiovascular and metabolic function during the daytime.
rather than on the absolute number of
Patient education
All patients with OSAS should be counselled

Key points about the potential benefits of therapy and
the hazards of going without treatment. The
N All patients with OSAS should be relative value of avoiding factors that
counselled about the potential increase the severity of UA obstruction, such
benefits of therapy and the hazards of as the use of alcohol, sedatives and
going without treatment. hypnotics, and weight gain, should be
N Patients with supine-position OSA discussed. Pharyngeal fat deposits lead to a
tend to have a lower AHI, to be decrease in pharyngeal patency and
younger and to be less obese. underline the risk factor of obesity. Weight
loss is recommended in .80% of patients
N In mild-to-moderate OSA, oral with OSAS and leads to a decrease in critical
appliances have a similar efficacy as closing pressure (Pcrit), and consequently
CPAP therapy in terms of changes decreases the severity of OSA.
in AHI. Unfortunately, only 5% of overweight
N Successful UA surgery is most persons are able to lose weight and
commonly defined as a .50% maintain weight loss. This problem is
reduction in AHI and a post-operative exacerbated when patients are sleepy during
AHI ,20 events?h-1. the daytime, tend to snack to stay awake and
are too tired to exercise. Most patients who
N Bariatric surgery is indicated in lose weight experience an improvement in
individuals with a BMI o40 kg?m-2 or apnoea, but it is difficult to predict the
with a BMI o35 kg?m-2 with amount of improvement associated with
important comorbidities (arterial loss of a specified amount of weight. Based
hypertension, diabetes and OSA). on a large epidemiological study, it was
N No specific drug is able to found that a 10% weight loss was associated
consistently reduce the severity of with a 26% decrease in AHI. Some patients
OSA by more than 50%. may be substantially better after a weight
loss of only a few kilograms, but others may
N OSA patients should be screened for continue to have symptoms despite a
cardiovascular and metabolic significant weight loss (50–70 kg). Diet
complications. intervention studies report a body weight
reduction of 3.4–27.2 kg (mean¡SD -15¡7 kg),

a change in BMI of 1.6–9.4 kg?m-2 CPAP compliance. Cognitive behavioural
(mean¡SD-4.7¡2.5 kg?m-2) and a decrease therapy is highly successful in terms of
in AHI from 42¡25 to 24¡15 events?h-1 objective compliance and leads to the
(mean change -23¡13 events?h-1 or -45%). largest increase in average machine usage
A partial improvement in AHI can be (+2.92 h per night), and also increases the
expected in 39% of patients, while a cure number of subjects using CPAP for .6 h
from OSA is observed in 23% of cases. per night. Overall, patient education will
Some patients being treated with CPAP increase the patient’s self-efficacy, treatment
find it easier to lose weight than before commitment and motivation for CPAP
treatment, probably because of increased nightly use.
activity during the day or decreased
ingestion of snacks to increase alertness. Positional treatment
Others report a weight gain, which could
Conservative treatment strategies also
be related to altered energy expenditure at
include the use of a lateral sleeping position.
night. However, weight loss takes time,
Studies have shown that the frequency of
and only a minority of patients
apnoea and hypopnoea is greater with a
successfully maintain it. As a primary
supine sleeping position. Clinical experience
treatment, weight loss should be targeted
and observational studies suggest that the
towards patients with mild-to-moderate
patients exhibiting a large decrease in AHI in
OSAS, especially if there is no interest in
the lateral position compared with the
other options. Alcohol selectively reduces
supine position tend to have a lower AHI,
UA muscle tone, and increases the
and be younger and less obese. This therapy
frequency of respiratory events during
is most adequate for patients with OSAS
sleep. Alcohol also prolongs apnoea or
who have most of their breathing
hypopnoea by delaying arousal and is a
abnormalities concentrated in the supine
major source of calories.
posture and, while sleeping in the lateral
In spite of the widespread recommendation postures, the number of these abnormalities
of CPAP (and other therapeutic modalities) is significantly reduced and, in some cases,
in the management of OSA, there are is totally eliminated. Originally, this therapy
concerns about its continued acceptance was suggested for OSAS patients with an
among people who have to use it in the long AHI in the supine posture that is double or
term. Side-effects, and psychological and greater than that in the nonsupine postures.
other social factors may impede sustained Recently, this has been refined to a more
and successful treatment. Improved clinically oriented definition in which the
adherence can be obtained with increased AHI in the nonsupine posture (obstructive
patient education, which guides treatment or other types of abnormalities) should be at
uses and sensitises patients to the benefits a nonpathological level (,5 events?h-1 or, at
of treatment and the risks of nontreatment. most, ,10 events?h-1). This therapy could
Three different educational and behavioural also be advisable for patients who did not
strategies for improving CPAP use in adults succeed with CPAP, an oral device or any
with OSA have been described. An intensive, surgical treatment, and mainly have
supportive intervention with additional breathing abnormalities in the supine
nursing input (including CPAP education at posture. Also, it is suitable for patients
home and involvement of partners, and without OSAS but with snoring that is
CPAP titration in the sleep centre followed confined mainly to the supine posture.
by additional home visits) improves average Positional therapy is not recommended for
CPAP usage over a limited period of time in patients who for any reason (shoulder
symptomatic OSA (+0.59 h per night), while problems or any other physical disability
group education sessions can improve that interferes with their sleep in the lateral
compliance with CPAP therapy. Short-course position) cannot avoid the supine posture
education at titration (e.g. a 15-min during sleep. It is also inadequate for
videotape session) does not alter objective positional OSA patients who prefer to sleep

in the supine posture, but is mainly using positional therapy is imperative since
inadequate for nonpositional OSA patients increase in weight may convert positional
who have many breathing abnormalities in OSA patients into nonpositional OSA
the supine and lateral postures as well. For patients, and for them, CPAP is considered
these patients, CPAP is the treatment of the treatment of choice.
choice, since they also suffer from a more
severe disease. This therapy is also not an Oral devices
optimal solution for positional OSA patients Oral appliances for the treatment of snoring
who continue to snore loudly and perhaps and sleep apnoea include mandibular
also have events of flow limitation while advancement devices (MADs) and the less
sleeping in the lateral postures. Different common tongue-retaining devices. MADs
methods have been designed for positional represent the main non-CPAP therapy for
therapy: verbal instructions, the classical patients with OSAS. They are recommended
tennis ball technique, the positional alarm, a for patients with mild-to-moderate OSA and
triangular pillow with space to place an arm for those with more severe disease who do
and a soft vest attached to a board placed not tolerate CPAP. These devices aim to
under the pillow. A small individual cohort increase the UA size and reduce the risk of
study investigated the effects of elevating sleep apnoeas and snoring in patients with
the upper body by 60u and found a
OSAS. The UA is widened, particularly in its
moderate reduction of AHI. There are no
lateral dimension. The pharyngeal fat pads
data comparing the different devices with
relocate laterally from the airway and the
the exception that verbal instructions seem
tongue base muscles move anteriorly. This
to be less effective than the positional alarm.
leads to a reduction in pharyngeal
As described above, patients exhibiting a
collapsibility.
large decrease in AHI in the lateral
decubitus position compared with the A wide variety of appliances is available,
supine position tend to have a lower AHI, differing both in construction and in the
and be younger and less obese. Accordingly, manner in which they alter the oral cavity.
patients with a clear improvement in AHI With adjustable devices, it is easy for the
with positional therapy tended to be patient or the dentist to change the
younger, have a lower AHI and be less mandibular positioning in order to achieve
obese. It is not possible to extract from the the desired effects. The monoblock devices
data whether AHI, age or obesity is the best have to be adjusted at a dental laboratory.
predictor of treatment success. It is more The variety of device designs may explain
likely that AHI, age and obesity are mutually some of the variability in outcome between
interrelated. Cardiovascular sequelae, such patients and studies. The appliances are
as endothelial or left ventricular function, worn only during sleep and are generally well
were not investigated following positional tolerated. Not all patients have a clinically
therapy, while one study showed a decrease meaningful response to oral appliances.
in blood pressure. In some studies,
positional therapy is inferior, while in other The treatment effect of MADs has to be
studies CPAP is comparable to positional verified in a renewed sleep study with the
therapy. Overall, positional therapy can yield device in all patients with OSA, since
important reductions in AHI, but only in patients may have a suboptimal treatment
clearly selected positional OSA patients. In response. One major limitation of MAD
the very few follow-up studies, long-term treatment is its dependence on oral health
compliance with positional therapy was and the fact that it takes some time to
poor. Thus, it can be concluded that become accustomed to the device. Side-
positional therapy can be used in individual effects from the treatment, such as pain in
cases, but sleep studies are recommended the teeth and jaws, are generally mild and
to document individual success. Long-term transient. Patients therefore need an
compliance has to be secured by regular adaptation period that may sometimes last
follow-up studies. Follow-up of OSA patients for months before they become accustomed

to the device. In the longer term, bite mild-to-moderate disease compared with
changes become more common, but these patients with more severe OSAS. A mouth
are usually minor and do not disturb opening of 4–14 mm has not been found to
patients who are satisfied with the treatment influence the treatment outcome in terms of
outcome in terms of snoring and daytime sleep apnoea, although patients preferred
symptoms. Patients may continue using the device with a smaller opening. There is
their devices for many years, although the currently no agreement regarding the best
treatment needs to be followed up in terms method to measure and define the degree of
of side-effects and effectiveness. mandibular repositioning in the individual
patient. A custom-made device titrated from
Promising prediction methods based on an initial 50% of maximum mandibular
the mechanism of MADs and their advancement can be recommended.
influence on UA structures have been
proposed. Various imaging techniques have Self-reported short-term compliance with
been used to visualise the individual MAD treatment ranges from 76% to 95% of
increase in UA size during mandibular the patients. Some studies observe a higher
advancement. The velopharyngeal area is nightly compliance with MADs than with
central to this modification process, which CPAP, while other studies describe a similar
leads to reduced pharyngeal collapsibility nightly compliance. Compliance monitors
and sleep apnoea. Good responders have a have been introduced into the market and
larger increase in velopharyngeal airway are being evaluated. Objective compliance
size compared with poor responders. With monitoring of MAD use is currently not
nasendoscopy, it has been shown that the widely available and, generally, only
airway is still open during Müller’s subjective compliance reporting has been
manoeuvre and mandibular advancement relied upon in previous studies. In the
in good responders compared with a clear longer term, patients usually continue to use
collapse in poor responders. A model of their MADs, although compliance appears
the UA using combined UA imaging and to decrease slightly with time. After 1 yr,
computational fluid dynamics can be used 76% of the patients were still on treatment
to evaluate the influence of MADs on UA and, after 2–4 yrs, about half the patients
volume and resistance, and has potential were still using their devices. The treatment
for the prediction of treatment success in effect of MADs on AHI is usually stable or
the future. decreases slightly in patients who have a
good initial treatment outcome. About a
The degree of mandibular advancement is quarter of the patients discontinue MAD or
an important modulator of the treatment CPAP treatment, either because of side-
outcome, since there is a dose-dependent effects or ineffective treatment. Close
effect on nocturnal oxygenation and collaboration between physicians and
pharyngeal collapsibility. Mandibular dentists is necessary to ensure optimal
titration is, therefore, a key procedure when patient selection, and to avoid any alteration
it comes to obtaining optimal effects on of dental occlusion or temporomandibular
OSAS with the device. A small advancement joint discomfort. The treatment must be
produces a suboptimal treatment effect, followed up and the device adjusted or
while too large an advancement produces exchanged in relation to the outcome.
more side-effects. Moreover, there are also Surgery of the UA
studies showing a reduction of efficacy when
advancing the mandible too much. It is A significant proportion of patients is unable
believed that in some cases, the airway to tolerate or adhere to CPAP therapy.
dimension changes from a wide lateral Therefore, many patients turn to surgical
diameter to a narrow lateral diameter if options as a salvage treatment. Surgery can
titration is overdone. It is possible that the also be considered as a first-line treatment
exact degree of mandibular advancement is in mild OSA and in patients with moderate-
of less importance for patients with to-severe disease for whom other

noninvasive treatments have failed. Surgical OSAS should never be performed without a
treatment of OSA aims to correct pre-operative PSG and a post-operative
anatomical abnormalities in the UA, sleep study is mandatory in OSAS patients.
contributing to its collapse during sleep. OSAS patients have an increased
Various surgical modifications of the UA anaesthetic risk at the time of induction
have been proposed to manage and, in (difficult intubation) and upon awakening
some cases, treat OSA. Their efficacy, (respiratory compromise). A discussion
however, remains questionable. between the surgeon and the
anaesthesiologist about the pre- and post-
Since the results of UA surgery in unselected operative airway management is, therefore,
OSAS patients are poor, it was suggested required. The results of surgical procedures
that one should first try to identify the site of for OSAS should be objectively documented
UA obstruction and subsequently correct the by PSG 3–6 months post-operatively
anatomical abnormalities at this particular because of the discrepancy between
site. Patients may be identified with subjective and objective results. Appropriate
retropalatal collapse, retrolingual collapse or clinical follow-up is required since results
both, and the lateral pharyngeal walls may tend to deteriorate in the long term.
be involved. At present, sleep endoscopy is
the most commonly used technique in daily Considerable clinical experience with the
practice to evaluate the site(s) of UA various UA surgical procedures has been
obstruction during sleep. Several studies obtained over the past few years. The
demonstrate that there are many sites in the interpretation of surgical results reported in
UA, which may contribute to pharyngeal the literature is not always straightforward
collapse during sleep. Therefore, the because of different criteria for success,
concept of one obstruction site/one surgical limited numbers of patients and, often, a
treatment has been replaced by multilevel short follow-up time. The lack of a
surgery addressing several airway segments. consensus on the definition of OSAS and
surgical success seriously hampers the
Various surgical techniques might be interpretation of surgical results and
combined to correct abnormalities at the comparisons among different treatment
nose, soft palate and tongue base including options. The criteria employed by Sher et al.
soft tissue surgery and/or skeletal (1996) are a reduction of the respiratory
framework surgery. The addition of disturbance index (RDI) of o50% and a
hypopharyngeal surgery improves clinical post-operative RDI ,20 events?h-1 or a
outcome in many OSA patients. The results reduction of the apnoea index (AI) of
of isolated nasal surgery for OSAS are poor o50% and a post-operative AI
and it is impossible to predict who will ,10 events?h-1. These criteria are frequently
respond on clinical grounds. However, nasal employed in the current literature on OSA
surgery might significantly improve CPAP surgery but their validity might be
and mandibular repositioning appliance questioned given the recent data that even
(MRA) tolerance in those patients suffering mild forms of OSA might be associated
from chronic nasal obstruction. The with cardiovascular morbidity. Other PSG
selection of the appropriate treatments for a variables have been suggested, such as the
particular patient becomes more complex oxygen desaturation index, the amount of
and a thorough knowledge of the different sleep fragmentation, cardiac events, and
surgical options, their results and possible patient-based factors, such as the degree of
complications is required. Some authors daytime sleepiness or obesity, which are
have concluded that there is little role for UA probably better related to the long-term
surgery in the management of OSAS health consequences of OSA.
patients because high-evidence-level studies
are not available, but the body of evidence is Surgical procedures, listed according to the
growing with several recent controlled level 1 site of intervention and their indications, are
trials. Surgical treatment for snoring and listed in table 1.

Table 1. Main otolaryngological and maxillofacial surgical treatments for OSA and their indications.
Intervention Main procedures Main indications
site
Nose Septoplasty For subjects with nasal obstruction, mainly
Turbinoplasty to improve symptoms or feasibility of CPAP
Valvuloplasty or MRA
FESS
Nasopharynx Adenoidectomy Adenoid hypertrophy
Oropharynx Tonsillectomy Tonsillar hypertrophy; in adults, mainly with
Uvulopalatopharyngoplasty other procedures
Uvulopalatal flap Retropalatal obstruction
Lateral pharyngoplasty Retropalatal obstruction
Soft palate RFITT Lateral pharyngeal wall collapse
Palatal implants Alone, mainly for snoring
Laser-assisted Retropalatal obstruction in mild OSA
uvulopalatopharyngoplasty Not recommended for OSA
Hyoid bone Hyoid myotomy and suspension No longer used
Hyoid myotomy with Hypopharyngeal obstruction
thyroidpexia
Tongue Glossectomy Marked tongue hypertrophy; rarely used
Tongue RFITT today
Moderate macroglossia and retrolingual
obstruction, mainly in mild-to-moderate OSA
Maxillae/ Mandible osteotomy with GA Hypopharyngeal obstruction; rarely
mandible Maxillomandibular advancement performed alone
Distraction osteogenesis Mandibular deficiency, severe OSA with
obstruction at multiple sites
Mainly for children with craniofacial
abnormalities
Larynx Epiglottoplasty Obstruction at the epiglottic level
Trachea Tracheostomy Emergency situations; other treatments not
feasible in severe OSA
Multisite Variably combined procedures Obstruction at multiple sites in moderate-to-
severe OSA
FESS: functional endoscopic sinus surgery; RFITT: radiofrequency interstitial thermotherapy; GA:
genioglossus advancement. Modified from Marrone et al. (2010).
Bariatric surgery an improvement in sleep and breathing

pattern, and decrease hypersomnolence.
Obesity is one of the most important risk Bariatric surgery is an effective means to
factors for the development of OSA. ,70% achieve major weight loss and is indicated in
of OSA patients are obese, i.e. exhibit a BMI individuals with a BMI o40 kg?m-2 or those
o30 kg?m-2. In morbidly obese patients, i.e. with a BMI o35 kg?m-2 with important
a BMI o40 kg?m-2, the prevalence of OSA comorbidities (arterial hypertension,
varies between 40% and 90%. The severity diabetes and OSA) and in whom dietary
of OSA is also greater than in less obese attempts at weight control have been
patients. Weight reduction can, therefore, be ineffective. Bariatric surgery is not an option
an important strategy in the management of in mild-to-moderate OSA. The aims of
OSA. Even mild weight reduction can lead to bariatric surgery are to reduce caloric intake

and to alter the hormonal milieu involved in despite the usual massive weight loss
nutrient absorption. Procedures can be obtained with bariatric surgery, cure of OSA
classified as restrictive or malabsorptive is not systematically obtained and a
interventions, or a combination of both. The substantial number of patients have to
restrictive procedures have the intention to continue CPAP. This reflects a significant
restrict food intake by reducing the total interindividual variability and emphasises
stomach capacity, such as gastric banding, the need for ongoing clinical and PSG
the gastric balloon and gastric sleeve follow-up of these patients.
resection (gastroplasty). A purely
malabsorptive procedure is the The optimal time post-surgery to reassess
biliopancreatic derivation technique, also OSA severity is uncertain. The nadir of
called the Scopinaro technique. Due to weight loss reported following bariatric
substantial malabsorption problems, this surgery occurs after 1 yr and, subsequently,
technique is no longer used. Currently, the weight is regained.
Roux-en-Y gastric bypass is the most
Reassessment of AHI away from this nadir
commonly available, and combines
may underestimate the benefit of bariatric
restrictive and malabsorptive effects.
surgery, while reassessment at the nadir
Overall, gastric bypass is more efficacious
may overestimate the long-term benefit. The
than gastric banding or gastroplasty, but
lack of randomised controlled trials in this
with higher complication rates. At present,
field has been argued to be because it is
these techniques can be performed as a
unethical to randomise patients at future
laparoscopic procedure. As with other major
risk due to their comorbidities to nonsurgical
surgical interventions, considerable
treatment. This point of view, however,
morbidity and mortality have been
neglects the increased peri- and post-
described. Along with deep venous
operative risks following bariatric surgery.
thrombosis and impaired functional status,
OSA itself is one of the three conditions Drug treatment
associated with a risk of major adverse
outcome during the peri- and post-operative Although there may be a predisposing
period of bariatric surgery. Leakage at the airway abnormality, it is changes in
stapler line is the most feared immediate respiratory drive, airway tone or surface
post-operative complication and occurs in forces that cause airway closure during
1–5% of cases. In gastric banding, frequent sleep. Pharmaceutical agents might reduce
vomiting can lead to slipping of the band sleep apnoea by increasing respiratory drive,
with obstruction and semiurgent changing sleep structure (in particular,
reintervention as a consequence (in 10% of suppressing REM sleep), increasing upper
patients). In addition, erosion of the gastric airway muscle tone, changing respiratory
wall occurs in 1–4% of these cases. and cardiovascular reflexes that may
perpetuate apnoeas, and reducing surface
Studies have shown the beneficial effect of forces that encourage closure of the upper
bariatric surgery on OSA. The ERS Task airway. Several attempts have been made to
Force on Non-CPAP Therapies in OSA identify an effective pharmacological
reported a change in BMI of 10–24.4 kg?m-2, treatment in patients with OSA and several
with a decrease in AHI of 44¡22 events?h-1 potential targets have been considered.
(-77%) after bariatric surgery. 94 (34.2%) Most studies in this area have applied drugs
patients were identified who showed a that are already in use in other medical
partial improvement in AHI, while 177 conditions. Since OSA comprises a
(64.4%) patients were cured of OSA. In spectrum of phenotypes (sex, age of onset,
another meta-analysis, a reduction in AHI of body composition, craniofacial
34 events?h-1 was reported and 85.7% of the abnormalities and comorbid conditions)
cases were cured. Positive results have also that require specific approaches, we cannot
been reported for metabolic consequences expect that a single drug therapy will fit all
and comorbid conditions. Unfortunately, OSA patients. The challenge will be to

identify various subgroups of OSA patients Acetazolamide inhibits carbonic anhydrase,
that selectively respond to a specific producing a metabolic acidosis that
pharmacological intervention. Based on the increases ventilatory drive. It was shown to
ERS Task Force report on Non-CPAP reduce AHI in a study of 10 subjects but
therapies, 24 studies of sufficient quality can there was no positive impact on daytime
be identified, reporting the effects of 24 symptoms after 1 week of treatment. The
drugs and recruiting between them 413 subjects who had responded best to the
subjects. Most studies have addressed the drug were offered a more prolonged trial of
direct interventional effects on OSA. treatment but only one could tolerate it in
However, no currently described drug the long term. Therefore, it has no role in the
consistently reduces the severity of the routine management of OSA.
condition by more than 50%.
Among the other drugs that have been
Protriptyline is a tricyclic antidepressant that trialled, naltrexone, theophylline and
inhibits re-uptake of serotonin and aminophylline have been shown to reduce
noradrenaline. It might reduce the the number of respiratory events overnight,
proportion of REM sleep in people with but this was at the expense of sleep
REM-predominant OSA and increase the continuity and total sleep time, which makes
airway tone mediated by serotonin acting on them unsuitable agents for the treatment of
genioglossus via the hypoglossal nerve. OSA. Intranasal steroids, as a single
There is no impact on the respiratory indices intervention, are also not recommended for
but there was an improvement in daytime treatment of adult OSAS.
symptoms in two out of three trials,
presumably due to a nonspecific alerting effect At the present time, there is no evidence
of the drug. Adverse side-effects, such as dry that any drug is likely to benefit an
mouth and urinary symptoms, are commonly unselected patient with OSA. It is likely that
reported. Protriptyline does not have any place better characterisation of the predominant
in the routine treatment of OSA. mechanisms of OSA in individual patients
will lead to better results and this also needs
Specific serotonin re-uptake inhibitors, such further study. It is recommended that none
as paroxetine, have been investigated as of the drugs investigated to date is used to
possible treatments for OSA. In a small treat OSA.
single-night study, paroxetine (40 mg) had
no impact on AHI compared with placebo, Recognition and initial treatment of
in severe OSA. By contrast, in a study with 6- comorbidities
week treatment arms, paroxetine (20 mg)
was shown to reduce AHI to 23.3 events?h-1, It is recognised that OSA patients often
compared with 30.3 events?h-1 for placebo. present with cardiovascular risk factors at
There was a positive impact on respiratory diagnosis, which gives them a predicted 10-
events in non-REM, but not REM, sleep and yr cardiovascular risk of .30% according to
no improvement in daytime symptoms. Framingham studies. 46% have
dyslipidaemia, 33% are obese, 11% have
Mirtazapine is another drug with clinical diabetes mellitus, 4% have glucose
antidepressant activity that acts as an intolerance, 11% have established
agonist of some serotonin receptors and can cardiovascular consequences and 68% have
also increase serotonin secretion. This arterial hypertension. This multi-comorbidity
might increase serotonergic tone to the of OSA lends itself to a multidisciplinary
hypoglossal nerve, which could be approach, incorporating dieticians,
particularly helpful during REM sleep. psychologists, physiotherapists, sleep
Reductions in the AHI were reported in one specialists, cardiologists and surgeons. If
study but could not be reproduced in two sleep apnoea is associated with severe
multicentre trials, while many participants obesity, lowered energy intake and/or
reported side-effects of sleepiness and greater energy consumption are required.
weight gain. Pharmacotherapy can be considered, but at

Table 2. Screening for cardiovascular (CV) and metabolic consequences.
Undiagnosed hypertension Clinical and ambulatory blood pressure
measurement
Early atherosclerotic processes PWV
IMT
CT angiography
Diastolic dysfunction Transthoracic echocardiography
Global evaluation of CV risk (obesity, Glycaemia
diabetes, dyslipidaemia) HbA1c
Cholesterol
Triglycerides
PWV: pulse wave velocity; IMT: intima-media thickness; CT: computed tomography; Hb: haemoglobin.
present, only the lipase inhibitor orlistat is considered, such as attention deficits and
available and its long-term effects are early cardiovascular changes (table 2).
limited. The best weight loss results with Regarding this latter point, it would seem
pharmacotherapy are obtained when appropriate to use subclinical cardiovascular
medication is used as an adjunct to an markers, since they have been demonstrated
intensive diet and lifestyle-change as predictors of future cardiovascular
programme, and the effects of these morbidity. CPAP treatment could be
strategies are additive. Overall, the target indicated when OSA is associated with
weight does not need to be the normal cardiovascular disorders, regardless of the
weight, which is usually an unrealistic presence of related symptoms. This is of
objective for severely obese patients. paramount importance in mild or
Arresting the accumulation of weight can asymptomatic OSA, given its frequency.
already be a significant initial result. The Identification of cardiovascular phenotypes
morbidly obese can be referred to a bariatric may be helpful in difficult therapeutic
surgeon. Added metabolic benefits may be decisions. Effects of other therapies, like oral
achieved with weight reduction, including appliances, on cardiovascular and metabolic
improvements in insulin resistance, high- outcomes remain to be further evaluated.
density lipoprotein cholesterol, and visceral
and subcutaneous abdominal fat, which are Although CPAP is effective regarding
associated with a reduction in cardiovascular sleepiness, daytime functioning and blood
risk. Moreover, the association between OSA pressure, it is also obvious that most
and traffic accidents or metabolic disorders chronic consequences of OSA may not be
could broaden the scope of the indication of fully reversed by CPAP alone. The degree of
CPAP treatment, because physicians could be blood pressure reduction achieved by
tempted to opt for treatment with CPAP, treatment in hypertensive OSA varies
despite the absence of OSA-related symptoms. between the therapies, with a b-blockers
being the treatment of choice in one study.
Overall, cardiovascular comorbidities are However, antihypertensive drugs are far
related to OSA severity, including AHI and more effective than CPAP at controlling
oxygen desaturation severity indices. This is blood pressure, although there is a
true, both in general and clinical beneficial effect when combining CPAP with
populations, regarding arterial hypertension, the angiotensin II receptor antagonist
nocturnal arrhythmias, ischaemic heart valsartan compared with CPAP alone. In
disease and stroke. This is also found with addition, residual excessive daytime
regard to vascular subclinical markers, such sleepiness is relatively prevalent in OSA,
as carotid intima-media thickness and pulse despite adequate CPAP treatment, which
wave velocity. Additional outcomes could be may require use of wakefulness stimulants,

after excluding any specific cause of N Kiely JL, et al. (2000). Cardiovascular risk
suboptimal objective adherence to CPAP, factors in patients with obstructive sleep
such as ill-fitting PAP masks, insufficient apnoea syndrome. Eur Respir J; 16: 128–133.
sleep, poor sleep hygiene or other sleep N Lévy P, et al. (2010). Outcomes of OSA
disorders, (e.g. narcolepsy, periodic leg and indications for different therapies.
movements, restless legs syndrome and Eur Respir Monogr; 50: 225–243.
depression), and improving CPAP duration, N Marklund M, et al. (2012). Non-CPAP
if feasible. Last but not least, sleep apnoea therapies in obstructive sleep apnoea:
may be associated with depression, which mandibular advancement device therapy.
Eur Respir J; 39: 1241–1247.
must be treated appropriately using
N Marrone O, et al. (2010). Upper airway
modern antidepressants.
surgery. Eur Respir Monogr; 50: 286–301.
In conclusion, comorbidities are highly N Montserrat JM, et al. (2007). Diagnostic
prevalent in OSA and should be screened for and therapeutic approach to nonsleepy
apnea. Am J Respir Crit Care Med; 176: 6–9.
in order to stratify these patients to the
N Oksenberg A, et al. (1998). The effect of
optimal treatment modality. Moreover,
body posture on sleep-related breathing
outcome of OSA treatment has not only to disorders: facts and clinical implications.
be evaluated in terms of AHI, but also to be Sleep Med Rev; 2: 139–162.
rated in terms of sleep improvement, N Oksenberg A. (2005). Positional and
wellbeing, improved cognitive function, non-positional obstructive sleep apnea
reduction of comorbid metabolic or patients. Sleep Med; 6: 377–278.
cardiovascular disorders, and modification N Pépin JL, et al. (2010). Comparison of
of the risk of developing cardiovascular continuous positive airway pressure and
complications in OSA. It is also obvious that valsartan in hypertensive patients with
most chronic consequences of OSA may not sleep apnea. Am J Respir Crit Care Med;
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disease-modifying drugs, should be further therapies in OSA. Eur Respir J; 37: 1000–
evaluated. This will broaden the spectrum of 1028.
N Sher AE, et al. (1996). The efficacy of
therapeutic choice, but also emphasises the
surgical modifications of the upper airway
need for specific training for physicians to
in adults with obstructive sleep apnea
enable them to make the right choices.
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N Smith CE, et al. (2009). Patient education
Further reading combined in a music and habit-forming
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N Boudewyns A, et al. (2006). Surgical positive airway (CPAP) prescribed for
treatment for obstructive sleep apnea. sleep apnea. Patient Educ Couns; 74:
Prog Respir Res; 35: 167–173. 184–190.
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treatment for OSA: medical and surgical supportive and behavioural interventions
options. Eur Respir Monogr; 50: 302–320. to improve useage of continuous positive
N Epstein LJ, et al. (2009). Clinical guideline airway pressure machines for adults with
for the evaluation, management and obstructive sleep apnoea. Cochrane
long-term care of obstructive sleep apnea Database Syst Rev; 2: CD007736.
in adults. J Clin Sleep Med; 5: 263–276. N Strollo PJ, et al. (1996). Obstructive sleep
N Hedner J, et al. (2010). Pharmacological apnoea. New Engl J Med; 334: 99–104.
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ing. Eur Respir Monogr; 50: 321–339. education and progressive muscle relaxa-
N Hui DSC, et al. (2000). Effects of tion alone or combined on adherence to
augmented continuous positive airway continuous positive airway pressure treat-
pressure education and support on comment in obstructive sleep apnea patients.
pliance and outcome in a Chinese Sleep Breath; [Epub ahead of print DOI:
population. Chest; 117: 1410–1416. 10.1007/s11325-011-0600-3].

Positive airway pressure
treatment
Anita K. Simonds
Principles and machines (Gordon et al., 2005). The relative

importance of these mechanisms is unclear,
The fundamental cause of OSA is upper but upper airway stenting seems to be the
airway collapse. Positive airway pressure dominant factor. By preventing recurrent
therapy (PAP) is used to redress this collapse and trauma throughout the night,
collapse, working as a pneumatic splint. PAP CPAP use may secondarily reduce upper
can be delivered constantly at a fixed level airway oedema, and this combined with
throughout inspiration and expiration improvement in sleep quality may improve
(continuous positive airway pressure, upper airway reflexes.
CPAP), as a variable pressure via an auto-
adjusting device (APAP), or as a bi-level PAP machines For CPAP, either
pressure support system that provides a compressors or, more usually, blower
higher level of inspiratory and expiratory devices, are used to deliver bias flow. Flow
support sufficient to maintain airway rates of 20-60 L?min-1 are required to deliver
patency (box 1). CPAP may also improve pressures of up to 20 cmH2O. To ensure a
functional residual capacity (by recruiting constant pressure throughout the
alveoli), reduce the work of breathing and respiratory cycle, flow is increased during
improve haemodynamics in patients with inspiration and reduced during expiration.
heart failure, by reducing preload and CPAP is delivered to the patient via an
afterload. An increase in lung volume has interface, and each circuit requires an
relevance, as it has been suggested that this exhalation option to minimise rebreathing.
volume change associated with PAP pulls
down on the trachea and stretches the A wide range of portable CPAP systems is
airway open. Alternatively, it may reflexively available. Ideally, these should be reliable,
increase upper airway dilator muscle tone small, portable and inexpensive and should
function as noiselessly as possible. They
should provide compliance data, and most
Key points produce additional data on leaks, flow, and
respiratory events. It should be noted that
N Auto-adjusting CPAP may be as effective respiratory events as determined by the
as PSG titration in establishing CPAP machine algorithm may not be directly
overnight pressure requirements. comparable to events detected by other
sleep monitoring systems.
N Use of CPAP for at least 4 h per night
is required to control sleepiness. Use Many machines provide a gradual ramped
for longer periods, e.g. 5–6 h, may be increase in CPAP to the preset level in the
required to control cardiovascular first 5–20 min of use. Some individuals,
variables and produce further particularly those beginning treatment or
cognitive benefit. who require high CPAP levels, find this
N CPAP adherence may be improved helpful. Others find the ramp unnecessary
with a problem-solving approach. and prefer to ’get on with’ the
predetermined pressure as soon as the

Box 1. Terminology of positive airway pressure (PAP). autotitrating devices to determine an
appropriate fixed-level pressure setting is
Continuous positive airway pressure (CPAP) considered below.
Autoadjusting positive airway pressure
(APAP) PAP interfaces
Bi-level positive airway pressure
Expiratory positive airway pressure (EPAP) A significant part of the improvement of
CPAP delivery over the past decade can be
attributed to improved mask design and
mask is in place. Expiratory pressure release comfort. Broadly, interfaces can be classified
approaches are employed in an attempt to as: a) nasal; b) oro-nasal; c) full-face
improve patient comfort. Here, the flow (covering last part of face/head); or d) oral.
generator detects the start of inhalation and The advantages and disadvantages of each
decreases motor speed to reduce the are given in table 1. Oro-nasal interfaces
pressure level during expiration. These minimise problems from mouth leak, as leak
modifications might help some patients promotes increased flow, which can increase
tolerate therapy better empirically, but have nasal resistance, in turn leading to
not been evaluated in crossover trials. symptomatic rhinitis, which may limit
adherence. While heated humidification may
Autotitrating positive airway pressure
reduce nasal symptoms and aid compliance
(APAP) devices have been developed, in
in some patients, trials of humidification
which pressure is varied throughout the
have produced equivocal results for
night with the aim of matching patient
enhancing adherence in a general CPAP
requirements better. A meta-analysis of
population. Leaks from around the interface
long-term fixed-level versus autotitrating
are addressed by ensuring optimal mask fit
devices, has shown that, compared to
and by design features that include
standard CPAP, APAP is associated with a
reduction in mean pressure. However, APAP inflatable or mouldable mask cushions.
and standard CPAP were similar in terms of There is good evidence that mask leaks not
patient adherence, their ability to eliminate only limit the efficiency of ventilation but
respiratory events and their ability to also impair sleep quality. Furthermore, noisy
improve subjective sleepiness. Given that air leaks can affect sleep quality in partners.
APAP is more costly than standard CPAP, Most nasal and oro-nasal CPAP interfaces
APAP should not be considered first-line are vented, such that dead space is flushed
chronic therapy in all patients with OSA. by continuous flow through the circuit. Dead
However, APAP may be useful in other space is also a vital determinant of efficacy.
situations, e.g. home titrations (see below) It is important to consider effective (or
or detection of mouth leak, or in certain dynamic) dead space, rather than static
subgroups of patients with OSA who require dead space, as the flow through the interface
high pressures. Crucially, when considering and position of vents are vital. For example,
APAP devices, attention should be paid to although the Total face mask (Philips
the type of breathing event the algorithm Respironics, Best, The Netherlands), which
responds to (flow limitation, snoring, covers the whole face, has a large static
apnoea, etc.), whether the device responds dead space, effective dead space is very
to the severity of the event, whether it small as exhalation ports are closely
responds pre-emptively, the ability to detect adjacent to the nares. A further complication
and respond to leak, the rate of response, of interfaces is pressure sores or discomfort,
and how it deals with ‘false’ events such as particularly affecting the bridge of the nose,
swallowing, coughing, arousal from sleep or forehead and maxillary region. While
central apnoeas – plus, of course, whether alternation of interfaces may help (e.g.
the algorithm has been validated in clinical swapping to nasal plug system in some
circumstances. It is probable that response patients and in children), customised masks
to flow limitation is more effective than have been shown to be superior to
response to apnoeas. Short-term use of commercial interfaces in reducing pressure

area problems. In addition, a problematic N Use of autotitrating devices for a single
adverse effect of long-term CPAP or NIV in night or longer periods.
children is facial skeletal maldevelopment, N Empirical (educated ‘guesstimate’) e.g.
usually mid facial hypoplasia. Newer, 10 cmH2O
smaller nasal interfaces can help but a
switch to a customised interface may be the Algorithms are attractive and several have
best solution (Fauroux et al., 2005). Facial been validated (Stradling et al., 2004;
development should be assessed Miljeteig et al., 1993). See Box 2.
radiologically and photographically every PSG titration versus algorithm or unattended
1–2 years in children requiring long- autotitrating device In a large clinical trial
term CPAP. (n.300) of newly diagnosed OSA patients
PAP titration with AHI .30 events?h-1 and mean ESS of
15, randomised to standard PSG titration,
While detailed PSG-directed manual titration unattended home autotitrating device or
of CPAP has a long track record, recent work algorithm-generated (Miljeteig–Hoffstein
has shown that PSG is not necessary to method) determination of CPAP level, Masa
establish a therapeutic CPAP level. Clinical et al. (2004) found similar improvement in
alternatives include: AHI, subjective sleepiness and compliance
in all three groups over 12 weeks’ follow-up.
N Algorithmic derivation of CPAP based A further study in CPAP-naı̈ve patients
on AHI or SaO2 dip rate and neck size, showed similar outcomes in terms of
and/or BMI. efficacy, symptom control and adherence,
Table 1. Advantages and disadvantages of interfaces for CPAP.

Interface Advantages Disadvantages
Nasal mask Allows feeding, speech Mouth leaks
Easier for coughing Can be a problem to use in
Can be less claustrophobic edentulous patients
Less risk of aspiration of Limited efficacy and may cause
vomit, or gastric distension side-effects in patients with
nasal obstruction, rhinitis and
nose bleeds
Oro-nasal or full-face mask No leak from mouth May be claustrophobic
May be more stable pressure (although total face mask may
during sleep reduce this)
Helpful in patients with nasal Can be associated with
obstruction aspiration of vomit (but rare in
stable patients)
May be more likely to cause
gastic distension
Nasal plugs Less surface area in contact Mouth leaks
with face Can be more unstable fit than
Can be used to vary pressure full-face mask
effects on face and allow
healing of nasal bridge
pressure sores, and reduce
mid-facial hypoplasia in
children
Can be helpful in
claustrophobic patients

Box 2. Algorithms for setting CPAP level.
Oxford algorithm CPAP level 5 .4% oxygen saturation dip rate
Stradling et al., 2004 6 0.048) + (neck size (inches#) 6 0.325) + 2.1
Miljeteig–Hoffstein method CPAP level 5 (0.16 6 BMI) + (0.13 6 neck
Miljeteig et al., 1993 circumference) + (0.04 6 AHI) - 5.12
#
: If neck size measured in cm, multiply CPAP level by 0.128.
when comparing algorithm-designed fixed the patients studied had relatively severe,
level CPAP followed by self-adjustment at symptomatic OSA: the results cannot be
home with standard titration. West et al. readily translated to individuals with mild
(2006) compared three methods of CPAP OSA, although they should at least
delivery over 6 months. In this study of 98 provide a useful guide to set-up in the
patients with an SaO2 .4% dip rate of majority of patients.
.10 events?h-1 and ESS of .9 were
randomised to: 1) Autotitration CPAP PAP adherence
(Autoset Spirit; ResMed, San Diego, CA,
Optimal CPAP use has previously been
USA) throughout the study period; 2)
defined as use for .4 h for .70% of nights.
Autotitration CPAP (Autoset Spirit) for
However, a linear relationship has been
1 week followed by remaining period with
shown between CPAP use and improvement
CPAP fixed at 95th centile of pressure in first
in ESS up to 5 h, and improvement in
week; and 3) fixed CPAP level set using
memory was significantly greater in those
Oxford algorithm. Outcome measures
using CPAP for .6 h per night compared
assessed at 1 and 6 months were ESS,
with ,2 h (Weaver et al., 2007). The
OSLER wake test, 24-h blood pressure, SF-
relationship between CPAP ‘dose’ and
36 health status score, sleep apnoea-related
subjective and objective sleepiness and
quality of life and CPAP compliance. The
functional outcomes is shown in figure 1.
authors found no difference in any of these
Barbé et al. (2010) found the reductions in
variables, nor in the CPAP monitoring data
blood pressure were seen only with CPAP
between the groups. The 95th centile
pressure levels in the 6-month autotitration used for .5.6 h per night in hypertensive
and 1-week autotitration groups were higher
than in the algorithm-generated pressure 0.7
■
group, although mean pressure was lower in 0.6 ■ ■
■
◆
Normal values %
the 6-month autotitration group. ■ ◆

0.5 ◆
◆
In an earlier investigation comparing 0.4 ■
◆
pressure determined by 1 month of ▲ ▲
◆ ▲
0.3 ▲
autotitrating CPAP, 4 nights of autotitrating ▲
CPAP, Oxford algorithm or standard fixed- 0.2
▲
pressure (10 cmH2O) CPAP, Stradling et al. 0.1
(2004) found no disadvantage to using the 0
algorithm, and indeed the empirical ≤2 >2–<4 ≥4–<5 ≥5–<6 ≥6–<7 ≥7
10 cmH2O setting was reasonably effective. Nightly CPAP use h
All of these studies confirm that complex FIGURE 1. Dose of CPAP and effects on sleepiness
laboratory PSG manual titration does not and functional outcomes. Cumulative proportion
offer advantages over autotitrating devices of participants obtaining normal threshold values
or simple algorithm set-up. This is clearly an on the ESS (squares), MSLT (triangles), and
important finding from a cost-efficiency Functional Outcomes of Sleep Questionnaire
viewpoint, and useful for those managing (diamonds). Reproduced from Weaver et al.
clinical pathways. It should be noted that (2007), with permission from the publisher.

Review download data from PAP device
Discuss with patient Sleep problems,

Examine patterns of use persistent somnolence
Examine AHI, leaks Insomnia, sleep
initiation, sleep
maintenance difficulty,
Problems with Poor control of SDB noise
rationale, concept, Mask discomfort,
acceptability rhinitis, upper
airway dryness, Check device
pressure sores, performance, review
leaks diagnosis. Are Consider other pathology
Consider patient obstructive events e.g. restless legs (assess with
education and controlled? Consider more detailed sleep study)
psychological further titration and Consider course of
support, more
Consider different pressure settings short-acting sedative e.g.
interface, change. Are leaks zopiclone to aid sleep
intensive home
humidification, responsible? Does initiation
support
education on patient have
mask fit additional Consider bi-level
hypoventilation? ventilation if hypercapnic
FIGURE 2. Adherence to PAP and problem solving.
OSA patients. Theoretically it is possible technique and limiting factors, useful

that differing periods of use determine information can be obtained from download
different outcomes, including cognitive, data from the device. A variety of patterns of
autonomic and cardiovascular short- and use can be seen but use every night for short
long-term effects. Data so far would suggest interrupted periods often indicates interface,
that at least 5–6 h use is necessary. There is leak and upper airway problems, while
a variety of predictors of compliance related erratic and only occasional night use may
to the patient, equipment, initiation of indicate limited understanding of the
therapy and social environment (Sawyer rationale of therapy, inappropriate pressure
et al., 2011). Not surprisingly, severity of setting, poor buy-in to the concept of
OSA and high symptom burden are therapy, insomnia or noise problems. A
associated with better adherence, as is the guide to problem solving is given in figure 2.
presence of a supportive partner. Upper
airway side effects, increased nasal CPAP use and comorbidity In individuals
resistance, depression, claustrophobia and who remain hypersomnolent or
passive coping personality type limit use symptomatic despite satisfactory adherence
and should be specifically addressed. Long- and demonstration of effective delivery of
term adherence to CPAP can be predicted therapy on titration study, a further cause for
within the first 3 nights’ use, so attention sleep disruption may be present. Relatively
directed to educational assistance and common causes include restless legs
problem solving at the outset is vital. syndrome, inadequate sleep opportunity
and conditions such as arthritis, poor
PAP problem solving A step-wise, asthma control or back pain, which may
collaborative approach with the patient is fragment sleep. Additional intrinsic sleep
best. After discussion with the patient to disorders should be explored by PSG
determine acceptance, understanding of the (Simonds, 2007).

Alternatives to CPAP events are dealt with by setting a fixed level
of CPAP. Short-term trials have shown that
Bi-level positive airway pressure ventilators ASV may be more effective than CPAP in
Use of inspiratory pressure support (IPAP) CSA. The approach is being evaluated in the
combined with expiratory positive airway European multicentre SERVE-HF trial, and
pressure (EPAP) is indicated in patients with management of CSA in HF is discussed
upper airway obstruction coupled with further later in this chapter.
alveolar hypoventilation. In practice, this is
commonly seen in patients with obesity Mandibular advancement splints (MAS) are
hypoventilation syndrome (Piper et al., 2011) an important alternative to CPAP in mild
or neuromuscular disorders such as and moderate OSA, and may be used in
Duchenne muscular dystrophy, where patients who fail to tolerate CPAP. MAS are
obstructive apnoeas may be seen in the considered in the next section of this book.
teenage years only to be followed by
nocturnal hypoventilation as diaphragm Expiratory positive airway pressure (EPAP) A
strength progressively deteriorates. A recent development is the application of
combination of OSA and nocturnal nasal valves designed to increase expiratory
hypoventilation may also be seen in some resistance and thus generate a level of
COPD patients, and hypopnoea and positive airway pressure on expiration which
hypoventilation are more commonly seen is proportional to respiratory flow. In early
than pure obstructive apnoeas in children trials, the device has been shown to reduce
with OSA. As a rule, bi-level pressure AHI and daytime subjective sleepiness
support is required in patients with diurnal compared to sham control and was well
hypercapnia (PaCO2 .7 kPa) or nocturnal tolerated. Since no flow occurs during an
hypoventilation not controlled by CPAP, apnoea, the device cannot control events
and may be successful in patients with that have already occurred, and mouth leak
high pressure requirements who fail to may be a limiting factor. Further work is
tolerate CPAP. continuing to explore the role of EPAP in
OSA therapy in comparison to CPAP and
CPAP versus ASV and bilevel ventilation in HF alternative approaches.
patients with SDB Over 50% of patients with
chronic HF have SDB and, contrary to
previous belief, this is true not just in
patients with end-stage disease but those in
Further reading
New York Heart (NYHA) classification
groups II–IV. CPAP in patients with OSA N Barbé F, et al. (2010). Long-term effect of
produces improvement in symptoms, continuous positive airway pressure in
quality of life and left ventricular ejection hypertensive patients with sleep apnea.
fraction. However, in HF patients with Am J Resp Crit Care Med; 181: 718–726.
predominantly central sleep apnoea, a N Bradley TD, et al. (2005). Continuous
randomised controlled trial (Bradley et al., positive airway pressure for central sleep
2005) showed no advantage of CPAP – apnea and heart failure. New Engl J Med;
353: 2025–2033.
indeed there was excess mortality in the
N Fauroux B, et al. (2005). Facial side
CPAP group, although post-hoc analysis
effects during noninvasive ventilation in
showed that the latter occurred in patients children. Int Care Med; 31: 965–969.
in whom CPAP did not suppress respiratory N Gordon P, et al. (2005). Positive airway
events (Arzt et al., 2005). Identifying HF pressure for obstructive sleep apnoea/
patients with CSA is difficult, as their ESS is hypopnoea syndrome. Thorax; 60: 68–75.
usually normal. Adaptive servo ventilation N Masa JF, et al. (2004). Alternative meth-
(ASV) varies IPAP delivery to smooth out ods of titrating continuous positive air-
central apnoeas and subsequent way pressure. A large multicenter study.
hyperpnoeas in the Cheyne–Stokes pattern Am J Respir Crit Care Med; 170: 1218–1224.
of breathing, while concomitant obstructive

N Miljeteig H, et al. (1993). Determinants of N Stradling JR, et al. (2004). Relative
continuous positive airway pressure level accuracy of algorithm-based prescrip-
for treatment of obstructive sleep apnea. tion of nasal CPAP in OSA. Respir Med;
Am Rev Respir Dis; 147: 1526–1530. 98: 152.
N Piper AJ, et al. (2011). Obesity hypoventi- N Weaver TE, et al. (2007). Relationship
lation syndrome. Am J Resp Crit Care Med; between hours of CPAP use and achiev-
183: 292. ing normal levels of sleepiness and day-
N Sawyer AM, et al. (2011). A systematic time functioning. Sleep; 30: 711–719.
view of CPAP adherence across age
groups: clinical and empiric insights for N West SD, et al. (2006). Comparison of
developing CPAP adherence interven- three ways to determine and deliver
tions. Sleep Med Rev; 15: 1–14. pressure during nasal CPAP therapy for
N Simonds AK. (2007). Continuous positive obstructive sleep apnoea. Thorax; 61:
airway pressure therapy for sleep disor- 226–231.
dered breathing in adults. In: Simonds N Arzt M, et al. (2005). Association of sleep-
AK, ed. Non-Invasive Respiratory Support. disordered breathing and the occurence
A Practical Handbook. London, Hodder of stroke. Am J Respir Crit Care Med; 172:
Arnold; pp. 291–322. 1447–1451.

Treatment of central sleep
apnoea
Winfried Randerath
Optimal treatment for patients with CSA is Central apnoea associated with
still under investigation. However, a clear hypoventilation
definition of the disease and diagnosis of
Central apnoea associated with
underlying diseases forms the basis of any
hypoventilation appear in patients with
therapeutic approach.
insufficient respiratory drive or reduced V9E
due to neuromuscular or thoracoskeletal
disorders. For these patients, NIV is the
Key points treatment of choice. It normalises V9E and
may also improve survival (Aboussouan
N NIV is the therapy of choice in central et al., 2001; Bourke et al., 2006).
disturbances associated with CSA associated with hyperventilation
hypoventilation, if there are no
sufficient options to treat the There is currently a lack of evidence proving
underlying disease in those patients. a survival benefit under treatment of CSA
associated with hypoventilation. However,
N The therapeutic approach to patients many studies have shown that survival of
with central disturbances associated patients with cardiovascular disorders is
with hyperventilation begins with significantly reduced when associated with
optimal treatment of any underlying central breathing disturbances (Yumino
disease, including pharmacological or et al., 2008). In addition, CSA is a marker of
interventional cardiac or cerebral poor outcome in patients with stroke and
options. renal failure. Therefore, it can hardly be
accepted from a clinical point of view to
N There is limited evidence showing leave CSR in patients with cardiovascular
effectiveness of treatment with oxygen diseases or central breathing disturbances
or pharmaceutical agents in patients with stroke or renal failure
(theophylline, acetazolamide). untreated. In addition, it is unclear to what
degree central breathing disturbances impair
N After optimal treatment of underlying quality of life or daytime functioning in
diseases, the application of positive patients with underlying cardiovascular
airway pressure, especially CPAP, diseases or organ failure. Therefore, diagnosis
should be trialled. The evidence for bi- and evaluation of treatment efficacy during
level therapy is limited. titration and follow-up must be based on PSG
analysis of central respiratory disturbances in
N There is growing evidence that these patient groups.
adaptive servo ventilation normalises
The overwhelming majority of CSA is
ventilation, improves cardiac function
associated with the aforementioned
and quality of life in CSA patients if
disorders, so the first step of treatment is
CPAP fails.
the abolition of these causes. This includes
pharmaceutical or surgical improvement of

cerebral blood flow, therapy of inflammatory clearly above the threshold and thus
or tumorous brain diseases or stabilises respiration. It has been shown that
pharmacological or interventional treatment elevation of the CO2 level by external
of cardiac disorders. Few non-randomised application or by enlargement of dead space
studies have investigated the effect of is able to normalise ventilation in CSA
cardiac drugs in HF patients with breathing patients (Xie et al., 1997; Andreas et al.,
disturbances. ACE inhibitors and b-blockers 1998; Lorenzi-Filho et al., 1999). However,
have been shown to improve cardiac the application of CO2 might increase
function and reduce CSA in small groups of sympathetic activity (Andreas et al., 1998).
these patients. Cardiac resynchronisation Nevertheless, this treatment option cannot
(CRT) therapy effectively improves severe be recommended until safety concerns of
left ventricular systolic dysfunction. Therapy gas application have been resolved.
with atrial synchronised bi-ventricular Moreover, long-term prospective data are
pacemakers reduced the duration and needed to define clinical outcome and
number of central disturbances. If central adverse effects.
disturbances remain after optimal treatment
of the underlying disease, strategies Pharmaceutical options
interfering with hypoxia, apnoeic threshold,
Acetazolamide and theophylline have been
chemosensitivity or cardiac or lung mechanics
considered to improve central respiratory
may be discussed (Brack et al., 2012).
disturbances by influencing the respiratory
However, it is unclear whether therapy control system in the brain stem.
generally improves survival or quality of life Acetazolamide is a mild diuretic and
in patients with primary CSA. Thus, the respiratory stimulant. A randomised,
indication for treatment should be based on double-blind, cross-over, placebo-controlled
both PSG parameters such as breathing short-term study showed a reduction of
disturbances and sleep profile on the one central disturbances by half, but failed to
hand, and impairment of quality of life on normalise the disturbances (Javaheri, 2006).
the other. In a single-blind, randomised placebo-
controlled study, theophylline reduced the
Oxygen transcutaneous PtcCO2 indicating the
The application of oxygen may improve left stimulation of ventilation (Andreas et al.,
ventricular function and reduce the reflex 2004). However, there are concerns that this
activation of the peripheral chemoreceptors. might aggravate the loop gain. Therefore,
Several studies have shown that the oxygen pharmaceutical treatment cannot currently
desaturation index can be normalised under be recommended for patients with CSA.
oxygen supply. However, AHI has only been Positive airway pressure treatment
reduced by about 50% and sleep
parameters, clinical symptoms and Positive airway pressure (PAP) can be
cognitive impairment have not been applied constantly (CPAP), varying between
sufficiently influenced in patients with inspiration and expiration (bi-level) or
chronic HF and CSR (Staniforth et al., 1998; continuously changing on a breath-by-breath
Krachman et al., 1999). Finally, there are basis (ASV). PAP options are commonly
conflicting results on the influence of oxygen considered to maintain airway patency and
on sympathetic activity (Staniforth et al., enhance alveolar ventilation. Consecutively,
1998). Based on these data, oxygen supply ventilation/perfusion mismatches in the
cannot be recommended as a first line lungs improve and the intrapulmonary gas
therapy in CSA patients. reservoir enlarges, which reduces the
Application of CO2 variation of gas proportions. Moreover, PAP
influences cardiac function mechanically.
Central apnoeas emerge when the prevailing Positive pressure application may reduce
CO2 level falls below the apnoeic threshold. the venous return to the heart and the
The application of CO2 raises its blood level cardiac index in healthy persons. In contrast,

PAP reduces pleural pressure swings and overcome the overshooting and
thus left ventricular afterload in HF patients. undershooting of ventilation in CSR.
Moreover, it reduces the work of breathing
and therefore the oxygen consumption of The expiratory pressure is set to eliminate
the respiratory muscles. These effects upper airway obstructions. It can be fixed
improve heart function (Kaneko et al., 2003). based on manual titration. The most recent
algorithms adapt the expiratory pressure
Several studies have shown that CPAP automatically according to the prevailing
reduces AHI by about 50% but does not level of obstruction. In addition, all devices
normalise respiration. Ongoing therapy apply mandatory breaths in case of central
might lead to additional improvement after apnoeas.
3 months in some individuals (Arzt et al.,
2009). A larger study (the CanPAP trial) ASV has been compared with oxygen, CPAP
confirmed the reduction of respiratory and bi-level PAP in a small-sized randomised
study in 14 patients, and proved to be superior
disturbances by half, improvements of
to all other treatment options (Teschler et al.,
minimum oxygen saturation and left
2001). ASV has shown to improve chronic HF
ventricular function, but failed to show a
sympathetic activity and daytime performance
survival benefit over 3 years. Interestingly, a
(Pepperell et al., 2003). There is growing
post-hoc analysis of the CanPAP data showed
evidence that ASV is superior to CPAP in
that optimal suppression of respiratory
terms of left ventricular function and
disturbances was associated with
compliance (Kasai et al., 2010; Philippe et al.,
improvement of survival (Bradley et al.,
2006). Most of these studies have been
2005; Arzt et al., 2007 and 2008).
performed in patients with almost pure CSA/
There are limited data on the use of bi-level CSR. However, in patients with co-existing
PAP in central breathing disturbances. OSAS and CSA/CSR, ASV has been shown to
Small-sized studies in CPAP non-responders improve obstructive disturbances as
showed a better reduction of central effectively as CPAP but to suppress central
respiratory disturbances. However, there is a apnoeas and hypopnoeas more sufficiently
lack of clinical data comparing bi-level PAP (Arzt et al., 2008; Randerath et al., 2009).
with other treatment options. Long-term In recent years, other complicated breathing
trials and data on cardiovascular parameters patterns have been discussed intensively.
are lacking. Therefore, bi-level PAP has not These include central breathing disturbances
been proven to be superior to CPAP (Dohi in patients using opioids and CSA emerging
et al., 2008). under CPAP therapy. Data on the optimal
therapy of opioid-induced sleep apnoea are
Adaptive servo ventilation controversial. While a retrospective analysis
found no difference between CPAP and ASV,
ASV applies two different pressure levels
a prospective small sized case series showed
during expiration and inspiration, similar to
superiority of ASV by using higher pressure
bi-level treatment. However, the inspiratory
support (Farney et al., 2008; Javaheri et al.,
pressure changes continuously to overcome 2008). Finally, ASV was compared to CPAP,
central disturbances and CSR. The CPAP plus oxygen, bi-level PAP in
difference between inspiratory and spontaneous and spontaneous/timed mode
expiratory pressure defines the tidal volume, in patients with complicated breathing
i.e. the pressure support. By elevating the patterns (CSA/CSR/CPAP emergent CSA).
inspiratory pressure, tidal volume is ASV normalised breathing disturbances in all
increased, which is needed during the subgroups and was more effective than the
hypoventilation periods in CSR. In contrast, other treatment options.
during hyperventilation, the difference
between inspiration and expiration is Despite the growing evidence on the efficacy
minimised because no additional pressure of adaptive servoventilation in patients with
support is needed. Thus, the algorithms central breathing disturbances, there is still

a lack of data on survival. Early long-term N Arzt M, et al. (2009). Time course of
data show that ASV improves central continuous positive airway pressure
disturbances better than CPAP (Randerath effects on central sleep apnoea in
et al., 2012). Moreover, two large sized studies patients with chronic heart failure. J
on long-term outcome have been started. Sleep Res; 18: 20–25.
N Bourke SC, et al. (2006). Effects of non-
In conclusion, the clinical pathway generally invasive ventilation on survival and qual-
starts with optimising the treatment of any ity of life in patients with amyotrophic
underlying disorder. In patients with cardiac lateral sclerosis: a randomised controlled
disorders and CSR or CSA, a CPAP trial is trial. Lancet Neurol; 5: 140–147.
recommended for two reasons. Firstly, CPAP N Brack T, et al. (2012). Cheyne–Stokes
sufficiently suppresses central respiratory respiration in patients with heart failure:
disturbances in about 50% of patients. prevalence, causes, consequences and
Secondly, the CPAP titration determines the treatments. Respiration; 83: 165–176.
expiratory pressure necessary to overcome N Bradley TD, et al. (2005). Continuous
upper airway obstruction. If CPAP does not positive airway pressure for central sleep
normalise CSA/CSR, a switch to ASV should apnea and heart failure. N Engl J Med; 353:
be considered. As survival is significantly 2025–2033.
reduced in patients with HF and CSA/CSR, N Dohi T, et al. (2008). Bi-level positive
airway pressure ventilation for treating
we generally recommend sufficient positive
heart failure with central sleep apnea that
pressure treatment (CPAP or ASV). Oxygen
is unresponsive to continuous positive
or bi-level PAP cannot generally be
airway pressure. Circulation; 72: 1100–1105.
recommended in advance to ASV. As CSA/
N Farney RJ, et al. (2008). Adaptive servo-
CSR is a marker of poor prognosis in stroke ventilation (ASV) in patients with sleep
and renal failure, we also recommend disordered breathing associated with
positive pressure treatment in these chronic opioid medications for non-
patients. Patients with primary CSA should malignant pain. J Clin Sleep Med; 4: 311–319.
be treated if they suffer from clinical N Javaheri S, et al. (2008). Adaptive pres-
symptoms, cognitive impairment or daytime sure support servoventilation: a novel
sleepiness. Finally, in patients with central treatment for sleep apnea associated
apnoea associated with hypoventilation, NIV with use of opioids. J Clin Sleep Med; 15:
is the treatment of choice if no causal 305–310.
therapeutic options are available. N Javaheri S. (2006). Acetazolamide
improves central sleep apnea in heart
failure a double-blind, prospective study.
Further reading Am J Respir Crit Care Med; 173: 234–237.
N Andreas S, et al. (2004). Differential N Kasai T, et al. (2010). Effect of flow-
effects of theophylline on sympathetic triggered adaptive servo-ventilation com-
excitation, hemodynamics, and breathing pared with continuous positive airway
in congestive heart failure. Circulation; pressure in patients with chronic heart
110: 2157–2162. failure with coexisting obstructive sleep
N Andreas S, et al. (1998). Treatment of apnea and Cheyne-Stokes respiration.
Cheyne–Stokes respiration with nasal Circ Heart Fail; 3: 140–148.
oxygen and carbon dioxide. Eur Respir J; N Krachman SL, et al. (1999). Comparison
12: 414–419. of oxygen therapy with nasal continuous
N Arzt M, et al. (2007). Suppression of positive airway pressure on Cheyne–
central sleep apnea by continuous positive Stokes respiration during sleep in conges-
airway pressure and transplant-free sur- tive heart failure. Chest; 116: 1550–1557.
vival in heart failure: a post hoc analysis of N Lorenzi-Filho G, et al. (1999). Effects of
the Canadian Continuous Positive Airway inhaled carbon dioxide and oxygen on
Pressure for Patients with Central Sleep Cheyne–Stokes respiration in patients
Apnea and Heart Failure Trial (CANPAP). with heart failure. Am J Respir Crit Care
Circulation; 115: 3173–3180. Med; 159: 1490–1498.

N Mansfield DR, et al. (2004). Controlled (ASV) in patients with co-existing
trial of continuous positive airway pres- obstructive sleep apnoea (OSAS) and
sure in obstructive sleep apnea and heart Cheyne–Stokes respiration (CSR). A ran-
failure. Am J Respir Crit Care Med; 169: domised CPAP-controlled trial. Eur
361–366. Respir J; 34: 38s.
N Pepperell JC, et al. (2003). A randomized N Staniforth AD, et al. (1998). Effect of
controlled trial of adaptive ventilation oxygen on sleep quality, cognitive func-
for Cheyne–Stokes breathing in heart tion and sympathetic activity in patients
failure. Am J Respir Crit Care Med; 168: with chronic heart failure and Cheyne–
1109–1114. Stokes respiration. Eur Heart J; 19: 922–928.
N Philippe C, et al. (2006). Compliance with N Teschler H, et al. (2001). Adaptive
and effectiveness of adaptive servoventi- pressure support servo-ventilation: a
lation versus continuous positive airway novel treatment for Cheyne–Stokes
pressure in the treatment of Cheyne– respiration in heart failure. Am J Respir
Stokes respiration in heart failure over a Crit Care Med; 164: 614–619.
six month period. Heart; 92: 337–342. N Yumino D, et al. (2008). Central sleep
N Randerath W, et al. (2009). Longterm apnoea and Cheyne–Stokes respiration.
efficacy of adaptive servo-ventilation Proc Am Thorac Soc; 15: 226–236.

Treatment of hypoventilation/
chronic respiratory
insufficiency
Anita K. Simonds
Treatment algorithms cut-off point of daytime PaCO2 .7.3 kPa or

50 mmHg to indicate requirement for
The management plan should include the nocturnal NIV rather than CPAP. A variety of
steps in box 1. approaches have been applied (Masa et al.,
2001; Piper et al., 2008). A randomised
The considerations below relate to particular
controlled trial (RCT) by Piper et al. (2008)
pathophysiological causes of nocturnal
found that treatment choice of CPAP or NIV
hypoventilation, which also influence
could be best ascertained after an initial
treatment choices.
night of CPAP to see whether CPAP alone
Obesity hypoventilation syndrome effectively controlled AHI, SaO2 and PtcCO2
overnight; however, more severe patients
In the long term, weight loss is clearly were excluded. Masa et al. (2001) found that
crucial, coupled with treatment of patients with OHS treated with either
underlying SDB. In patients with pressure- or volume-cycled NIV had
predominant OSA, CPAP is the treatment of improved arterial blood gas tensions and
choice. In those with nocturnal this gain was similar to that found in
hypoventilation, CPAP may be effective in patients with kyphoscoliosis treated with
about 50–80% of patients, but this is NIV. Marked hypercapnia during the day
predominantly in those with mild and acute ventilatory decompensation
hypoventilation. Some algorithms use a favour the use of NIV. In these patients with
ventilatory decompensation, NIV may
increase hypercapnic ventilatory drive and
decrease leptin resistance or increase leptin
Key points levels in those with low baseline levels.
Janssens et al. (1998) found a 5-year survival
N Symptomatic nocturnal rate of 88% in OHS patients using nocturnal
hypoventilation is usually the trigger NIV, and in a further retrospective analysis
for elective initiation of NIV. 2-year survival was 92% and 5-year survival
70%. In contrast, there is a reported 40%
N OHS patients with mild nocturnal
mortality over 50¡25 months in OHS
hypoventilation and/or OSA can be
patients who refused NIV. This outcome
managed with CPAP; those with
may be influenced by other factors such as
severe nocturnal hypoventilation
poor adherence to other therapies. Bi-level
warrant NIV.
NIV titrated appropriately will control
N Overnight monitoring of simple hypoventilation, and expiratory positive
measures of oximetry and airway pressure (EPAP) should be titrated to
transcutaneous CO2 tension plus deal with upper airway collapse and
ventilator download data can be obstructive apnoeas/hyponoeas. EPAP may
used to assess the adequacy of also recruit basal alveoli and improve
ventilatory support. functional residual capacity. Up to 50% of
OHS patients may require supplemental

Box 1 Steps in the management plan Bariatric surgery is appropriate in morbidly
obese patients, and guidelines exist for
N Identification of high-risk cases eligibility for weight-reducing surgery in
some countries. Patients should use CPAP
of nocturnal hypoventilation
or NIV in the peri-operative period and
(see table 1)
careful liaison should be carried out with the
N Regular evaluation with sleep studies surgical and anaesthetic team. There is no
including assessment of PaCO2 evidence that use of positive airway pressure
N Treatment of reversible causes therapy in the post-operative period
e.g. weight reduction for obesity increases the risk of surgical dehiscence.
Weight following bariatric surgery is
N Initiation of ventilatory support in
associated with improvements in the
neuromuscular and chest wall disease complications of obesity such as type II
patients at the development of
diabetes and metabolic syndrome.
symptomatic nocturnal
Corrections of obstructive events overnight
hypoventilation
are seen, associated with improvement in
N Supplemental oxygen therapy if SaO2 diurnal ventilation. Weight loss achieved
, 90% despite optimum control using high-intensity diets can improve OSA,
of PaCO2 but there is less evidence in patients with
N Follow-up to assess adequacy of nocturnal hypoventilation
ventilatory control Neuromuscular/skeletal disorders
Broadly speaking, neuromuscular and chest

oxygen therapy and this should be entrained wall disorders can be categorised as static or
into ventilator circuit to increase SaO2 to slowly progressive (e.g. congenital muscular
.90%. It is often possible to reduce or dystrophies), or markedly progressive (e.g.
discontinue oxygen therapy and continue on motor neurone disease). While many
NIV alone following acute ventilator failure conditions are genetic in aetiology, gene
or as the patient loses weight. A suggested therapy has not yet reached clinical practice
algorithm is given in figure 1. and few diagnoses have specific therapies.
Table 1 Risk of ventilatory decompensation.

Risk Disorder
High Spinal muscular atrophy type I (in infancy)
MND/ALS
Duchenne muscular dystrophy (age .12 years)
High spinal cord lesions (above C5)
Early onset nemaline myopathy (in infancy)
X-linked centronuclear/myotubular myopathy (in infancy)
Merosin deficient congenital muscular dystrophy (in early childhood)
Congenital scoliosis associated with ostegenesis imperfecta, neurofibromatosis
Medium Morbid obesity
Limb girdle muscular dystrophy variants
Early-onset scoliosis (at age ,5 years) with vital capacity ,50% predicted and
proximal curvature
Spinal muscular atrophy type II
Overlap syndrome (COPD plus OSA) with FEV1 ,1.5 L
Low Spinal muscular atrophy type III
Emphysema patients on LTOT (unless end-stage disease)
Interstital lung disease (unless end-stage disease)

The exceptions to this include medical and case series (Ward et al., 2005; Mellies
therapies for congenital and acquired et al., 2003) show that NIV should be
myasthenia and immunosuppressive introduced at the time of nocturnal
therapy for polymyositis. hypoventilation before the development of
daytime hypercapnia. Large cohort studies
NIV is the treatment of choice for nocturnal show that NIV improves survival, improves
hypoventilation and in patients with arterial blood gas tensions during the day,
scoliosis shows preferable results to controls nocturnal hypoventilation and
long-term oxygen therapy (LTOT). An RCT improves quality of life in conditions such
Hypercapnia in an obese subject
pH
<7.35 >7.35
Severity criteria PG/PSG

(enoephalopathy, shock (1)
or NIV contraindication)
Yes No No OSA OSA
Endotracheal NIV NIV PaCO2

intubation (acute setting) ± O2
Endotracheal NIV >50 mmHg >50 mmHg

intubation (acute setting)
NIPPV CPAP trial
± O2
Nocturnal Remained
SaO2 hypercapnic
(or PG/PSG)
Continuous SaO2 dips No Yes

desaturation (or obstructive
events if PG)
Continue Switch to
CPAP NPPV
Persisted Increase
elevated PaCO2 EPAP
Yes No
Increase O2 addition
IPAP (or increase)
FIGURE 1. Management of nocturnal hypoventilation in obese patients. PG: respiratory polygraphy.

Reproduced from Veale (2008), with permission from the publisher.

Counselling, anticipatory plan of ventilatory support
at diagnosis
Respiratory symptoms, SDB,

orthopnoea, FVC <70%, PaCO2 >6 kPa
Trial of NIV/cough
Ventilatory support assist
declined
Disease progression
Palliative care Daytime NIV plus cough

assistance ± PEG
Disease progression
Withdrawal of Ceiling of non-invasive
ventilation support (patient choice)
Tracheostomy - IPPV
Disease progression
FIGURE 2. Suggested respiratory management algorithm for motor neurone disease/ALS. Reproduced
from Simonds (2007), with permission from the publisher.
as Duchenne muscular dystrophy and spinal Tracheostomy ventilation is indicated in

muscular atrophy. It would be difficult patients with severe bulbar disease,
ethically to carry out RCTs in these groups. recurrent aspiration pneumonia, 24-hour
In an RCT of NIV in motor neurone disease/ ventilator dependency (although some
amyotrophic lateral sclerosis (MND/ALS) patients prefer to use 24-hour NIV), if NIV
(Bourke et al., 2006), NIV produced a fails to control nocturnal hypoventilation, or
survival advantage of approximately there are difficult to control secretions or
7 months and improved quality of life. In a upper airway/interface problems.
subgroup with severe bulbar MND/ALS,
mortality did not decrease, but there were
Box 2. Indications for initiating nocturnal NIV in COPD.
gains in quality-of-life measures associated
with SDB. This raises the valid point that
NIV can be used to palliate symptoms of
N In patients with recurrent acute
nocturnal hypoventilation, with the sole aim exacerbations responding to NIV
of symptom control, rather than to extend (.2 per year) and PaCO2 .50 mmHg
life in progressive conditions. This approach but ,54 mmHg
has also been used in infants with nocturnal N In those with symptomatic
hypoventilation secondary to severe type I hypoventilation and diurnal PaCO2
spinal muscular atrophy (Chatwin et al., .55 mmHg
2011). Importantly, each case should be N Or in those with PaCO2 .50 mmHg
individually assessed with the purpose of but ,54 mmHg with nocturnal
setting measurable treatment goals for desaturation ,88% for o5 min while
NIV. A suggested respiratory management receiving oxygen therapy at
plan for MND/ALS patients is shown in o2 L?min-1
figure 2.

SpO2
100
90
85
00:30 01:00 01:30 02:00 02:30 03:00 03:30 04:00
SpO2 SpO2 SpO2

90 89 94 92 91 89
THO
THO
THO
ABD ABD
ABD
PTT
PTT
FLO
FLO FLO
PRE
PRE PRE
(i) Decrease of ventilatory (ii) Residual obstructive (iii) Leaks
command events
100 SpO2
90
80
70
60
02:30 03:00 03:30 04:00 04:30 05:00 05:30 06:00
REM sleep Awake
SpO2 07 11 07 84 94 96 91
SpO2
THO
THO
ABD ABD
FLO FLO
PRE PRE
(i) Leaks (ii) Insufficient pressure support
Figure 3. Evaluating adequacy of ventilatory support and problem-solving. Oximetry traces from a patient
on overnight NIV. (a) shows recurrent episodic dips in SpO2. (b) shows persistent periods of desaturation.
The further data below each example show thoracoabdominal activity, flow and ventilator pressure
demonstrating, how the underlying cause of the events can be determined, e.g. leaks, inadequate pressure,
upper airway obstruction or desynchrony with ventilator. Reproduced from Janssens et al. (2011), with
permission from the publisher.

Ventilatory support in CCHS is considered Assessing adequacy of control of nocturnal
in Module 8, ‘‘Management of SDB hypoventilation and follow-up
in children’’.
Bi-level positive pressure ventilation is the
Nocturnal hypoventilation in obstructive most commonly used form of ventilatory
lung disease support, although volume-preset ventilators
have a long track record in neuromuscular
The majority of COPD patients who fulfil
patients. Set-up of the ventilator using
criteria for LTOT tolerate oxygen therapy at
clinical guidance has been shown to be as
night and do not develop significant
effective as detailed set-up using complex
hyercapnia during sleep.
physiological measures such as
However significant nocturnal oesophageal pressure (Fauroux et al., 2004).
hypoventilation occurs in a proportion of Volume-assured modes such as AVAPS have
people with severe COPD and will inevitably not been shown to produce major long-term
be present in those with daytime advantages over standard bi-level pressure
hypercapnia. While NIV is strongly evidence- support in OHS (Storre et al., 2006; Murphy
based therapy for acute acidotic hyper- et al., 2012), and produced equivalent
exacerbations of COPD, the only guidelines control of nocturnal ventilation in
for use of nocturnal NIV in stable COPD neuromuscular patients (Jaye et al., 2009).
patients were published over a decade ago Monitoring of overnight oximetry and
(Consensus Conference, 1999) and based transcutaneous CO2 tension can be used to
on consensus conference assess control of hypoventilation. Janssens
recommendations. There have been several et al. (2011) have demonstrated how the
RCTs of NIV versus LTOT plus NIV in stable combination of this information with data
hypercapnic COPD patients with nocturnal downloaded from the ventilator can be used
hypoventilation. The most recent showed to solve common ventilator-related
increased survival with NIV, but health- problems (figure 3).
related quality-of-life measures were not
enhanced (McEvoy et al., 2009). Further trials
are due to report soon. Pragmatically, some
teams now use the indications shown in Further reading
box 2 for initiation of nocturnal NIV in COPD.
N Bourke SC, et al. (2006). Effects of non-
In cystic fibrosis and bronchiectasis, airway invasive ventilation on survival and qual-
and parenchymal lung disease cause ity of life in patients with amyotrophic
predominant ventilation/perfusion gas- lateral sclerosis: a randomised controlled
exchange problems and alveolar trial. Lancet Neurol; 5: 140–147.
hypoventilation causing nocturnal SDB are N Chatwin M, et al. (2011). Outcome of
fairly late-stage phenomena. As indicated in goal-directed non-invasive ventilation and
module 8, worsening hypoventilation can be mechanical insufflation/exsufflation in
seen in REM sleep due to reduction in spinal muscular atrophy type I. Arch Dis
Child; 96: 426–432.
intercostal and postural muscle tone,
N Consensus Conference. (1999). Clinical
increased work of breathing and decreased
indications for noninvasive positive pres-
ventilatory reponses to hypercapnia and
sure ventilation in chronic respiratory
hypoxia. In patients with marked failure due to restrictive lung disease,
hypercapnia, NIV may reduce symptoms, COPD, and nocturnal hypoventilation – a
reduce failure to thrive and result in fewer consensus conference report. Chest; 116:
infective exacerbations. In two RCTs, 521–534.
improved gas-exchange was seen, with no N Fauroux B, et al. (2004). Setting of
effect on lung function. NIV has been noninvasive pressure support in young
successfully used to bridge end-stage cystic patients with cystic fibrosis. Eur Respir J;
fibrosis patients with chronic ventilatory 24: 624–630.
failure to transplantation.

N Janssens JP, et al. (2008). NIV and ventilation in patients with super-obesity
chronic respiratory failure secondary to and chronic respiratory failure: a rando-
obesity. Eur Respir Monogr; 41: 251–264. mised controlled trial. Thorax; [Epub
N Janssens JP, et al. (2011). Nocturnal ahead of print DOI: 10.1136/thoraxjnl-
monitoring of home non-invasive ventila- 2011-201081].
tion: the contribution of simple tools N Piper AJ, et al. (2008). Randomised trial
such as pulse oximetry, capnography, of CPAP vs bilevel support in the treat-
built-in ventilator software and auto- ment of obesity hypoventilation syndrome
nomic markers of sleep fragmentation. without severe nocturnal destauration.
Thorax; 66: 438–455. Thorax; 63: 395–401.
N Jaye J, et al. (2009). Autotitrating versus N Simonds AK. (2007). Home ventilation in
standard noninvasive ventilation: a ran- progressive disorders, quadriplegia and
domised crossover trial. Eur Respir J; 33: palliative non-invasive ventilation. In:
566–573. Simonds AK, ed. Non-invasive Respiratory
N Masa JF, et al. (2001). The obesity Support: a practical handbook. London,
hypoventilation syndrome can be treated Hodder Arnold; pp. 193–207.
with noninvasive mechanical ventilation. N Storre JH, et al. (2006). Average volume-
Chest; 119: 1102–1107. assured pressure support ventilation in
N McEvoy RD, et al. (2009). Nocturnal non- obesity hypoventilation. A randomised
invasive ventilation in stable COPD: a crossover trial. Chest; 130: 815–821.
randomised controlled trial. Thorax; 64: N Veale D. (2008). Respiratory complica-
561–566. tions of obesity. Breathe; 4: 210–223.
N Mellies U, et al. (2003). Long-term N Ward SA, et al. (2005). Randomised
noninvasive ventilation in children and controlled trial of non-invasive ventilation
adolescents with neuromuscular disor- (NIV) for nocturnal hypoventilation in
ders. Eur Respir J; 22: 631–636. neuromuscular and chest wall disease
N Murphy PB, et al. (2012). Volume targeted patients with daytime normocapnia.
versus pressure support non-invasive Thorax; 60: 1019–1024.

Treatment of nonrespiratory
sleep disorders
Dirk Pevernagie
Because of their diverse nature, there is no International Classification of Sleep

generic approach to the treatment of Disorders 2nd Edition (ICSD-2) lists .70
nonrespiratory sleep disorders. Various nonrespiratory nosological items in various
medical and nonmedical conditions are sections, including insomnia, hypersomnia
implicated in disturbed sleep. The of central origin, circadian rhythm sleep
disorders, parasomnias, sleep-related
movement disorders and other categories of
impaired sleep. Treatment of this
Key points heterogeneous group of sleep disorders is
based on nonpharmacological approaches
N Due to the heterogeneous nature of as well as the prescription of agents
the various sleep disorders, no belonging to particular drug classes. Since
generic approach to treatment can be therapy must be tailored to the individual
proposed. In each of the major patient’s needs, choices between different
nosological categories,
pharmacological and nonpharmacological
pharmacological and
treatment options, or combinations of
nonpharmacological treatment
these, are to be made. Pharmacological
modalities are available.
therapy requires adjustment of the choice,
N The mainstay of treatment of dose and regimen of drugs in keeping with
insomnia is nonpharmacological. A the treatment response. Finally, patients may
stepwise treatment plan is proposed. suffer from a combination of sleep disorders.
Treatment with hypnotic drugs is Concurrent sleep disorders call for an
appropriate as a primary step in integrated therapeutic approach based on
situational insomnia. In chronic combining different treatment modalities.
insomnia, hypnotics may be added as
adjuvant treatment to cognitive Proficient management of sleep disorders is
behavioural therapy. based on detailed knowledge of sleep and its
disturbances. The scope of this chapter is
N The mainstay of treatment of not to elaborate on the intricacies of the
hypersomnia of central origin is based
entire spectrum of pathological sleep, as
on prescription of stimulant drugs.
this would require a thorough review of all
Other medications are available for
the nosological items listed in the ICSD-2.
cataplexy, one of the core symptoms
The aim is, rather, to provide a general
of narcolepsy.
overview of treatment principles in
N RLS and PLMD are responsive to nonrespiratory sleep medicine. The
treatment with medications belonging respiratory physician should have a broad
to various pharmacological classes. knowledge of the available treatment
Currently, DA agents are the first-line options and strategies, but is not compelled
of treatment. Opioids may be used in to take the lead in the management of
severe cases of RLS. nonrespiratory sleep problems.
Nevertheless, the respiratory physician must

be able to handle comorbid issues (e.g. sleep appropriate. The treatment goals are to
apnoea complicated by insomnia). Treatment improve duration and quality of sleep,
of sleep patients requires a multidisciplinary and to improve daytime dysfunction due
setting. In sleep medicine, diagnostic and to insomnia.
therapeutic management is founded on
cooperation between professionals with a Nonpharmacological treatment
different specialty background. As respiratory Nonpharmacological treatment of insomnia
disturbances are among the most prevalent comprises a stepped care approach. The
sleep disorders, there is a prominent role for incremental steps include general
the respiratory physician in this recommendations, specific (tailored)
multidisciplinary process. This role, however, recommendations, and structured
implies appropriate knowledge of the relevant psychological and behavioural interventions
respiratory and nonrespiratory aspects of (e.g. cognitive behavioural therapy (CBT)).
sleep and its disorders. Furthermore, the level of support may be
scaled up progressively, starting with self-
Rather than split this chapter into sections support, then group therapy at the nursing
on pharmacological and level and individual treatment administered
nonpharmacological therapy, both by specifically trained professionals
treatment aspects will be discussed under (medical psychologists).
four main themes, namely insomnia,
At all times, irrespective of whether
hypersomnia of central origin, sleep-related
insomnia is primary, secondary or
movement disorders and miscellaneous
comorbid, the patient should be provided
conditions. The content and relative role of
with proper general information. Explaining
either treatment option will be discussed in
the nature of insomnia and the principles of
each of these categories. Where appropriate,
its management is a starting point.
the special interest for the respiratory
Recommendations on good sleep hygiene
physician will be indicated.
are a default step in the treatment plan
Insomnia (table 1). Adherence to these instructions
often results in better coping with the
In line with the many components that play problem, and in some patients, no additional
a role in the causation and maintenance of therapeutic measures are required.
insomnia, several treatment methods have
emerged. The various factors that play a role For unremitting chronic insomnia,
in the pathogenesis of insomnia are psychological and behavioural approaches
reviewed in chapter 3. The usefulness of are the treatment of choice. Some of the basic
different therapeutic modalities depends on methods are briefly explained here; for more
the contributing factors and the time course detailed information, see Further Reading.
of the illness. Whether insomnia is acute or Stimulus control is a structural behavioural
chronic and whether insomnia is associated approach aimed at turning the negative
with medical or psychiatric comorbidities feelings associated with going to bed into a
will influence the management strategy. The positive anticipation. Patients are taught to
treatment may be general in scope or break with habits that are adverse to sleep.
targeted to specific adverse factors, such as The sleeping environment is re-established
socioprofessional stressors, environmental as a stimulus for good sleep.
triggers, maladaptive behaviour or
underlying disease. Prescription of Sleep restriction is based on curtailing time
hypnotics is common and accepted practice in bed. Opportunities for sleep such as
for acute insomnia. For chronic insomnia, napping are limited. This intervention first
the emphasis is on a nonpharmacological induces additional sleep deprivation. The
approach. The use of hypnotic drugs is drive to sleep will thus increase and,
adjuvant in this setting. Diagnosis and eventually, sleep will be more consolidated.
treatment of underlying causes is pertinent When sleep continuity improves, time in bed
and should be considered whenever is progressively extended. Ultimately, there

Table 1. Principles of sleep hygiene: recommendations for the insomnia patient.
N Limit time in bed for sleeping; lying awake in bed weakens sleep
N Get out of bed when you are not feeling sleepy
N Improve environmental conditions of the bedroom (noise, light and temperature)
N Take a light snack before going to bed but avoid consuming large beverages
N Avoid too much alcohol and stimulants (e.g. nicotine and caffeine)
N Schedule stressful activities so that they occur a long time before bedtime; unwind and
relax in the hours prior to going to sleep
N Do not check your alarm clock at night
N Restrict the use of sleeping pills
should be sufficient sleep time for the situational insomnia. For this indication,
patient to feel rested during the day. hypnotics are prescribed to be taken nightly
for a couple of weeks. Some caveats must be
As insomnia is associated with increased borne in mind when hypnotics are
somatised tension, relaxation training is considered for treatment of chronic
indicated in some patients. Several insomnia. While successful in the short
techniques have been described, including term, the effect of hypnotic drugs may wear
alternating tensing and relaxing of muscle off over time. As habituation takes effect,
groups, concentrating on abdominal incremental doses may be necessary to keep
breathing, and guided imagery. up the initial pharmacotherapeutic results.
Therefore, hypnotics carry an intrinsic risk of
CBT for insomnia (CBT-I) is the collective
tolerance, and physical and psychological
name for a combination of the
dependence. The latter problem may occur
aforementioned techniques with a
especially in patients with a history of drug
psychotherapeutic method to restore
or alcohol abuse. Increased sleeplessness is
appropriate cognitive pathways. The aim is
a frequent complaint following abrupt
to identify disbeliefs about sleep and to turn
discontinuation of hypnotic treatment. This
these cognitions into positive and realistic
condition, known as rebound insomnia, may
concepts. There is ample scientific evidence
be accompanied by other symptoms of
that CBT-I is beneficial, and that the positive
withdrawal, e.g. anxiety and agitation. These
effects on sleep quality are durable.
drawbacks are the prime reasons why
Pharmacological treatment In contrast to hypnotics may not be suitable for long-term
nonpharmacological treatment, there are no use. One way to circumvent the problem of
established guidelines on pharmacotherapy tolerance is to prescribe hypnotics for
for chronic insomnia. While effectiveness of intermittent use, and to restrict intake to
hypnotic medications has been confirmed in three times per week, at maximum.
randomised controlled trials (RCTs), none of
these studies has been designed to assess Many hypnotics, especially those with long
the superiority of one medication over elimination half-lives, may have a carry-over
another in terms of efficacy and safety. effect and cause unwanted sedation in the
Neither is there any systematic study morning. Long-acting hypnotics should not
comparing hypnotics with be prescribed in patients who drive motor
nonpharmacological interventions. vehicles. Short-acting drugs avoid this
complication but may be inefficacious at
Hypnotic drugs are the first-line treatment in controlling sleep maintenance insomnia.
the acute setting, i.e. in patients with There are several accounts of inappropriate

behaviour in individuals who were awakened (N3) and REM sleep may be variable and
at night after taking sleeping pills. In the depend on the class of drugs selected.
elderly, confusional arousals and falls are
serious side-effects. Inability to rapidly When choosing a specific drug among the
regain consciousness upon awakening is an different available medications, the
intrinsic disadvantage of hypnotic prescriber should take into account the key
treatment. Moreover, hypnotics may cause characteristics of that particular agent,
anterograde amnesia, rendering some including drug class, mode of action, and
pharmacokinetic and pharmacodynamic
individuals unable to recall their nocturnal
properties. In this chapter, hypnotics are
behaviour. There are concerns over impaired
classified into two general categories: BZD
cognition and a tendency towards
receptor ligands and non-BZD sedative drugs.
developing depression with chronic use.
BZDs are a group of compounds that share
Some hypnosedative drugs inhibit
a common structure of a benzene ring fused
respiratory neurons in the brainstem and
with a diazepine ring. These drugs bind to a
thereby suppress the drive to breathe. This
specific locus of the c-aminobutyric acid
is especially relevant in OSA patients, in (GABAA) receptor complex, called the BZD
whom hypnotics increase the incidence and receptor. Activation of the BZD receptors
duration of disturbed breathing events. increases the effect of GABA-ergic
Unless these patients are adequately treated neurotransmission. BZDs have anxiolytic,
with CPAP, the use of hypnotics (particularly hypnosedative, anticonvulsant, amnesic and
benzodiazepines (BZDs)) is muscle-relaxant properties. They may be
contraindicated. Finally, hypnotics should prescribed for various medical and
not be used in pregnancy, during lactation psychiatric indications. While a sedating
or by patients with hepatic failure. effect is a prominent and common feature,
not all BZDs are labelled for the specific
As a rule of thumb, in insomnia, the lowest
treatment of insomnia. Based on their
effective dose of a single hypnotic drug
pharmacokinetic profiles, BZDs are divided
should be prescribed for the shortest
into three categories pertaining to duration
amount of time. Indeed, the primary
of action: long-, intermediate- and short-
intention of prescribing hypnotic medication acting (table 2). BZDs decrease SL and #A,
is to achieve symptomatic control. In increase TST, SEF and N2, and tend to
contrast with nonpharmacological treatment decrease N3 and REM. In general, BZDs are
modalities, drug treatment fails to address safe and efficacious in the treatment of
the causative mechanisms of insomnia, situational insomnia. When prescribed
including precipitating factors, dysfunctional cautiously and restrictively, BZDs also have
beliefs and maladaptive behaviour patterns a place in the treatment of chronic insomnia
that tend to sustain the insomnia process. (e.g. on an intermittent prescription basis).
Therefore, hypnotic drug prescription is to
be considered an adjuvant treatment to BZD receptor ligands that lack a BZD
other therapeutic interventions. In all chemical structure have been introduced in
instances where hypnotics are prescribed for the last two decades. These agents are
long-term use, the option to taper and called non-BZD BZD receptor agonists
discontinue the sleep medication should be (NBBRAs) or ‘Z drugs’, because their
reassessed on a regular basis. generic names begin with a ‘Z’ (zolpidem,
zopiclone and zaleplon; table 2). They are,
Hypnotic agents have several effects on to date, the most extensively studied
sleep structure. Most often, there is a hypnotics. They have a similar effect on
decrease of sleep latency (SL) and number sleep architecture as the classical BZDs. The
of nocturnal awakenings (#A) versus an combination of efficacy with reasonable
increase in total sleep time (TST) and sleep safety promotes this class of drugs as a
efficiency (SEF). Often, stage 2 NREM sleep plausible first-line pharmacotherapy for
(N2) is increased. Effects on deep sleep insomnia. However, despite acceptable

180
Table 2. Hypnotics.
Compound Class Mode of action Hypnotic tmax min t1/2 h Duration of Metabolism Side-effects
dose mg action
Amitriptyline TCA Inhibition of NA and 25–100 .120 10–28 Long Hepatic; active Cardiac arrhythmias;
5HT reuptake; a1, M1 and metabolite(s) anticholinergic and
H1 receptor antagonism antihistaminic effects;
aggravation of RLS
Flurazepam BZD GABA-ergic 15–30 47–100 Long Hepatic; active Generic side-effects of BZD
metabolite(s)
Gabapentin Structural analogue of Probably GABA-ergic 300–600 180 5–9 Intermediate Renal clearance Residual effects in the
GABA morning; dizziness; ataxia;
headache; rarely leukopenia
Lormetazepam BZD GABA-ergic 1–2 120 12 Intermediate Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Midazolam BZD GABA-ergic 7.5–15 30–90 2–3 Short Hepatic; active Generic side-effects of BZD
metabolite(s)
Mirtazapine Noradrenergic and a1, a2, 5HT1, 5HT2 and 15–30 60–190 13–40 Long Hepatic; active Residual effects in the
specific serotoninergic H1 receptor antagonism metabolite(s) morning; weight gain;
antidepressant aggravation of RLS
Nitrazepam BZD GABA-ergic 5–10 120 30–40 Long Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Ramelteon Melatonin I and II Unknown 8 45 1–3 Short Hepatic; active Nonspecific
receptor agonist metabolite(s)
Quetiapine Dibenzothiazepine a1, M1, H1, 5HT2 and D2 25–50 60–120 7 Intermediate Hepatic; inactive Sedation; aggravation of RLS
antipsychotic receptor antagonism metabolite(s)
Temazepam BZD GABA-ergic 10–30 50 7–11 Intermediate Hepatic; inactive Generic side-effects of BZD
metabolite(s)
Trazodone HCA 5HT2 and a1 receptor 50–100 60–120 5–9 Long Hepatic; active Residual effects in the
antagonism metabolite(s) morning; cardiac arrhythmias;
orthostatic hypotension; rarely
priapism (not dose related)
Triazolam BZD GABA-ergic 0.125–0.250 120 2–6 Short Hepatic; inactive Generic side-effects of BZD
metabolite(s)
ERS Handbook: Respiratory Sleep Medicine

overall safety, anterograde amnesia,
Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life; TCA:
Generic side-effects of BZD

confusional nocturnal behaviour and
dependency have been reported with some
NBBRAs in some susceptible patients. The
NBBRAs are less likely than the usual BZDs
to cause rebound phenomena after
Side-effects
discontinuation. These advantages are

counterbalanced by the higher cost of
treatment in comparison with the older BZDs.
Several psychotropic drugs outside the class

Hepatic; inactive
Hepatic; inactive
Hepatic; inactive
of BZD receptor agonists have potent

metabolite(s)
metabolite(s)
metabolite(s)
sedating side-effects. Among these agents

Metabolism
tricyclic antidepressant; HCA: heterocyclic antidepressant; NA: noradrenaline; 5HT: 5-hydroxytrypamine (serotonin); M: muscarinic; H: histamine.
are antidepressants, neuroleptics,

antiepileptics, melatonin receptor agonists,
antihistaminics and nonprescription
substances. Depending on the clinical
Intermediate
Duration of
context, the sedative action may be adverse

or beneficial. Sedation is an undesirable
Short
Short
action
side-effect when treatment is aimed at

mobilising and stimulating the patient.
When given in nightly dose, sedation may
t1/2 h
2–3
5–7
improve sleep and may be helpful to

1
manage comorbid insomnia. Therefore, a

single psychotropic agent may serve a dual
tmax min
30–180
45–120
purpose of treating the underlying disorder

120
and controlling insomnia as a symptom at

the same time. However, the dosage needed
to improve sleep is generally much lower
than the dosage required to observe any
Hypnotic
dose mg
treatment effect on the disorder for which

5–10
7.5
10
the medication is registered. In depression,

for instance, a low-dose sedative
antidepressant at bedtime is not sufficient
to improve depressive symptoms. To
Mode of action
achieve this goal, the low-dose hypnotic

GABA-ergic
GABA-ergic
GABA-ergic
antidepressant should be combined with

therapeutic dosages of other antidepressants
administered during the daytime. It is
increasingly common practice, however, to
prescribe some of these agents for the
symptomatic treatment of chronic insomnia
irrespective of its cause. While there is
insufficient medical evidence to support the
NBBRA
NBBRA
NBBRA
off-label use of non-BZD psychotropic agents,

Class
empirical results provide no motive to

discourage this practice. Moreover, these
Table 2. Continued
agents are not prone to tolerance to the same

extent as classical BZDs. Some of the
Compound
Zopiclone
Zolpidem
Zaleplon
commonly used medications are described

below. Their pharmacological profiles are
shown in table 2.

Trazodone is a heterocyclic antidepressant, recommended and they are not further
with weak antidepressive but strong reviewed in this chapter.
sedative effects. This agent increases TST,
SEF and N3, and has variable effects on Special interest for the respiratory physician
REM sleep. Trazodone has little potential for Comorbid insomnia in OSA is a prevalent
tolerance or dependence. clinical problem that presents a particular
therapeutic challenge to the patient and
Amitriptyline is a classical tricyclic physician. The prescription of sleep-
antidepressant with sleep-enhancing promoting drugs may worsen SDB and the
properties. This agent increases TST, SEF application of nasal CPAP may worsen
and REM latency, and has variable effects on insomnia. The resolution of this enigma
N3. Cardiac, antihistaminic and requires a multidisciplinary approach.
anticholinergic side-effects limit the use of Depending on the relative severity of either
amitriptyline and other tricyclic of the components, treatment for insomnia
antidepressants. In low doses, however, and OSA may be initiated simultaneously or
these side-effects are minimal, whereas sequentially. In this category of patients,
sleep-promoting effects are still present. there is a prominent role for
nonpharmacological treatment of insomnia
Mirtazapine is a noradrenergic and specific and for intensive nursing support to
serotoninergic antidepressant. Effects on optimise adherence to CPAP treatment.
sleep are similar as those observed with Prescribing hypnotics without CPAP
trazodone. Due to a substantial treatment is considered unsafe.
antihistaminic action, weight gain is a
common side-effect. Hypersomnia of central origin
Ramelteon is a potent melatonin agonist. Sleepiness is a natural phenomenon. It may

The hypnotic action is limited to decreasing be a normal physiological manifestation (e.g.
SL and probably results from an effect on occurring at bedtime), or it may be induced in
the suprachiasmatic nucleus. This agent is certain conditions (e.g. sleep deprivation) or
not commercialised in Europe. in the context of certain diseases (e.g. sleep
apnoea and narcolepsy). Excessive daytime
In the class of neuroleptics (antipsychotics), sleepiness (EDS), also known as
among other agents, quetiapine is a drug hypersomnia, is a term reserved for a clinical
that can be used for treating insomnia condition in which a subject experiences
outside the context of psychotic and bipolar recurrent, abnormal lapses of alertness and
disorders. It is known to increase TST, SEF, has a strong tendency to fall asleep
N2 and N3, whereas SL and #A are decreased. involuntarily. This condition entails secondary
problems due to impaired performance in
Gabapentin belongs to a class of private, professional and social areas of life.
anticonvulsant medications. This agent also Lost productivity, increased risk of causing
has hypnotic and analgesic properties. personal injury and public damage, and
Effects on sleep include an increase in N3 significantly decreased quality of life are
and a reduction of #A. In addition, beneficial sequelae that are regularly observed in
effects have been observed on restless legs patients suffering from EDS. Hypersomnia is
syndrome, periodic limb movements a common symptom in several sleep
(PLMs) and parasomnias of N2. disorders, including sleep disturbances due
to medical or psychiatric causes, sleep
Other agents are available to treat insomnia. apnoea syndromes and hypersomnias of
This group of miscellaneous central origin. In this chapter, the discussion
nonprescription drugs includes melatonin, of treatment of excessive sleepiness will be
valerian, antihistaminics and chloral limited to the latter group of disorders.
hydrate. Prescription of melatonin is
discussed later. Use of valerian, Hypersomnias of central origin are listed in
antihistaminics and chloral hydrate is not the third section of the ICSD-2 and are

reviewed in chapter 3 of this handbook. It is hypersomnia of central origin, especially in
a collective name for disorders in which EDS young people. It may prove difficult to
is a primary complaint that is not estimate the extent of sleep deprivation in
attributable to disturbed nocturnal sleep or these patients. Nevertheless, sleep
a circadian rhythm misalignment. Other extension (i.e. prolonging the nocturnal
sleep disorders may co-exist, but must be sleep period) should be recommended
treated appropriately prior to establishing a whenever this diagnosis is suspected. With
diagnosis in this category. a successful outcome, the need for treatment
with stimulating drugs may be obviated.
Narcolepsy is one of the main entities in the
category of the central nervous system While nonpharmacological treatment for
(CNS) hypersomnias. This disease is known narcolepsy and other CNS hypersomnias is
to result from the loss of hypocretin- part of an integrative therapeutic approach,
producing neurons in the hypothalamus. evidence of its effectiveness is limited.
Most often, narcolepsy is associated with Patients are advised to adhere to regular
paroxysmal episodes of muscle atonia, bedtimes, to take care to get sufficient night-
called cataplexy. Cataplexy is typically time sleep and to schedule ‘strategic’ naps
elicited by sudden emotion. Some variants during the daytime, at least when short
of narcolepsy lack this symptom. Cataplexy bouts of sleep have a restorative effect. In
is a disabling manifestation that requires IHS, for instance, naps are often not
special therapeutic attention. refreshing and may even cause additional
drowsiness. These patients should abstain
In contrast with narcolepsy, the
from napping during the daytime. Neither is
pathogenesis of other disorders in this
there strong evidence to recommend
group is still unknown. Recurrent
behavioural treatment for cataplexy. Patients
hypersomnias and idiopathic hypersomnia
should avoid circumstances that elicit
(IHS) are believed to be caused by a
strong emotions, as cataplexy is precipitated
temporary or permanent dysfunction of the
by these conditions. Avoiding situational
sleep/wake regulating mechanisms in the
emotions will certainly reduce the number of
CNS. Behaviourally induced insufficient
attacks, but the downside of this ‘remedy’ is
sleep syndrome and hypersomnias due to
that patients tend to withdraw from social
medical causes constitute a miscellaneous
life. This is obviously an undesirable
group of conditions that are primarily
outcome. Therefore, lifestyle issues seem to
related to the effect of external factors on
have minimal impact and pharmacological
nocturnal sleep and, as a consequence, on
daytime alertness. treatment is mandatory in most of the patients.
Pharmacological treatment Stimulating
The principles of treating hypersomnia of
agents are key to the treatment of EDS
central origin encompass improvement of
associated with narcolepsy and IHS.
daytime alertness and the control of
Amphetamines and methylphenidate
associated features such as cataplexy.
increase the release and block the reuptake
Stimulants are the cornerstone in the
of monoamines and, thus, produce central
treatment of EDS. Nonstimulating drugs are
and peripheral sympathomimetic effects. At
used for the treatment of cataplexy. This
the cognitive level, they increase alertness
symptom may fully remit with proper
and psychomotor activity. Modafinil is an
treatment. In contrast, it proves very
atypical nootropic and stimulant agent that
difficult, if not impossible, to restore a
is chemically different from the
normal level of alertness in hypersomnia
amphetamines and has a weaker wake-
patients with the administration of the
currently available stimulating agents. promoting effect. This substance has an as
yet undisclosed mode of action. While RCTs
Nonpharmacological treatment Behaviourally are lacking regarding the use of
induced insufficient sleep is the most methylphenidate and amphetamines in
pertinent differential diagnosis in narcolepsy and IHS, available evidence

suggests that these agents are capable of
enhancing alertness to at least two-thirds of
Headache most frequently;
Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life.
drowsiness, confusional
normal levels, whereas with modafinil, this
Generic side-effects of
Generic side-effects of
rarely toxic epidermal
arousal, constipation
effect is less pronounced. Side effects are
Nausea, headache,
psychostimulants
psychostimulants
highly variable among patients and are dose-
dependent. Methylphenidate and
Side-effects
necrolysis
amphetamines are associated with classical
monoaminergic side-effects, including
insomnia, loss of appetite, tremor,
irritability, headache, palpitations and
inactive metabolite(s)
Hepatic and minimal
Hepatic and variable
elevated blood pressure. Within the
Hepatic; inactive
recommended dose range, the risk of
renal clearance;
renal clearance
metabolite(s)
tolerance and dependence is low in
Metabolism
narcolepsy and IHS, and there is no need to
Hepatic
schedule ‘drug-free holidays’. In higher than
recommended dose ranges, patients should
be monitored carefully with respect to
Intermediate
developing mental problems and
Duration of
hypertension. Modafinil has been studied action
Short
Short
Long
more extensively than the other stimulants.
It has a good benefit-to-risk ratio with fewer
and milder side-effects. Because of its safety
10–12
0.5–1
t1/2 h
7–14
2–4
and long-acting profile, modafinil has been
recommended by the American Academy of
tmax h
Sleep Medicine as first-line treatment for
0.5–2
2–3
narcolepsy. Therapeutic efficacy is usually
2
3
preserved in the long term. The higher cost

of treatment, however, is an obvious
doses per
Posology
disadvantage. The aforementioned agents

3–4
2–3
day
1–2
are listed in table 3.

2
The only drug that is labelled for the

Dose mg
100–400
4.5–9.0
treatment of cataplexy is sodium oxybate

20–60
10–60
(pharmaceutical name for c-

hydroxybutyrate; GHB). It is administered in
Increases the release and
Increases the release and
two doses: at bedtime and once again after

inhibits the reuptake of
inhibits the reuptake of
3–4 h of sleep. With chronic administration,

NA and dopamine
NA and dopamine
sodium oxybate improves sleep continuity

Mode of action
and reduces cataplectic attacks as well as

Unknown
Unknown
EDS. Because sodium oxybate has powerful

CNS depressant effects, it should not be
used in combination with alcohol or
sedative drugs, and is contraindicated in
Indication
SDB and respiratory failure. Elimination of

Cataplexy
and EDS
this agent involves conversion to succinic

EDS
EDS
EDS
semialdehyde that is subsequently

transformed to succinate. Following
Dextroamphetamine
Table 3. Stimulants.
metabolisation of succinate in the Krebs

Methylphenidate
Sodium oxybate
cycle, the end product is carbon dioxide. The

mode of action is unknown. GHB belongs to
Compound
Modafinil
the class of hypnotics. It can be abused,

however, as a recreational drug. GHB as an
illicit compound is known for significant

associated morbidity and mortality. While pathophysiological background. RLS is a
sodium oxybate should be prescribed neurological disorder with sensory and motor
cautiously and its use should be monitored, manifestations. The diagnosis is based on a
the abuse potential in narcolepsy seems to tetrad of symptoms: there is an irresistible
be low. urge to move the legs due to an unpleasant
‘creepy’ sensation, this urge increases upon
Tricyclic antidepressants and selective resting, movement temporarily relieves the
serotonin reuptake inhibitors are effective unpleasant sensation and these symptoms
(but prescribed off label) in the treatment of are worse in the evening and in the initial part
cataplexy and other manifestations of of the night. RLS is relevant for sleep, as it
narcolepsy, including sleep paralysis and may be associated with difficulties initiating
hypnagogic hallucinations. Inhibition of sleep (DIS) or difficulties maintaining sleep
noradrenaline (NA) reuptake presumably (DMS). PLMD is associated with recurrent
mediates the effect of antidepressants on stereotyped leg movements that may induce
cataplexy. At present, there is no evidence to arousals and, thus, disrupt sleep. Treatment
accept that particular antidepressants are of PLMD is largely empirical, as well-
more powerful than others in controlling designed RCTs are lacking. At present, it is
cataplexy, despite different properties not clear whether PLMD outside the context
regarding NA reuptake inhibition. A review of RLS is clinically relevant, and whether there
of antidepressants prescribed for cataplexy is an indication to treat. Neither are there any
is outside the scope of this chapter. guidelines with respect to choosing the
A disturbance of maintaining sleep is a primary outcomes that should guide the
frequent complaint in narcoleptic patients. treatment strategy. In contrast, the treatment
Sleep disruption in narcolepsy may require of RLS is well documented, as many RCTs are
treatment with hypnotic drugs. When now available. Guidelines for the treatment
cataplexy is also present, sodium oxybate is and follow-up of RLS have been published.
the treatment of choice. Therefore, the therapeutic options that follow
deal mainly with the management of RLS.
Special interest for the respiratory physician
Residual hypersomnia is a problem that is Nonpharmacological treatment RLS patients
encountered in 5–10% of well-treated OSA should avoid smoking and consuming food
patients. Hypersomnias of central origin, as and beverages that contain CNS-stimulating
described above, should be considered in substances, such as alcohol, caffeine and
the differential diagnosis. If this condition chocolate. Some patients may benefit from
remains unexplained after appropriate aerobic exercise, manipulating the legs, or
clinical investigation, symptomatic applying warm or cold water to the legs. In
treatment with stimulants should be addition, good sleep hygiene should be
considered. In the USA and some European maintained to avoid the development of
countries, modafinil is approved for treating insomnia as a comorbid factor. These
OSA patients with persistent EDS despite measures are often insufficient and cannot
adequate CPAP treatment. However, careful replace pharmacological treatment in
monitoring is required and modafinil use is moderate-to-severe RLS.
not recommended in individuals with
Pharmacological treatment Several classes of
uncontrolled hypertension, ischaemic heart
drugs are available for the treatment of RLS,
disease or epilepsy.
including mineral supplements, BZD
Sleep-related movement disorders receptor agonists, dopaminergic (DA)
agents, opiate agonists and anticonvulsants.
The most prominent nosological items in the Only DA agonists have been the subject of
ICSD-2 section on sleep-related movement extensive RCTs.
disorders are restless legs syndrome (RLS)
and PLM disorder (PLMD). While these RLS may be a clinical manifestation of iron
entities often co-occur, it is uncertain deficiency. When serum ferritin levels are
whether they share a common ,50 mg?L-1, the patient should be checked

for concealed loss of blood and iron expectation needs confirmation by
supplementation should be commenced. appropriately designed prospective RCTs.
Magnesium sulfate can temporarily relieve
symptoms of RLS, but there are no data on Rarely, RLS patients on DA agents develop
long-term benefits. disturbances of impulse control, and show
an increased desire for gambling and sexual
Clonazepam, a long-acting BZD, is cited in interactions. In up to one-third of the
the older literature as effective for treating patients, the use of DA agonists may be
RLS. There are no convincing studies to limited by augmentation. This dose-
show that clonazepam and other BZDs dependent phenomenon is characterised by
sufficiently control RLS symptoms. BZDs the unpleasant sensation and urge to move
shorten sleep onset and suppress the occurring earlier during the day, being more
arousals resulting from movements rather severe and spreading to the upper limbs. In
than the movements themselves. Symptoms cases of severe augmentation, treatment
of discomfort as well as PLMs usually with DA agonists should be discontinued
persist despite the use of these agents. and agents from another class of drugs
Therefore, BZDs are not considered first-line should be prescribed temporarily.
treatment of RLS.
Opioids have also proven therapeutic
DA agents are the best studied and most efficacy and durability, but are restricted to
successful drugs for treatment of RLS (and the treatment of severe RLS. Patients who
PLMD). Levodopa improves the symptoms are unresponsive to other medications or
of RLS and reduces the number of PLMs. who have developed augmentation are
The use of this medication is limited candidates for opioid therapy. While there is
because of rapid emergence of worsening a low risk of tolerance in RLS patients,
symptoms in the hours prior to opioids should not be prescribed to
administration (augmentation; see later). individuals with a previous history of alcohol
Dopamine agonists are now considered the or substance abuse. These agents carry a
first-line treatment for RLS. The older ergot risk for respiratory depression during sleep
medications (e.g. pergolide) have been in susceptible patients.
abandoned because of rare but serious
Gabapentin improves RLS symptoms at
adverse effects, including the development
doses between 300 and 2,400 mg a day.
of pleuropulmonary fibrosis or cardiac
This medicine is an alternative choice for
valvulopathy.
patients with mild symptoms or for
Nonergot preparations are preferred and replacement of DA agents when
currently three dopamine agonists have a augmentation becomes an issue. Moreover,
label for RLS in this category. Pramipexole is gabapentin may be prescribed as an add-on
a full dopamine agonist with high affinity for when night-time symptoms are severe or
the D3 receptor subtype. This agent is very pain is a prominent complaint.
effective in controlling RLS and PLM. Some frequently used agents from the four
Ropinirole has a similar pharmacodynamic drug classes described here are presented
and clinical profile. Rotigotine is a D3 and D2 in table 4.
dopamine agonist that has been developed
for transdermal administration. It may be Special interest for the respiratory physician
used to treat night-time and daytime When reading PSG recordings, it may prove
symptoms of RLS. Mild skin reactions may difficult to distinguish hypopnoeas from
be seen at the application site of the patch. PLM events. Hypopnoeas are temporary
These compounds are highly effective and reductions in airflow terminated by a few
have mild (mostly transient) side-effects, hyperpnoeic breaths. In PLMD, the limb
including nausea and drowsiness. Recent movements are often accompanied by a
evidence suggests that these dopamine temporary increase in amplitude of tidal
agonists are also safe and efficacious in the breathing. The (normal) breathing between
long term. However, this optimistic PLM events may be mistakenly identified as

hypopnoeas. Careful reading of the
Residual effects in the morning; dizziness;
Generic side-effects of dopamine agonists

polysomnogram is of prime
Dose to be reduced in the elderly and those with hepatic or renal failure; pregnancy and lactation are contraindications. tmax: time to maximum concentration of the drug; t1/2: half-life.
importance for making the correct
ataxia; headache; rarely leukopenia

Generic side-effects of opioids diagnosis of SDB versus PLMD
Generic side-effects of opioids

and, therefore, for choosing
Generic side-effects of BZDs
appropriate treatment.
Miscellaneous sleep disorders
Parasomnias Parasomnias are
Side-effects
subdivided into disorders of NREM

and REM sleep. NREM parasomnias
are primarily disorders of arousal:
patients awaken partially from deep
sleep and demonstrate strange
Hepatic; inactive
Hepatic; inactive
Renal clearance
Renal clearance
Hepatic; active
Hepatic; active
Hepatic; active
behaviours before returning to sleep.

metabolite(s)
metabolite(s)
metabolite(s)
metabolite(s)
metabolite(s)
Metabolism
Conservative measures are the

mainstay of managing these
disorders. Patients should avoid a
stressful lifestyle and should secure
the bedroom environment against
30–40
19–55
t1/2 h
8–12
self-inflicted injury. Drug treatment is

5–9
3–4
5–7
6
empirical. REM sleep parasomnias are

characterised by vivid dream
tmax h
experiences or unusual dream

1.5–3
1–4
1–2
1–3
1–3
1.5
enactment (see section on REM sleep

3
behaviour disorder). Antidepressants

Doses per day
may be indicated for these disorders,

Transdermal
because of their REM sleep-

suppressive properties. There is a
1–2
1–2
special interest for the respiratory

1
physician, because some parasomnia

manifestations may be triggered by
0.125–0.500
disturbed breathing events. In this

0.25–1.00
Dose mg
300–600
case, the underlying respiratory

10–30
0.5–2
5–40
disorder should be treated before

1–3
considering other treatment options.

D2 dopamine agonist (affinity for D3
D2 dopamine agonist (affinity for D3
Delayed sleep phase syndrome Among

the different circadian rhythm sleep
disorders, jet lag disorder, shift work
Table 4. Drugs used to treat RLS and PLMD.
D3, D2 dopamine agonist

Opioid receptor agonist
Opioid receptor agonist
disorder and delayed sleep phase

syndrome (DSPS) are the most
receptor subtype)
receptor subtype)
prevalent clinical entities. DSPS is a

Mode of action
Anticonvulsant
condition in which the patients have

difficulties in falling asleep at normal
bedtimes and waking up in the
BZD
morning: the nocturnal sleep phase is

shifted by o2 h relative to
conventional or socially accepted
Pramipexole
Clonazepam
Gabapentin
times. Because the patients tend to

Methadone
Compound
Rotigotine
Ropinirole
Codeine
oversleep, significant sociofamilial

disharmony may ensue. The
treatment is based on a combination

of nonpharmacological measures and N Billiard M, et al. (2006). EFNS guidelines
prescription of melatonin. An intervention on management of narcolepsy. Eur J
whereby a shifting sleep schedule is Neurol; 13: 1035–1048.
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may either be systematically delayed or of other drugs used as hypnotics. In:
advanced, until sleep is synchronised with Kryger MH, et al., eds. Principles and
the desired bedtime. Light therapy in the Practice of Sleep Medicine. 5th Edn. St
morning (10,000 lux for 30 min) may be Louis, Elsevier-Saunders; pp. 492–509.
supplemented with formulations of N Espie CA. (2009). ‘‘Stepped care’’: a
health technology solution for delivering
melatonin, which is a natural hormone
cognitive behavioral therapy as a first line
secreted by the pineal gland. In a dose range
insomnia treatment. Sleep; 32: 1549–1558.
of 0.5–3 mg, administered o3 h before the N Hening WA, et al. (2004). An update on
endogenous dim-light melatonin onset, the dopaminergic treatment of restless
melatonin may advance sleep. In addition, legs syndrome and periodic limb move-
melatonin has weak hypnotic properties but ment disorder. Sleep; 27: 560–583.
is not often powerful enough to be N Mendelson W. (2011). Hypnotic medica-
prescribed as a hypnotic drug. tions: mechanisms of action and phar-
macologic effects. In: Kryger MH, et al,
Sleep in somatoform disorders Many eds. Principles and Practice of Sleep
psychosomatic and somatoform disorders Medicine. 5th Edn. St Louis, Elsevier-
(chronic fatigue syndrome, fibromyalgia, Saunders; pp. 483–491.
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complaints, including insomnia, syndrome and periodic limb movements
hypersomnia and nonrestorative sleep. In during sleep. In: Kryger MH, et al, eds.
some patients, a primary sleep disorder can Principles and Practice of Sleep Medicine.
be diagnosed. Appropriate treatment of the 5th Edn. St Louis, Elsevier-Saunders;
underlying sleep disturbance should result pp. 1026–1037.
in an improvement of the psychosomatic N Morgenthaler T, et al. (2006). Practice
complaints. Often, however, the findings parameters for the psychological and
from the diagnostic work-up are nonspecific behavioral treatment of insomnia: an
or no obvious sleep disturbance can be update. An American Academy of Sleep
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demonstrated. In this case, no therapeutic
N Morin CM, et al. (2006). Psychological
recommendations can be made. At present,
and behavioral treatment of insomnia:
there are no compounds available that update of the recent evidence (1998-
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ment of chronic insomnia in adults. J Clin
N American Academy of Sleep Medicine. Sleep Med; 4: 487–504.
(2005). The International Classification of N Wise MS, et al. (2007). Treatment of
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Medicolegal and economic
aspects of sleep disorders
Gimbada B. Mwenge and Daniel Rodenstein
Sleep is a constitutive component of human hypertension, weight gain and, probably,

life. Both sleep quality and duration are type 2 diabetes mellitus, cardiovascular
factors that influence health and wellbeing. complications and an increased risk of
Quantitative and qualitative sleep deficits motor vehicle accidents (MVAs)) (George,
lead to a deterioration of health (Magee 2007). OSA is characterised by objective
et al., 2011) and impaired cognitive function. physiopathological alterations, such as
According to a recent review of the literature intermittent hypoxia, which could plausibly
(Grandner et al., 2010), the ideal duration of be linked to the pathogenesis of those
sleep would be ,7 h. 7-h sleepers complications (Ryan et al., 2005). However,
experience the lowest risks for all-cause insomnia, RLS and excessive daytime
mortality, whereas those with shorter or sleepiness (EDS) are subjective complaints
longer sleep duration have significantly and frequently lack any objective correlate.
higher mortality risk.
Sleep disorders, like any chronic disease,
It has been reported that 20% of the may carry a significant economic cost. Costs
population suffer from sleep disorders in can be direct or indirect. Direct costs are
Europe. The most frequently found sleep defined as hospital care, cost of drugs, cost
disorders are insomnia (6–15%), OSA (5%) of medical care and cost of care at other
and restless legs syndrome (RLS) (4%). To institutions, whereas indirect costs are
date, the deleterious effects of sleep defined as the value of lost production,
disorders on health have been well including sick leave, short- or long-term
demonstrated only in OSA (it promotes disability and early mortality. This chapter
describes the medicolegal aspects of the
most frequent sleep disorders and their
Key points economic consequences.
N To evaluate the cost–benefit, cost– To evaluate the cost–benefit, cost–utility

utility and cost-effectiveness of and cost-effectiveness of insomnia
insomnia therapies, and even to therapies, and even to compare them to
compare them to each other, we need each other, we need a common tool of
a common tool of measure: the QALY. measure: the quality-adjusted life-year
(QALY). QALYs are the most common
N OSA is associated with an increased outcome measure in cost–utility analyses of
risk of MVAs; driver licensing laws healthcare programmes. The QALY offers a
vary greatly within the EU with regard straightforward procedure for combining the
to OSA. two most important outcomes of healthcare
N Pharmacological intervention for RLS programmes, quality of life (change in the
has favourable cost–utility balances. health status as perceived by the patient,
due to a disease or to a medical
N Insomnia is a cause of workplace intervention) and quantity of life (the
disability. duration of this change), into one single
measure. QALYs can be separated into two

components: survival time and the quality of sleep fragmentation and repetitive
life during this survival. This score ranges hypoxaemia, which leads to poor,
from zero (representing death) to one nonrestorative sleep, EDS, neurocognitive
(representing perfect health) for 1 yr. Utility impairment, arterial hypertension,
represents the subjective weight of health myocardial infarction, stroke and increased
improvement as perceived by the patient, risk of MVAs. The main severity parameter is
who attributes a value to this change. This the AHI, the number of complete (apnoeas)
may differ from what a physician may think or incomplete (hypopnoeas) interruptions in
about the change in health status of the breathing per hour slept. It is also well
patient, but utilities are determined by documented that OSA is associated with
patients, not doctors. Thus, a patient who early mortality.
lives for 1 yr in a health status with a utility
of 0.5 accumulates only 0.5 QALYs (i.e. The degree of daytime sleepiness is
1 yr 6 0.50 utility). However, as insomnia generally not as extreme as in narcolepsy,
is defined by subjective scales, the QALY is, but it is consistently described to be in the
in this case, strictly subjective, especially upper limits of what is considered normal,
since there is no change in survival in or already within the boundaries of EDS.
insomniacs. When assessing treatments, Moreover, sleepiness (quantified by the
once QALYs are determined for each of the ESS) is not always perceived by the subject.
different treatments being compared, one Indeed, studies show that the average ESS in
must determine their cost-efficiency. This narcolepsy is o15, whereas it is around 11–
ratio is simply the cost divided by the output 12 in OSA. The prevalence of OSA is
expressed in QALYs. estimated at 5% of adults according to
various studies (Young et al., 1993).
The advantage of this complex concept is However, professional drivers are believed
that one can compare the QALYs bought per to have an increased prevalence of OSA
Euro in different diseases or in a given (Gurubhagavatula et al., 2004). An
disease by different treatments. This can Australian report found, in a sample of
help one to decide whether to allocate commercial lorry drivers, that 15% had OSA
resources in a more efficient way, by (assessed by questionnaires and PSG),
spending money in health sectors where the whereas a study from Brazil found a quarter
gain in QALYs will be maximal, or in of lorry drivers to be at risk for OSA
deciding to stop the reimbursement of a according to the Berlin questionnaire
medical intervention because a second one (Moreno et al., 2004). A previous report
will cost less and grant the same QALYs, or from the USA found that 10% of long-
cost the same but obtain more QALYs. distance lorry drivers had .30 falls in
oxygen per hour of sleep (Stoohs et al.,
It is generally assumed that when the cost- 1995). However, there is a lack of uniformity
effectiveness ratio of a medical intervention in the way the driving licence regulations
is below a given threshold, the intervention consider OSA in their medical annexes
is worth paying for. In international terms, worldwide and even within the European
the threshold is assumed to lie between two Union (EU).
and three times the per capita gross domestic
product of a given country. Therefore, the Professional performance and work disability
economic status of the country has a definite OSAS leads to a certain degree of
impact on the type of treatments that can be neurocognitive impairment, which could
afforded in that country. This is about affect professional activities.
J30,000 per QALY in Europe. Mulgrew et al. (2007) studied patients with
Obstructive sleep apnoea SDB referred for PSG. They found work
limitations (assessed by a multidimensional
OSA is the most common type of SDB, and occupational questionnaire) to be
is characterised by periodic complete or significantly more present in the most sleepy
partial upper airway obstruction causing quartile of patients compared with the least

sleepy quartile. This was independent of the increased risk for occupational accidents
severity of OSA itself and seemed to depend (retrieved from a national database) during
solely on the degree of daytime sleepiness. It a 10-yr follow up, with an adjusted odds
should be mentioned that the sleepier group ratio of 2.2 (95% CI 1.3–3.8). This increased
was indeed extremely sleepy, much more risk took into account differences in age,
than is usual for OSA patients. BMI, smoking, alcohol dependence, years at
work, blue-collar job, shift work, and
Engleman et al. (2000) studied cognitive exposure to noise, organic solvents, exhaust
performance in SAHS. They suggested that fumes and whole-body vibrations. Neither
deficits broadly worsen with disease snoring alone nor daytime sleepiness alone
severity, with large average values for
were associated with an increased
attention and executive functions. They
occupational risk.
concluded that sleepiness and hypoxaemia
might contribute to cognitive deficits. Krieger et al. (1997) showed that in the
12 months after initiation of CPAP, both
Finally, through a meta-analysis of
occupational and domestic accidents and
randomised placebo-controlled crossover
near-missed accidents decreased; the
studies of CPAP treatment involving 98
number of patients declaring an accident or
SAHS patients (AHI .5 events?h-1 and two
a near-missed accident also decreased.
or more symptoms), Engleman et al. (2000)
showed trends towards better cognitive Increased MVA risks and legal aspects
performance on CPAP than on placebo, Patients with OSA have been shown to have
although the enhancements were small. more MVAs than drivers from the general
population. OSA represents a risk factor for
More recent studies have assessed the
MVA estimated at three- to seven-fold that
involvement of OSA in work disability
of the general population. The first reports
without assessing sleepiness or cognitive
of an increased number of MVAs in patients
performances.
with sleep apnoea were published in the late
Omachi et al. (2009) performed PSG in a 1980s (George et al., 1987). Many studies
group of 153 employees and they found 83 have been published since then, using
subjects with sleep apnoea (AHI different methodologies, from
.5 events?h-1). They found prospectively epidemiological studies to cohort studies,
that the combination of OSA and EDS case–control studies and follow-up studies.
contributes to work disability, but that OSA Several investigators relied on patient
itself contributes to recent work disability in responses (subjective data), whereas many
people who have OSA but do not have EDS. others turned to official databases of MVAs
(in general, these record more serious
Those data were confirmed in another study accidents involving personal injury or
conducted in Finland (Sjösten et al., 2009) significant financial consequences). Several
in a total of 766 employees, which found articles have reported on the effects of
that employees with OSA (both females and treatment (usually CPAP) on MVA rate,
males), compared with controls, had a comparing, in a cohort of patients, the rate
particularly pronounced risk (two-fold of MVAs for a given time before and after
increase) of long-term disability caused by the institution of therapy. Patients were
injury or mental disorders. frequently compared with a control sample,
Finally, accidents in the workplace either limited in number and matched to the
represent a significant economic burden for patient group on several aspects or
employers and a significant health risk for including all of the population in a given
employees. OSA may represent a causal geographical area (an island or state). In
factor in work accidents. most studies, many factors that could
influence the comparisons were accounted
Lindberg et al. (2001) showed that subjects for in the calculations. These included, for
with snoring and daytime sleepiness had an instance, distance driven per year, visual

problems, medications and alcohol visual defect, to stop driving for a specified
consumption, BMI, smoking, work schedule period after a heart attack, etc.). Within the
and comorbidities. Most studies have tried EU, there is still a lack of uniformity
to assess the possible relationships between concerning driving licence regulations.
the severity of the disease, either through Drivers with undiagnosed OSA may freely
the AHI or the desaturation index, or the drive across Europe, crossing borders
severity of the disease-related sleepiness, between member states with different rules.
usually assessed with the ESS, or some Annex III does not mention OSA, nor does
index of sleep fragmentation, such as the the next modification of the directive, which
Movement Arousal Index, on the one hand, will come into effect in 2013, even though
and the rate of MVAs on the other hand. OSA is probably the disease with the greatest
Results are concordant: there is an risk of MVAs (Barbé et al., 2007). Beyond
increased risk of MVAs in patients with OSA, abiding by directive 91/439/CEE, individual
either for MVAs in general or for serious states are free to institute more stringent
MVAs only, and this excess is cancelled out rules. When it became evident that OSA was a
when patients start and remain on treatment serious risk factor for MVAs, some medical
with CPAP. The average increase in risk experts started national lobbying actions and,
across all studies is in the range of three-fold sometimes, succeeded in modifying their
with respect to the general population. national driving licence regulations. However,
this is far from being generalised. Moreover,
A meta-analysis was performed comparing the EU has extended its geographical
the risks of MVAs in all medical conditions boundaries far beyond what they were in 1991.
reported in the literature. The summary of Therefore, the present situation resembles
this meta-analysis is that most medical chaos more than a rational plan. A survey
conditions confer a risk increased between published in 2008 and concerning 25
1.2- and two-fold with respect to a healthy European countries showed that OSA was
population (meaning that the disease mentioned in the Annex III of the national
increases the MVA rate by 20–100%). OSA rules in 10 countries, whereas it is not
had the highest increased risk, with a relative mentioned at all in the 15 other ones
risk of 3.71, which is second only to age and (Engleman et al., 2000). Since free movement
sex as a general risk factor for MVAs. is a cardinal rule within the EU, drivers from
In some countries, the increased risk of countries where untreated OSA does not
MVAs has prompted a specific constitute a limitation to drive can freely drive
consideration of OSA in the legislation for in countries where there are restrictions for
driving licences. For instance, drivers with untreated OSA. This applies both
questionnaires for driving licence applicants to private and commercial drivers.
may include questions on OSA symptoms; It appears wise to continue lobbying actions
patients diagnosed but untreated may be to include the disease representing the most
considered unable to drive or some serious risk for MVAs in Annex III of the
restrictions may be applied to their driving, European directive. All the more so, as this
whereas treated patients may recover full is a treatable disease, and that it has been
permission to drive. Directive 91/439/CEE, shown time and again that compliant
published on July 29, 1991, is the legal basis patients treated with CPAP normalise their
for the common rules for driving licences in MVA risk (Barbé et al., 2007).
the EU. It includes an annex (Annex III) that
deals with all medical aspects, i.e. specific Economic consequences Studies from various
diseases that may impair driving abilities countries have shown that healthcare costs
and that need a specific assessment to are higher in patients with OSA, and that
evaluate whether it is safe to allow the they increase over time until a diagnosis is
candidate to drive, either as they are or made and decrease after the start of
providing remedial measures are adopted effective treatment. Costs are related to the
(for instance, to wear glasses to correct a severity of the disease, with more severe

patients costing more than less affected 20% diagnostic yield and a 70% therapy
ones (Tarasiuk et al., 2005). success rate), yet they concluded that the
net result would be a very significant saving
It seems beyond doubt that OSA increases of US$7.9 billion.
health expenditure during the silent phase of
the disease, i.e. when OSA is already present In the UK, a study (Guest et al., 2008)
but has not been diagnosed (this is also evaluated the cost-effectiveness of the
referred to as the pre-clinical phase of a treatment of OSA with CPAP. The authors
disease). Several well-conducted studies included the direct medical costs (including
have consistently shown that healthcare the costs of diagnosing and treating the
costs are increased by 50–100% in patients disease), the preventive effect of treatment
who will be diagnosed with OSA in the on cardiovascular and cerebrovascular
future, with respect to the general accidents, and the costs related to MVAs.
population. This is true not only in middle- They calculated that treating OSA is cost-
aged adults, but also in children, and in effective provided the treatment lasts for
older males and females (Tarasiuk et al., o2 yrs. The cost-effectiveness will improve
2004). These increased costs have been thereafter as the cost remains stable (the
analysed in some studies, and may be diagnostic process does not need to be
attributable to cardiovascular disease, repeated and the CPAP machine has already
digestive problems and metabolic disease in been bought) but the benefits increase year
adults, whereas in children, the excess costs after year. Considering the costs that would
are mainly due to ENT and respiratory have been incurred if the treatment had not
conditions (Smith et al., 2002; Tarasiuk been started, for instance, if an untreated
et al., 2005). patient has suffered a myocardial infarction,
the authors calculated that the treatment of
Once the disease has been diagnosed, a
OSA was not only cost-effective but it was
treatment may be proposed. The application
even cost-saving after 13 yrs of treatment.
of an efficient treatment in OSA results in a
This means that if treatment lasts for 13 yrs,
significant reduction in healthcare costs in
the entire health costs incurred by the
the months and years that follow. These
patient will be less than the cost of their
reductions narrow the difference between
treatment for OSA during those 13 yrs;
the costs of patients (that start to decrease)
society would save money (Guest et al.,
and those of the general population (that
2008). In other words, they estimated that:
continue to increase as time goes by, though
at year 1, the cost per QALY for CPAP
at a much slower rate). The treatment does
not completely cancel the difference, but compared with no CPAP is expected to
attenuates it by about half. Again, this exceed £20,000; after 2 yrs, the expected
appears to be true at all ages, from infancy cost per QALY gained is £10,000 or less;
to old age (Smith et al., 2002). and after 11 yrs, CPAP is the most cost-
effective treatment. For instance, after
The economic impact of MVAs related to 14 yrs, the cost per QALY gained compared
OSA was assessed in a theoretical study by with no treatment is £1,620 (£4,123 to
Sassani et al. (2004). Based on all available £259). Other reports coming from Canada
published evidence, they calculated the total or Spain have also found this treatment to
number of MVAs attributable to OSA in the be cost-effective (Banno et al., 2009;
USA. They then estimated the total cost due Wittmann et al., 2004). Ayas et al. (2006) in
to these accidents (medical and Canada performed a cost–utility analysis
nonmedical, including lost work days, comparing CPAP with no treatment for the
vehicles repairs, etc.). This resulted in a total treatment of patients with moderate-to-
cost of US$15.9 billion. The authors severe OSA. The base-case analysis was of
estimated then the cost of diagnosing and patients aged between 25 and 54 yrs who
treating all patients in the country, and the were newly diagnosed with moderate-to-
impact of this policy on MVAs. They used severe obstructive sleep apnoea/hypopnoea
very conservative estimates (for instance, a syndrome (OSAHS), classified as having an

AHI o15 events?h-1. In this study, the RLS in pregnant women, patients undergoing
authors took into account CPAP compliance. dialysis, type 2 diabetes patients, patients
A compliance rate of 70% was assumed. In with low iron levels and Parkinson’s disease
Spain, Mar et al. (2006) performed a cost– patients (Karroum et al., 2008).
utility analysis comparing CPAP with no
treatment for the treatment of patients with Medical and economic consequences
OSA. Table 1 summarises these findings, Diagnosis of RLS is based on subjective
which compare very favourably with other reports. The real impact of RLS on sleep is
publicly funded therapies, such as primary poorly understood. It is deemed to cause
prevention of cardiovascular events using insomnia, hypersomnia or EDS. RLS could
cholesterol-lowering therapy ($54,000 per also be associated with OSA; in this case,
QALY to $1.4 million per QALY gained) the treatment of OSA by CPAP may decrease
(Prosser et al., 2000). or remove RLS (Delgado Rodrigues et al.,
2006). However, objective measures, such
These values compare very favourably with as PSG, do not always show sleep
other publicly funded therapies, such as abnormalities, and the presence of periodic
primary prevention of cardiovascular events limb movements (PLMs) of sleep is
using cholesterol-lowering therapy ($54,000 inconstant and not considered as a formal
per QALY to $1,4 million per QALY gained) diagnostic criterion. However, this
(Prosser et al., 2000). syndrome is much discussed and is a source
Restless legs syndrome of controversy.
RLS is characterised by an irresistible urge Only one study performed PSG in RLS
to move the legs while resting (Innes et al., patients (a small simple size of 27 patients;
2011). This urge is usually accompanied by Kallweit et al., 2009). 10 of the patients
uncomfortable sensations (creeping or reported EDS assessed by the ESS; they had
burning) in the legs. Symptoms begin or lower sleep latency on the MSLT and longer
worsen during periods of inactivity, are total sleep time, but no differences between
partially or totally relieved by the movement, PLMs. Further studies are needed to better
and are worse in the evening or at night. The understand this sleep disorder, which seems
prevalence of RLS varies from 4 to 29% in not to lead to objective sleep impairment.
the general population. RLS can be primary
or secondary: primary RLS often appears RLS is a treatable disease. Once RLS is
before the age of 20 yrs and has a familial diagnosed, medication is given (usually
component; secondary RLS is usually dopaminergic agonists). These medications
associated with disorders such as peripheral have proven effective, with improvement in
neuropathy. There is a higher incidence of quality of life (Giorgi et al., 2006).
Table 1 Cost-effectiveness studies of CPAP treatment.

Guest et al. (2008) Ayas et al. (2006) Mar et al. (2006) Tousignant et al.
(1994)
Study design Compared CPAP, CPAP versus no CPAP versus no CPAP versus no
auto-CPAP and no treatment treatment treatment
treatment
OSAS patients n 120 99 46 19
Cost-effectiveness £1400 US$3354 (range J7861 US$9792
ratio per QALY US$1064–9715)
limited to 5 yrs
AHI events?h-1 .30 .15 41.3¡14.6 67.6¡24.3
ESS 12 Mean¡SD 13.8¡5.8
Country UK Canada Spain Canada

Some authors have tried to evaluate the insomnia (PI), insomnia related to a medical
economic burden of this disease. It has been or mental disease, and secondary insomnia
reported that RLS patients have mean related to the intake or substance abuse/
productivity losses of 1 day per week, and dependency (American Academy of Sleep
that treatment and rehabilitation cost about Medicine, 2005).
US$228 million per year (Allen et al., 2011).
Another study, conducted in Germany, found Insomnia is the most prevalent sleep
that direct and indirect medical costs over a 3- disorder, especially in the elderly, with a
month period amounted to about J2,090 per prevalence of 10–20% of the population in
patient (Dodel et al., 2010). Another recent Europe and Canada, and it is mostly
review of the economics of RLS confirmed its diagnosed in women. There is no relationship
impact on patient quality of life and equated between insomnia and sleep duration.
its burden to that observed in patients with Medical consequences Many studies based
other chronic conditions. on questionnaires and surveys or reviews
have reported cognitive impairment in
Among the drugs used to treat RLS, some
patients with PI (Fulda et al., 2001;
have been assessed for their cost–utility. In
Shekleton et al., 2010). However, a new
the UK, the incremental cost per QALY for
meta-analysis has shown that their
pramipexole (a dopaminergic agonist used
performance was comparable to that of
to treat RLS) was £3,349 versus no treatment
normal sleepers for other aspects of
and showed a cost-saving profile of £92
attention (alertness, divided attention,
against ropinirole. In Sweden, pramipexole
sustained attention and vigilance),
produced cost savings of SEK 2,381 versus no
perceptual and psychomotor processes,
treatment and SEK 3,564 versus ropinirole.
verbal functions, procedural memory and
QALY gains in both countries were 0.095
some aspects of executive functioning
versus no treatment and 0.007 versus (verbal fluency and flexibility), as well as
ropinirole. These results compare well with general cognitive functioning (e.g. memory
UK cost-effectiveness thresholds of £20,000 and concentration). This casts doubts on
per QALY and are cost saving for Sweden. the real impact of insomnia on cognitive
One-way and probabilistic sensitivity functions, which could be much less than
analyses showed results to be robust. previously thought.
Insomnia
Patients suffering from insomnia commonly
Epidemiology Insomnia is a subjective report poor sleep and significant reductions
perception of insufficiency of sleep duration in sleep duration and quality of life.
or quality. The diagnosis and assessment
Insomnia has also been related to impaired
are based on subjective reports (sleep
immune function, elevated BMI and type 2
questionnaires or scales) and sleep diaries.
diabetes (Motivala, 2011; Vgontzas et al.,
It can be defined as a complaint of 2009). A population sample study of 953
prolonged sleep latency, difficulty in falling patients in Canada that compared good
asleep or maintaining sleep, or sleepers with insomniacs showed that the
nonrestorative sleep accompanied by latter have a higher rate of prescription
significantly impaired daytime functioning in medications, most notably to treat insomnia
the absence of a specific physical, mental or (which is understandable), mood and
substance-related cause. The complaints anxiety disorders. But in terms of mortality,
have to last for o4 weeks to be diagnosed patients with insomnia without underlying
as insomnia. Insomnia can occur acutely or comorbidities appear to have no survival
become a chronic disorder when it occurs at risk, as long as they refrain from long-term
least three times per week, usually for use of sleeping pills.
o3 months’ duration. The American
Psychiatric Association Diagnostic and Economic consequences According to various
Statistical Manual of Mental Disorders studies, the use of healthcare resources is
(DSM) classifies insomnias into primary widely increased in insomnia patients.

For instance, in a study conducted in a considered only short sleepers. Another
randomly selected sample of 948 adults in Canadian study conducted in 900 patients
Quebec, Canada, the total cost of insomnia found that patients with insomnia are more
was estimated at CA$6.6 billion, while in the frequently absent from work, while some
USA, direct and indirect costs associated reported having experienced reduced
with insomnia may exceed US$100 billion productivity compared with good sleepers
annually. A variety of treatments are and higher rates of non-motor-vehicle
available for the management of chronic accidents. However, as insomnia is a
insomnia, including cognitive–behavioural subjective perception, one might wonder
therapy (CBT), which is believed to be the whether the perception of lower profitability
most effective treatment of PI, hypnotics in the workplace is not affected by the same
such as Z-drugs, and alternative therapies perception of cognitive dissatisfaction with
(e.g. off-label medicines, alcohol, herbal daytime functioning.
remedies and alternative activities), which
Legal aspects The ability to drive is
are supported by very little evidence. CBT influenced by many factors, such as
improves sleep quality, reduces hypnotic attention span, concentration ability,
drug use and improves health-related quality reaction time, good vision and social
of life at a favourable cost (Morgan et al., behaviour on the road. All these conditions
2004) even among long-term hypnotic users can be reduced by poor self-perception,
with chronic sleep difficulties. Z-drugs, such depression and the use of psychotropic
as eszopiclone, have been shown to improve medications.
quantitative sleep and quality of life, and
reduce insomnia severity and work limitations The literature is very sparse concerning
(Krystal et al., 2008; Walsh et al., 2007). insomnia and MVA risks, and the few data
available are controversial. In one study
A study conducted in 2004 by Morgan et al. mentioned previously, which compared
in the UK found that the mean cost per good sleepers and insomniacs, the authors
QALY at 6 months was £3,418 in 209 did not retrospectively find a higher risk of
patients with chronic insomnia treated by MVAs in insomniacs. A more recent study
CBT. Another study conducted to assess the conducted by Williamson et al. (2011)
cost-effectiveness of long-term treatment revealed that daytime fatigue and sleepiness
with eszopiclone compared with placebo as a consequence of insomnia are of direct
therapy found that the incremental cost per safety concern, as they can affect accident
QALY gained was approximately US$9,930 risk. Similarly, one retrospective study
including productivity gains and US$36,894 conducted in a population of patients who
excluding productivity gains in the had already had one or more accidents
eszopiclone group. This cost-effectiveness found an odds ratio .5 in patients with
was also confirmed in a more recent study, insomnia. Although a strong correlation has
which found a cost per QALY of US$4,800 been demonstrated between the risk of
for eszopiclone versus placebo. accidents in short sleepers (Marshall et al.,
2004) and subjects with EDS, we cannot
Work disability A cohort study (Sivertsen extrapolate from these data to insomniacs.
et al., 2009) conducted in 6,599 working Moreover, people suffering from insomnia
subjects over 4 yrs investigated the are not often short sleepers nor do they have
contribution of insomnia versus sleep real EDS confirmed by objective tests, so it
duration to later long-term work disability, is difficult to incriminate those parameters
where disability pension was chosen as the in explaining the accident risk.
outcome. Insomnia was a strong predictor
of permanent work disability (OR 4.56) and However, as previously stated, insomnia
this effect remained significant after patients consume more psychoactive drugs
controlling for sleep duration and other than good sleepers and, therefore, could
possible confounders (OR 1.88), but these have a higher risk of vehicle accidents
correlations were not found when they because of the treatment of insomnia, rather

than from the insomnia itself (Smink et al., N Banno K, et al. (2009). Expenditure on
2010). In Germany, driving licence health care in obese women with and
regulations refer specifically to people with without sleep apnea. Sleep; 32: 135–136.
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the text of this directive, unaccompanied uous positive airway pressure on the risk
people with insomnia no longer have of road accidents in sleep apnea patients.
permission to drive when they suffer from Respiration; 74: 44–49.
measurably pronounced somnolence during N Delgado Rodrigues RN, et al. (2006).
the daytime. As a condition of obtaining and Outcome of restless legs severity after
keeping a driving licence, the person has to continuous positive air pressure (CPAP)
treatment in patients affected by the
undergo continuous checks of their disease.
association of RLS and obstructive sleep
People with special driving licence classes,
apneas. Sleep Med; 7: 235–239.
i.e. for heavy goods vehicles, buses and N Dodel R, et al. (2010). Health economic
taxis, are regularly screened and have to be burden of patients with restless legs
examined by a doctor if they have typical syndrome in a German ambulatory set-
symptoms of insomnia. To our knowledge, ting. Pharmacoeconomics; 28: 381–393.
this German law seems to be unique. N Engleman HM, et al. (2000). Cognitive
function in the sleep apnea/hypopnea
Conclusion
syndrome (SAHS). Sleep; 23: Suppl. 4,
We have reviewed in this chapter three 102–108.
frequent sleep complaints or disorders N European Parliament. (2003). Directive
having medicolegal and economic 2003/59/EC of the European Parliament
and of the Council of 15 July 2003 on the
implications. We have purposely left
initial qualification and periodic training
narcolepsy aside due to its rarity and well-
of drivers of certain road vehicles for the
known consequences on working capacity,
carriage of goods or passengers, amend-
driving ability and quality of life. ing Council Regulation (EEC) No 3820/85
Sleep disorders, whether completely and Council Directive 91/439/EEC and
subjective or characterised by objective repealing Council Directive 76/914/EEC.
findings, may result in some impairment in Off J Eur Union; L266: 4–17.
N Fromm IE. (2008). The revision of the
social and professional behaviour, as well as
regulations concerning driving licences
in the risk of MVAs. In addition, by
(FeV) to combat the dangers of sleep
themselves or through the cost of apnoea and insomnia in road traffic.
treatments, they represent an economic Pneumologie; 62: 387–391.
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disease burden of primary restless legs tolerability of ropinirole in patients with
syndrome: results of a general population restless legs syndrome and a baseline
survey in the United States. Mov Disord; IRLS total score . or 5 24 points – data
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therapy for moderate to severe obstruc- associated with short sleep duration: the
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Development of breathing and
sleep and physiopathology of
apnoea in the first years of life
Gary Cohen, Miriam Katz-Salamon and Ha Trang
The scope of this section is to describe the low-voltage and rapid EEG, inhibited EMG
dramatic changes that occur in the first and burst of saccadic and rapid eye
months and years of life regarding sleep movements, associated with rapid and
organisation and breathing control, and to irregular respiratory and heart rates. In
use this as a background to explain the contrast, QS is characterised by high-voltage
pathophysiology of apnoea and apparent and slow EEG, inhibited EMG and rare eye
life-threatening events (ALTEs) in infants. movements, associated with slow and
Circadian sleep/wake rhythms are already regular respiratory and heart rates. Thus, AS
present in utero, observed during the last shares some features with the future REM
trimester of gestation. These fetal rhythms sleep and QS shares some features with the
are lost at birth but re-appear during the first future NREM sleep, sleep states that are
weeks and months of life. The organisation observed in adults.
of sleep/wake rhythms is driven by both an
endogenous biological clock and numerous In the first month of life, sleep duration lasts
external factors such as day/night variations nearly 16–17 h?day-1, structured upon an
and parental/social factors. These may at ultradian rhythm with alternate diurnal and
least in part underlie the large variability nocturnal sleep. Newborns begin to sleep in
observed with regard to sleep development AS, which occupies a high percentage of
and characteristics among individuals. sleep (50% of total sleep time). Sleep cycles
with alternate AS and QS last approximately
Development of sleep in the first years of life 50 min. No early- and late-night differences
in AS/QS distributions are observed.
Sleep and wakefulness states can be
identified in utero from the beginning of the Significant changes in sleep characteristics
third trimester of gestation. In human and organisation are observed in the first
newborns, sleep is divided into two 6 months of life, with development of the
differentiated states: active sleep (AS) and main features of adult sleep. Beyond the first
quiet sleep (QS). AS is characterised by few months of life, the proportion of AS/
REM sleep decreases significantly whereas
QS/NREM sleep increases and differentiates
Key points
into stages 1, 2 and 3 sleep with specific EEG
waveforms. Sleep onset no longer occurs in
N Breathing irregularities are common REM sleep after age 6 months. Organisation
in infancy but resolve spontaneously of sleep following a circadian rhythm is
by 3–6 months. established by age 1 yr.
N Breathing and cardiovascular control
With increasing ages, mean duration of total
are inextricably linked and should be
evaluated together. sleep time per day decreases progressively
(average 14–15 h at age 6 months, 13–14 h
N ALTEs are not benign and may impact at 1 yr, 12–13 h at 3 yrs, and 11 h at 6 yrs).
on long-term outcome. Diurnal sleep time shows greater reduction
than nocturnal sleep time. The

disappearance of diurnal naps between 2 appear to increase after birth, although
and 6 yrs of age is associated with whether this is due to an increase in CO2
substantial reorganisation of nocturnal chemosensitivity or improved lung
sleep. Sleep cycles that include REM and compliance and ribcage stability is uncertain.
NREM periods last longer (55 min at age
3 months, to 75 min at age 2 yrs). The Hypoxia Hypoxia stimulates mainly the
percentage of REM sleep decreases rapidly peripheral chemoreceptors. Newborns are
after age 9 months. REM sleep latency known to be less sensitive and responsive to
increases progressively (15 min at age hypoxia. Two events – an increase in carotid
3 months, 70 min at age 2 yrs, 143 min at body chemosensitivity, and the waning of
6–7 yrs). The duration and percentage of hypoxia’s depressant actions on the brain –
REM sleep increase progressively overnight, transform this situation. The first process is
being longer in the second half of the night rapid, and is normally well advanced by the
compared to the first. second post-natal day; it augments mainly
the amplitude of the VR. The second process
Parental/social factors and day/night occurs slowly over weeks to months and
variations play a key role in the development increases the duration of the response, i.e.
of the circadian rhythm of sleep. the increase in V9E/hyperpnoea lasts longer;
this largely explains why the response
Development of control of breathing becomes less ‘‘biphasic’’ and more
‘‘monophasic’’ with age.
The purpose of breathing is to match the
oxygen supply and demand and eliminate Asphyxia Asphyxia refers to a low O2–high
carbon dioxide – a precarious task in infancy CO2 state; it can develop for a variety of
when the metabolic rate is high, body reasons, e.g. central apnoea (no breathing
oxygen stores are low, and breathing is efforts), or airway obstruction at the level of
irregular. Specialised chemoreceptors the mouth and nose, pharynx or larynx.
facilitate this task by constantly monitoring Tolerance to asphyxia is particularly low. It
oxygen and carbon dioxide levels in the can quickly lead to organ damage, brain
blood and tissues. Functional depression, coma and death and poses a
chemoreceptors are not required to initiate particular danger in infancy because it
or maintain breathing at birth (neurogenic/ develops rapidly (for the reasons given
brain activity is sufficient to achieve this), above), and because sensitivity to hypoxia
but over subsequent days-weeks their input (although not CO2) is weak. Normally (in
(neural ‘‘drive’’) becomes progressively adults) when both stimuli occur together,
more important for sustaining breathing cardiorespiratory activation and arousal is
rhythm, especially during sleep. dramatically heightened. This
Chemoreceptor dysfunction consequently ‘multiplicative’ interaction (which occurs
underpins and exacerbates sleep-related within the carotid body and brainstem) is
breathing disorders. weak at birth but gradually develops as the
carotid chemoreceptors reset, although the
Carbon dioxide Carbon dioxide stimulates time course is uncertain.
the peripheral (carotid body) and central
(brainstem) chemoreceptors at all ages. The The upper airway The upper airway muscles
ventilatory response (VR) of the term-born are the accessory muscles of breathing. They
infant and adult are more-or-less equivalent, are normally activated in parallel with the
so CO2 sensitivity is normally well developed diaphragm and intercostal muscles to
if not fully mature at birth. The infant curve regulate airway calibre and resistance.
is however displaced to the left (it shifts During inspiration, the pharyngeal and
rightwards with age), which means minute laryngeal abductors tense and dilate the
volume (V9E) in infancy is greater at any airway to lower resistance and facilitate lung
PaCO2; this reflects a two-fold greater (weight inflation. During expiration, the adductors
adjusted) metabolic rate/CO2 production. constrict the larynx (in particular) to slow
For the infant born pre-term, the VR does expiration and maintain lung volume above

passive relaxation volume. The tone and intermittent hypoxia and/or hypercapnia, for
phasic activity of these muscles is example, can depress or enhance ventilatory
influenced by drive from the responsiveness, depending on the
chemoreceptors and airway and laryngeal developmental stage at exposure.
sensors that monitor pressure, flow and pH. Circumstances that alter, delay or otherwise
Upper and lower airway muscle coordination reprogramme chemoreflex development
improves with age; if poorly coordinated, it may exacerbate cardiorespiratory failure and
may cause obstruction or significantly vulnerability to asphyxia.
reduce airflow, especially when
Physiopathology, diagnosis and assessment
chemoreceptor drive is strong.
of apnoea and apparent life-threatening
Breathing and sleep During sleep, events
behavioural drives are lost or suppressed
Developmental aspects of respiratory rhythm in
and tonic drive from the chemoreceptors
health The breathing pattern of the newborn
helps sustain a normal breathing rhythm.
infant is often characterised by apnoeas of
Consequently, chemoreceptor dysfunction is
varying duration and frequency, and by
often unmasked and breathing irregularities
periodic breathing (cycles of 3–5 regular
accentuated, particularly during QS. The rate
breaths separated by pauses). Breathing
and depth of breathing fall at sleep onset;
irregularities are evident in almost all infants
both become more irregular and variable
born extremely pre-term (,28 weeks) and
during REM sleep and reach a nadir during
about 30% of those born at full term. The
NREM sleep (QS). Responsiveness to CO2
propensity for apnoea and periodic
and hypoxia is also attenuated during QS
breathing in infancy has been ascribed to a
and falls even further during REM sleep,
weak response to hypoxia and hypercapnia,
accentuated by chest wall instability due to
and/or a low CO2 apnoeic threshold. Most
muscle atonia. Short respiratory pauses are
breathing irregularities resolve
more frequent, particularly during REM
spontaneously by age 3–6 months due to
sleep. Premature and some full-term infants
maturation of central rhythm generators and
exhibit bouts of periodic breathing (cycles of
chemoreceptors, the two systems essential
regular breathing efforts separated by for maintaining a normal breathing rhythm
pauses lasting 3–10 s). The cyclical hypo- during sleep.
and hyperventilation may cause significant
hypo/hypercapnia and intermittent Aetiology of breathing irregularities Apnoea is
desaturation. Periodic breathing is common a symptom rather than a disease. Breathing
early on but decreases dramatically in irregularities occur in diseases of the central
frequency and duration with age as the nervous system, lungs, muscles,
chemoreceptors and central rhythm metabolism, upper airways, etc. Apnoea may
generators mature. Persisting immaturity in be aggravated by many factors, e.g.
either or both may accentuate periodic immature or abnormal chemoreception,
breathing and apnoea. lung disease, upper airway dysfunction,
systemic infection, intracranial haemorrhage,
Plasticity Development in general does not hypo- or hyperthermia, glucose/electrolyte
follow a fixed trajectory but is moulded by imbalance, anaemia, gastro-oesophageal
experience. Unusual perinatal reflux and patent ductus arteriosus.
circumstances (e.g. pre-term birth, fetal
exposure to drugs such as nicotine, Clinical diagnosis is complicated by the
repetitive apnoea, asthma or lung disease) intricate interaction between central and
can trigger long-lasting changes in peripheral control mechanisms. Central
chemoreception, reflecting structural or mechanisms control respiratory rhythm, as
functional ‘reprogramming’ of the well as the diaphragm and accessory muscles
chemoreceptors themselves, of processing of breathing. Weak or unstable central drive
centres within the brainstem, or of both. can therefore result in central, obstructive or
Exposure to chronic or repetitive mixed apnoea as well as irregular breathing.

Figure 1. The sequence of apnoea, bradycardia and desaturation. a) Physiological apnoea, no desaturation
or bradycardia. b) Short apneoa with rapid desaturation due to airway closure, low functional residual
capacity, ventilation/perfusion mismatch, intrapulmonary shunts and tachycardia. c) Apnoea with
bradycardia due to vagal and/or trigeminal inhibition during swallowing, obstruction or reflux.
Similarly, upper airway, lung and respiratory Apparent life-threatening events An ALTE is
muscle disease may further modify central ‘an episode that is frightening to the
drive via altered sensory feedback, and observer due to combination of apnoea,
exacerbate central irregularities. colour change (cyanotic or pallid), change in
muscle tone (marked limpness), choking, or
Clinical aspects of apnoea Control of gagging’. The mixture of breathing,
breathing is inextricably linked with circulatory and neuromuscular symptoms
cardiovascular control, particularly during makes separating coexisting and causative
sleep. Dysfunction in one affects the other factors difficult. ALTEs occur more
and vice versa, and can rapidly lead to a frequently in infants with pronounced
dangerous or fatal downward spiral of periodic breathing or apnoea and are often
events (see below). In clinics, the two heralded by repetitive apnoea, desaturations
systems should be carefully evaluated in and slow circulatory changes in the
tandem. Thus, duration and frequency of preceding hours. Clinical management
central, obstructive and mixed apnoea must should focus on excluding serious
be linked with concomitant changes in underlying causes such as seizures, cardiac
blood gases as well as in heart rate and diseases, bacterial infection, metabolic
blood pressure. Brief apnoea is often disorders and central hypoventilation.
regarded as physiological, but if frequent Subsequent investigation should include
and associated with significant blood gas cardio-respiratory function, blood gases,
and circulatory changes (e.g. bradycardia) polysomnography/polygraphy, and
may compromise health (fig. 1). (preferably) long-term home monitoring.

ALTEs should not be ignored; they cause N Dewolfe CC. (2005). Apparent life-threa-
severe hypoxia and are unlikely to be benign, tening event: a review. Pediatr Clin North
even if the link with sudden infant death Am; 52: 1127–1146.
syndrome (SIDS) is controversial. If there N Gauda EB, et al. (2004). Maturation of
are no serious underlying conditions, the peripheral arterial chemoreceptors in
risk of SIDS is certainly low, but the relation to neonatal apnoea. Semin
long-term outcome for these infants is yet to Neonatol; 9: 181–194.
be determined. N Hunt CE, et al. (2004). Cardiorespiratory
events detected by home memory mon-
itoring and one-year neurodevelopmental
Further reading outcome. J Pediatr; 145: 465–471.
N Katz-Salamon M. (2004). Delayed che-
N Carroll JL. (2003). Developmental plasti- moreceptor responses in infants with
city in respiratory control. J Appl Physiol; apnoea. Arch Dis Child; 89: 261–266.
94: 375–389. N Lorch SA, et al. (2011). Epidemiology
N Cherniack NS. (2006). Cardiopulmonary of apnea and bradycardia resolution
integration: the dark side. Respiration; 73: in premature infants. Pediatrics; 128:
733–734. e366–e373.
N Cohen G, et al. (2005). Development of N Poets CF, et al. (1991). Arterial oxygen
chemoreceptor responses in infants. saturation and breathing movements
Respir Physiol Neurobiol; 149: 233–242. during the first year of life. J Dev Physiol;
N Darnall RA. (2010). The role of CO2 and 15: 341–345.
central chemoreception in the control of N Praud JP. (2010). Upper airway reflexes in
breathing in the fetus and the neonate. response to gastric reflux. Paediatr Respir
Respir Physiol Neurobiol; 173: 201–212. Rev; 11: 208–212.

Sleep disordered breathing in
children
Ha Trang and Anita K. Simonds
Obstructive sleep apnoea syndrome It is currently thought that primary snoring

may not have adverse effects on health. In
OSAS is a public health problem affecting contrast, UARS, which is difficult to identify
2–5% of the paediatric population. Partial or in current practice, may progress towards
total obstruction of the upper airway results complications if undiagnosed.
in obstructive apnoeas and hypopnoeas
during sleep, with or without associated Epidemiology Prevalence of OSAS in
desaturation, hypercapnia and sleep children is estimated to range from 0.7% to
fragmentation. It is thought that there is a 10.3%, with a peak incidence between 5 and
continuum between the normal state and 10 yrs of age. An estimate of 6.4%
OSAS, which is the complete clinical prevalence in children 1–6 yrs of age and of
presentation of the disorder. Intermediate 3.7% for those 7–12 yrs of age was reported
presentations include: in one study. Prevalence of OSAS is
unknown in infants and toddlers.
1. primary snoring, which is chronic Nevertheless, all studies have shown that
snoring without associated apnoea or OSAS occurs equally in females and males.
arterial desaturation; and
Approximately 8–10% of children snore
2. upper airway resistance syndrome
regularly. However, not all children who
(UARS), characterised by inspiratory
snore have OSAS. Infants can snore without
respiratory efforts during sleep identified
apnoea, as shown in a case–control study
using oesophageal pressure, but without
including 400 patients.
typical apnoea or hypopnoea.
There are no large controlled longitudinal
studies relating to the natural history of
Key points OSAS in children. It is not known whether
childhood OSAS evolves into adult OSAS, or
N Childhood OSAS is under-recognised. whether there are two different diseases.
N Snoring is not predictive of the Only one case series reported that a
presence of OSAS. subgroup of infants who had previously
presented spells and obstructive apnoeas
N PSG is an important tool for were diagnosed with OSAS at 5 yrs of age.
diagnosing OSAS.
Physiopathology Factors underlying
N Paediatric rules for scoring sleep and development of OSAS in children are
respiration of PSG should be used. primarily associated with reduced patency of
N Paediatric criteria for OSAS should the upper airway. The main causes are
be used. enlarged tonsils and/or adenoids. However,
the pathophysiological mechanisms are
N Hypoventilation is more severe in multiple and intertwined, as follows.
NREM sleep than in REM sleep
in CCHS. N Abnormal craniofacial skeleton, ranging
from major malformations (such as Pierre

Robin syndrome, Crouzon syndrome, daytime hypersomnolence, resulting in
Apert syndrome or achondroplasia) to daytime naps, irritability, and impaired
milder abnormalities not falling within a concentration and attention.
labelled syndrome. The latter may be a Hypersomnolence is a difficult symptom to
moderate hypoplasia of the middle third of assess in children, as typical subjective
the face with an arched palate and narrow assessments using questionnaires may be
nasal cavity, or a narrow oropharyngeal not applicable in this age group. Occasionally,
cavity, with or without a retrognathia and a patients may report morning headaches.
lingual retrusion.
N Abnormal craniofacial and pharyngeal Clinical assessment should include a
soft tissue, resulting in reduction of the general paediatric evaluation and a
upper airway size: enlargement of comprehensive examination of craniofacial
lymphoid tissues (e.g. tonsils and segments and oropharynx (see chapter 4).
adenoids), cervical fat accumulation
(e.g. obesity), increased upper airway Confirmation of OSAS
collapsibility, nasal obstruction (Rapp,
2003) etc. Polysomnography is an important diagnostic
N Neuromuscular dysfunction, in the test PSG is an important tool that helps:
broadest sense of the term, including
impaired neurological control of breathing 1. to confirm or exclude OSAS;
or upper airway muscle tone, etc. 2. to determine the severity of the disorder
and therefore intervene in treatment
Moreover, genetic and environmental and treatment strategy decisions; and
factors have been identified in the 3. to exclude other possible causes of
predisposition to OSAS. The abnormalities sleepiness (Aurora et al., 2011).
are often numerous and complex. It is not
always easy to determine which PSG should include monitoring of
abnormalities are causes and which are neurological parameters EEG, EOG, chin
consequences of OSAS. and leg EMG and ECG) and of respiratory
parameters (nasal air pressure transducer,
Clinical presentation Clinical presentation of
oronasal thermal sensor, chest and
OSAS differs with age. Indeed, symptoms
abdominal respiratory movements, pulse
are dominated by respiratory difficulties at
oximetry, and carbon dioxide tension (PCO2)).
night in all age groups, with snoring during
sleep, breathing pauses, laboured breathing It is of importance to use paediatric scoring
or mouth breathing. Infants and younger and diagnostic criteria of sleep studies when
children (1–6 yrs of age) often struggle to managing children suspected of OSAS. A
remain awake at sleep times and take review of sleep and respiratory rules for PSG
unusual positions, such as prone with the in children has been released recently by the
neck extended during sleep. The parents American Academy of Sleep Medicine
complaint of sleep problems (restless sleep,
(Redline et al., 2007; see also ‘‘Diagnostic
frequent body movements, night sweats and
techniques in children’’). Obstructive
frequent nocturnal awakenings) or
apnoeas or hypopnoeas are considered
secondary enuresis. Morning sluggishness
when longer than two respiratory periods.
and occasional daytime fatigue are reported.
Typically, obstructive apnoeas and
Sometimes, nonrespiratory symptoms can
hypopnoeas may occur only during REM
be misleading: impaired attention or
sleep or be predominant in REM sleep.
concentration, hyperactivity and behavioural
There is no international consensus on the
problems all often manifested as altering
academic performance. PSG criteria for OSAS in children. However,
an apnoea index .1 event?h-1 or an AHI
In older children (pre-adolescent and .1.5 events?h-1 is considered abnormal in
adolescent), loud snoring and breathing children and used as a cut-off value in
difficulties are common. They may report many studies.

Meanwhile, young children, typically infants Nocturnal home oximetry is typically
or toddlers, may demonstrate sustained considered positive when the graph shows
obstruction of breathing during sleep with bursts of desaturations occurring during
hypercapnia and/or hypoxaemia, but without one or many periods of 10–30 min
typical apnoea or hypopnoea. This pattern is overnight. Positive oximetry may be
termed as obstructive hypoventilation and is relatively specific for OSAS, but negative
defined as sleep-related hypoventilation oximetry does not exclude the disorder.
associated with partial airway obstruction. Oximetry may be used as a screening tool in
selected populations, but there is no
Diagnosis of UARS is not performed in evidence supporting the idea that oximetry
routine practice as it requires invasive alone can replace PSG for OSAS diagnosis.
measurement of oesophageal pressure.
Further evaluation of noninvasive Respiratory polygraphy is a system for
techniques of diagnosis is needed. overnight recordings of respiratory
parameters without neurological
In summary, OSAS is confirmed by the parameters; thus, it does not allow
finding of either an elevated apnoea– determination of sleep periods and sleep
hypopnoea index (.1.5 events?h-1) or stages. No studies have assessed the
obstructive hypoventilation in conjunction validity of home respiratory polygraphy for
with the appropriate history and associated the diagnosis of OSA in children. Two
clinical features. studies have compared respiratory
polygraphy findings to PSG, both attended
Are there alternative diagnostic procedures to at hospital. Both show high sensitivity to
PSG for diagnosis of OSAS? An evidence- detect OSAS whenever the latter is defined
based review has recently been published for as apnoea–hypopnoea index .5 events?h-1.
respiratory indications for PSG in children
(Wise et al., 2011). Snoring is highly The validity of unattended home PSG for
associated with OSAS and, although the diagnosing OSAS in children has not been
presence of snoring does not always imply studied. When performed in children aged
OSAS, its intensity is correlated with the 5–12 yrs, 91% of unattended home PSGs are
severity of OSAS. Conversely, the absence of interpretable. Sensors were installed by
snoring does not exclude OSAS. Breathing professionals at home 1 h before bedtime.
pauses may be unrecognised by parents as Children were supervised by parents, of
they are predominant in REM sleep, which whom 46% said they had not slept at night.
often occurs late at night. Airflow is the signal most frequently lost.
A limited number of paediatric sleep In summary, at this time, there is no

questionnaires are available; some explore evidence supporting the idea that the
only respiratory symptoms (Brouillette ambulatory diagnostic techniques available
questionnaire) whereas the others explore have an acceptable degree of diagnostic
many domains, such as sleep quality, accuracy to replace PSG. There is a need for
hypersomnolence and behaviour. Some assessing these techniques in large
sleep questionnaires are generally in paediatric populations.
accordance with PSG results, but are not Associated complications OSAS adversely
able to discriminate children with primary affects neurocognition, behaviour, the heart
snoring from those with OSAS or measure and circulation, and growth and
the severity of OSAS. The ESS, which is metabolism, resulting in increased
widely used in adults, has been modified morbidity in affected children.
and adapted for children by changing the
nature of diurnal activities. However, this The effects of OSAS on neuropsychological
questionnaire has not yet been validated in and cognitive functions have caught much
large paediatric populations and no attention. Early studies reported learning
consensus exists on the cut-off score difficulties or school problems. A large
in children. number of studies have established that

neurocognitive deficits are highly prevalent that failure to thrive may be due to reduced
in children with OSAS. The latter release of growth hormone (caused by sleep
demonstrate memory and attention fragmentation) or increased energy
impairment, executive function impairment expenditure during sleep related to repeated
and lower intellectual quotient compared inspiratory efforts against upper airway
with controls. They may present behavioural obstruction. Finally, it is unclear whether
disorders also, with various degrees of OSAS is associated with insulin resistance
hyperactivity and aggressiveness, in children.
sometimes evolving to attention deficit
Conclusion OSAS is common in children,
hyperactivity disorder. These disorders
but still under-recognised and undertreated.
result in deterioration in learning abilities
There are a number of unaddressed
and school performance. Importantly,
questions on the pathophysiology,
neurocognitive deficits are found to be more
complications, diagnosis and treatment of
pronounced in children with more severe
OSAS in children. There is a need for
OSAS. Moreover, they are found not only in controlled, longitudinal, large-scale studies
children with identified OSAS, but also in in these fields in order to improve
those with primary snoring, i.e. without understanding and care of OSAS in children.
identified apnoeas or hypopnoeas. Finally,
tonsillectomy significantly improves Sleep hypoventilation syndromes
cognition and behaviour of children.
Different factors underlying brain deficits Sleep hypoventilation syndromes include a
have been suggested: hypoxaemia, wide variety of disorders that affect central
especially repeated hypoxaemic swings control of breathing and/or respiratory
overnight that may cause ischaemic injury in mechanics. Alveolar hypoventilation is due
to inadequate ventilation and results in
vulnerable brain regions including the
increased PaCO2 and concomitant
cerebellum and hippocampus, and sleep
hypoxaemia. Whatever the causative
fragmentation. Therefore, a number of
mechanisms, treatment aims to provide
studies show that OSAS is associated with
ventilation support by use of NIV and to
cognitive and behavioural disorders in
target the primary disease when possible.
children .2 yrs of age. No studies are
available on this aspect when OSAS occurs Central congenital hypoventilation syndrome
in infants or toddlers. (CCHS) is the result of congenital failure of
autonomic control of breathing. The
In early cases of OSAS, cor pulmonale with incidence of CCHS is estimated to be one in
heart failure was a presenting symptom. 200,000 (Trang et al., 2005). More than
Now, pulmonary hypertension may be more 90–92% of patients with CCHS harbour
commonly asymptomatic. Recent studies PHOX2B mutations, the most frequent
show that children with OSAS may have being polyalanine expansions. Treatment
systemic hypertension (both diurnal and is currently supportive, by lifelong
nocturnal systolic and diastolic blood ventilatory support.
pressure). More discrete abnormalities can
be observed: loss of wake–sleep modulation CCHS typically presents at birth. Neonates
of blood pressure (which is autonomic with CCHS demonstrate repeated apnoeas,
nervous system-mediated), left ventricular cyanosis during sleep, bradycardia and
remodelling or endothelial abnormalities. despite severe hypoxaemia, fail to increase
Cardiovascular abnormalities correlate with their breathing. PSG shows severe alveolar
desaturation index, suggesting the role of hypoventilation during sleep with shallow
repeated hypoxaemic episodes. breathing and a slow respiratory rate.
Hypoventilation is most severe during sleep,
Failure to thrive was a presenting symptom and especially during NREM sleep, a sleep
of childhood OSAS in early reports. state during which control of breathing
Resolution of OSAS produces significant depends nearly exclusively upon the central
growth rebound. It has been hypothesised carbon dioxide level. The hallmark feature of

CCHS is absent or markedly reduced central sleep quality, frequent awakenings, morning
hypercapnic ventilatory responses. A headaches, concentration problems or
ventilatory deficit persists throughout life. sleepiness during the day, and anorexia at
With increasing age, most patients can breakfast. The frequency of sleep studies
breathe spontaneously while awake. should increase if symptoms progress or
However, 5–10% of them also require lung function changes rapidly. At a
ventilatory support during daytime. minimum, PaO2 and transcutaneous/end-
tidal PCO2 should be monitored; respiratory
Milder CCHS can be diagnosed during events can be better characterised into
childhood or even adulthood, being typically central and obstructive by multichannel
manifested by cyanotic apnoea spells and respiratory monitoring. Arousals can either
unexplained convulsions resistant to be detected by full PSG or by measurement
treatment with a normal EEG, and the ability of autonomic surrogates, such as heart rate
to hold breath for prolonged periods. These variation. Oximetry alone is not sufficient to
presentations have been associated with fully exclude nocturnal hypoventilation, but
short expansion mutations containing 25 an overnight mean SpO2 of o93% in a child
alanine repeats (Weese-Mayer et al., 2010). who has slept well and who is entirely
Neuromuscular and related conditions asymptomatic makes significant nocturnal
Contrary to CCHS, ventilatory drive is hypoventilation, requiring ventilatory
usually well preserved in neuromuscular support, unlikely (Hull et al., 2012). The
disorders. Instead, alveolar hypoventilation treatment for children with symptomatic
occurs as weak respiratory muscles cannot nocturnal hypoventilation is positive
withstand the work of breathing. In pressure ventilation, usually NIV.
Duchenne muscular dystrophy, congenital
muscular dystrophies and myopathies,
inspiratory and expiratory muscle weakness
Further reading
usually progress in tandem. In spinal
muscular atrophy, expiratory muscle N Aurora RN, et al. (2011). Practice para-
weakness may initially outstrip expiratory meters for the respiratory indications for
muscle weakness. Scoliosis and upper polysomnography in children. Sleep; 34:
airway obstruction can add to the 379–388.
mechanical load. Hypoventilation occurs N Hull J, et al. (2012). British Thoracic
first in REM sleep and then progresses to Society guideline for respiratory manage-
NREM sleep, and finally to diurnal ment of children with neuromuscular
hypoventilation if the vicious cycle is not weakness. Thorax; [Epub ahead of print
addressed. A forced vital capacity of ,60% DOI: 10.1136/thoraxjnl-2012-201964].
predicted and raised serum bicarbonate N Redline S, et al. (2007). The scoring of
level are simple screening tools for respiratory events in sleep: reliability and
nocturnal hypoventilation, and probably validity. J Clin Sleep Med; 3: 169–200.
N Trang H, et al. (2005). The French
more useful than direct measurements of
Congenital Central Hypoventilation
respiratory muscle strength (Hull et al.,
Syndrome Registry: general data, pheno-
2012). Cough peak flow is a useful measure type, and genotype. Chest; 127: 72–79.
of cough efficacy. Children over ,10 yrs of N Weese-Mayer D, et al. (2010). An official
age with a cough peak flow of ,270 L?min-1 ATS clinical policy statement: congenital
are at risk of difficulty clearing secretions central hypoventilation syndrome. Am J
and have an increased rate of chest Respir Crit Care Med; 181: 626–644.
infections. Sleep studies should be carried N Wise MS, et al. (2011). Executive
out annually in children with a vital capacity Summary of respiratory indications for
of ,60% pred, as well as in those who have polysomnography in children: an evidence-
lost ambulation or who have any symptoms based review. Sleep; 34: 398A–398AP.
of nocturnal hypoventilation such as poor

Comorbid respiratory
disorders in children
Anita K. Simonds
In children with chronic lung disease (Meijer et al., 1995). Circadian variation in
associated with limited pulmonary reserve, lung function including reduction in peak
the normal physiological changes in sleep flow during sleep, decreased lung volume,
can cause significant gas exchange and possible allergen exposure to dust mites
abnormalities. Furthermore, these episodes in bedding, are factors. Nocturnal asthma is
can fragment sleep, as can problems with associated with impaired attention and
cough, wheeze, nasal blockage, chest wall cognitive performance in the day which
asynchrony and side-effects from medication improve on optimising asthma control.
(Gaultier, 2000), with consequent adverse Enhancement of mood and improvement in
effects on daytime function. daytime behaviour can also be achieved
after interventions to improve nocturnal
Asthma
asthma control (Stores et al., 1998).
Sleep disturbance is common in children However, some deficits may remain in
with asthma; both objective and subjective children with well-controlled asthma. This is
measures confirm decreased total sleep likely to be related to the fact that therapies,
time, and increased nocturnal awakenings. such as corticosteroids and theophylline,
Reduced slow-wave sleep and increased cause sleep disruption and there are case
daytime sleepiness may occur. In a survey of reports of insomnia as a side-effect of
8–9-yr-old children, 32.6% of those with leukotriene inhibitors. The situation is
asthma reported sleep disturbance at least complicated by the fact that asthma is an
once a week and one-third experienced independent risk factor for SDB in children.
nocturnal cough once a week or more Redline et al. (1999), showed that a history
of asthma was associated with an odds ratio
of 3.83 (95% CI 1.39–10.55) for SDB, whereas
Key points the odds ratio for persistent wheeze was 4.71
(95% CI 1.3–16.76), with both ratios
N Chronic respiratory disorders such as adjusted for race and obesity. The
cystic fibrosis and interstitial lung underlying mechanisms are speculative.
disease can be associated with OSA/H syndrome is associated with swings
worsening gas exchange overnight. in intrathoracic pressure which may provoke
N Asthma and rhinitic symptoms can reflux and increased bronchial
fragment sleep. hyperreactivity, and heighten cholinergic
tone. Furthermore, improved asthma
N Asthma is an independent risk factor control was seen in asthmatics with OSA/H
for SDB. treated with CPAP therapy. The dynamic is
N Improvement in control of asthma likely to be complex and bidirectional, as
and rhinitis usually leads to an sleep deprivation can worsen OSA/H, and
improvement in sleep quality. both asthma and OSA/H are associated with
activation of pro-inflammatory cascades.

Allergies desaturation during sleep and daytime
oxygenation or pulmonary function. Arterial
Rhinitis Allergic rhinitis, nasal blockage, blood gas tensions during wakefulness are a
postnasal drip and sinusitis can cause poor reasonable guide in that CF patients with a
sleep quality and delayed sleep initiation. In diurnal PaO2 ,8 kPa (60 mmHg) spend
a community based study of 7-yr-olds, 60% of total sleep time with SaO2 ,90%,
snoring frequency and loudness showed a whereas those with diurnal PaO2 .9.3 kPa
seasonal variation, peaking in spring and (70 mmHg) spent only 20% of sleep time
summer, suggesting that both allergens and with SaO2 ,90%. Arousals during sleep may
viral aetiology play a role. Allergy is strongly be related to SDB, but more prolonged
associated with SDB (Storms, 2008), in one episodes are often related to coughing
study of children who habitually snored, spasms. In general, the main form of SDB is
39% had evidence of allergy which is around nocturnal hypoventilation; rarer obstructive
three times the norm. Intranasal events may be due to polyps or rhinosinusitis.
corticosteroids are first-line therapy for
moderate-to-severe and perennial allergic The indications for oxygen therapy or
rhinitis. Antihistamines reduce sneezing and ventilatory support during sleep in CF are
rhinorrhoea but may not be as effective as not precisely defined. Oxygen therapy is
intranasal corticosteroids at reducing nasal used in those with diurnal hypoxaemia. In
obstruction. In an open study of children those with nocturnal hypoxaemia alone, it
with allergic rhinitis, arousal frequency was may improve cognitive function and school/
significantly reduced by intranasal work attendance, but most of these studies
budesonide with reported improvements in have been in young adults. Significant CO2
sleep quality and rhinitis symptoms. Allergy retention is unlikely in hypoxaemic patients
control measures are also likely to be who are normocapnic during the day, but
beneficial. Any child with persistent rhinitis with more advanced disease marked
should be closely examined for adenoidal nocturnal hypoventilation with high CO2
and tonsillar hypertrophy. levels can be seen. In this situation the use
of nocturnal NIV may bridge the patient to
Cystic fibrosis Nocturnal arousals, poor sleep
transplantation, or can be used to enable
efficiency and decreased REM sleep
optimal oxygenation without worsening
duration are associated with disease severity
PaCO2, and achieve a reduction in associated
in cystic fibrosis (CF), and worsen at the
symptoms such as morning headaches and
time of infective exacerbations. Sleep
sleep fragmentation.
disturbance is related not only to chronic
lung disease but also to the frequent Interstitial lung disease Chronic interstitial
presence of chronic sinusitis and nasal lung disorders are rare in childhood. As a
polyps. Nocturnal hypoxaemia in CF has rule, chronic hypoxaemia during the day
been demonstrated for decades. worsens during sleep with the nadir
Desaturation is most pronounced during occurring in REM sleep. Oxygen flow rate
REM sleep due to a combination of may, therefore, need to be increased
ventilation/perfusion imbalance and overnight. Progressive hypoventilation may
hypoventilation. A decrease in tonic be seen in advanced lung disease. This can
diaphragm and intercostal muscle tone be a challenging situation to address in
leads to a decrease in end-expiratory lung those with obliterative bronchiolitis
volume which in turn causes closure of complicating transplantation. Here
dependent areas of lung (Muller et al., profound desaturation and hypercapnia can
1980). In addition, REM sleep is associated be seen due to extreme ventilation/perfusion
with a decrease in ventilatory drive, and mismatch and hypoventilation. NIV and
arousal mechanisms. While SDB is seen in supplemental oxygen therapy may reduce
adolescents and young adults with more symptoms of SDB, but are unlikely to reduce
advanced CF lung disease, there is only a daytime breathlessness. When setting the
weak correlation between the extent of ventilator care must be taken not to induce

high inspiratory airway pressures as the the small subset with nocturnal
risk of barotrauma and pneumothorax hypoventilation and CO2 retention that
is increased. might benefit from NIV.
Bronchopulmonary dysplasia/chronic lung
disease A US study showed that 10% of Further reading
infants weighing 1,500 g at birth developed
N Gaultier C. (2000) Effects of breathing
bronchopulmonary dysplasia (BPD), during sleep in children with chronic lung
whereas this rose to over 80% in those disease. In: Loughlin GM, Carroll JL,
weighing ,800 g. Hypoxaemia during the Marcus CL, eds. Sleep and Breathing in
day can worsen during sleep due to further Children. New York, Marcel Dekker; pp.
derangements in pulmonary mechanics and 661–689.
hypoventilation. This can be seen even in N Katz-Salamon M, et al. (1995). Blunted
those with SaO2 .93% on air during peripheral chemoreceptor response to
wakefulness. REM sleep-related hyperoxia in a group of infants with
disturbances cause sleep disruption and bronchopulmonary dysplasia. Pediatr
when supplemental oxygen therapy is Pulmonol; 20: 101–106.
provided sleep quality and duration may N Meijer GG, et al. (1995). Frequency of
improve through lengthening of REM sleep nocturnal symptoms in asthmatic chil-
period. Chest wall asynchrony during sleep dren attending a hospital out-patient
and desaturation have been associated with clinic. Eur Respir J; 8: 2076–2080.
changes in heart rate variability and N Muller NL, et al. (1980). Mechanism of
hemoglobin desaturation during rapid-
significant impairment of right ventricular
eye-movement sleep in normal subjects
function with a lesser effect on left
and patients with cystic fibrosis. Am Rev
ventricular function. In infants with BPD, Respir Dis; 121: 463–469.
ventilatory control including hyperoxic N Redline S, et al. (1999). Risk factors for
ventilatory response can be abnormal or sleep-disordered breathing in children.
absent (Katz-Salamon et al., 1995). This is Assocations with obesity, race and
probably the consequence of repeated respiratory problems. Am J Respir Crit
episodes of hypoxaemia, but adds a further Care Med; 159: 1527–1532.
layer of vulnerability and to the risk of N Stores G, et al. (1998). Sleep and
sudden infant death. psychological disturbance in nocturnal
asthma. Arch Dis Child; 78: 413–419.
In BPD and chronic lung disease the aim is N Storms W. (2008). Allergic rhinitis-
to increase mean SaO2 to .92% overnight induced nasal congestion:its impact on
and normalise as far as possible. sleep quality. Prim Care Resp J; 17: 7–18.
Transcutaneous CO2 monitoring will identify

Nonrespiratory conditions in
children
Ha Trang, Michel Lecendreux and Eric Konofal
Children present a large range of sleep Narcolepsy and other hypersomnias

problems, including SDB and, even more
frequently, nonrespiratory disorders, such as Hypersomnias of central origin are a rare
hypersomnias, insomnias and parasomnias. cause of excessive daytime sleepiness (EDS)
These sleep disorders adversely affect health but should be considered in children and
in children and may differ greatly with regard adolescents as well as in adults. Narcolepsy,
to diagnosis and management. A with or without cataplexy, remains the most
comprehensive understanding of specific well studied of the primary hypersomnias.
physiopathological mechanisms and Narcolepsy is a chronic and disabling
disorder affecting sleep and wakefulness,
therapeutic strategies is required in order to
which is characterised by EDS, sudden sleep
optimise diagnosis and management of
episodes and attacks of muscle atonia
these patients. Indeed, clinicians should be
mostly triggered by emotions (cataplexy)
able to identify these nonrespiratory sleep
(Challamel et al., 1994). Narcolepsy with
disorders, which may be diagnosed as a
cataplexy is a rare disorder with a prevalence
primary sleep disorder or be associated with
estimated at 56 per 100,000 in the general
SDB in a number of cases. Here we will
population. The prevalence of the disorder
focus on narcolepsy, which is one of the
in children remains unknown; however,
well-studied hypersomnias, and attention based on studies conducted in the USA, the
deficit hyperactivity disorder (ADHD), which disorder could affect 0.02–0.05% of the
is one of the most common sleep-related paediatric population (Longstreth et al., 2009).
behavioural disorders.
Narcolepsy is a lifelong disorder, the
occurrence of which during childhood is
Key points frequent. The occurrence of the disorder
during childhood and adolescence should
N Nonrespiratory sleep disorders are be taken into consideration. Narcolepsy in
treatable in children. children and adolescents is still
N Excessive daytime sleepiness is not underdiagnosed and is often mistaken in its
a common symptom in children onset for other diseases or even neglected.
with SDB. Based on clinical experience, young patients
affected by the disorder often show dramatic
N Excessive daytime sleepiness is a and abrupt impairment in their social skills
common symptom in narcolepsy. and academic performance due to EDS,
N Children with iron deficiency can fatigue and lack of energy. Symptoms may
develop sleep disorders such as RLS start abruptly and sometimes very
or PLM syndrome. dramatically, with the occurrence of sudden
and complete cataplexy, or progressively
N Sleepiness or drowsiness is and insidiously, with EDS, weight gain or
commonly reported in children with precocious puberty being the only
ADHD with predominant inattention. symptoms over weeks or months; this leads
to difficulties in recognising the condition or

making the diagnosis difficult at an early many cases, soon after the diagnosis is
stage. Indeed, if cataplexy is the most specific confirmed. Given the long-term nature of
symptom of the disorder, it is usually not the the treatment, the disease must be
first symptom to appear. EDS appears initially diagnosed and assessed as precisely as
in the majority of patients and cataplexy may possible before medication-based therapy is
manifest within 1–5 yrs. initiated (Lecendreux et al., 2008).
For instance, in our own cohort (Paris, For those children who will receive
France), all of the patients (100%) pharmacotherapy from a very young age, but
complained of EDS, which was the first also in adolescents, training and education
symptom to occur (97% of the cases) are crucial to enhance the benefit of the
besides weight gain. Clear-cut cataplexy was treatment. Having to be treated on a daily
reported or observed in 82% of the cases at basis represents a challenge for many
the first evaluation. Furthermore, hypnologic youngsters, who may be reluctant to take
hallucinations and sleep paralysis were medication every day. Most medications are
reported in 33% of the subjects. prescribed during the daytime period and
given during main meals. However, recent
Narcolepsy is believed to be caused by the treatments, such as sodium oxybate,
selective loss of a population of although not yet approved in children and
hypothalamic neurons producing the adolescents, are given at bedtime and 4 h
neuropeptide hypocretin-1 (Nishino et al., after sleep onset, requiring specific and
2000). Since 1983, it has been demonstrated operant strategies from the child as well as
that narcolepsy is associated with the efficient supervision from the parents (Aran
human leukocyte antigen (HLA) allele of the et al., 2010).
HLA-DQ gene, HLA-DQB1*0602. Because
of this close HLA association, the disorder Although no studies demonstrating their
has been suggested to be autoimmune. In effectiveness are available, measures aimed
August 2010, the Medicinal Product Authority at enabling one or more daytime sleep
(MPA) in Sweden announced a special periods are generally recommended. One to
investigation regarding narcolepsy following two routine naps of 20–30 min increase
the influenza virus A H1N1 outbreak. During daytime wakefulness and psychomotor
the summer of 2010, the MPA received, in performance. Nutritional advice, regular
total, 22 reports of narcolepsy as an adverse meal times and physical activity should also
reaction after (A)H1N1 vaccination. The be encouraged at an early stage in children
reports concern children aged 12–16 yrs and adolescents, in order to avoid weight
where symptoms were compatible with gain and to help maintain regular growth.
narcolepsy, were diagnosed after thorough Counselling or brief psychotherapy is often
medical investigation, and had occurred 1– required to enable the child to accept the
2 months after vaccination. This particular loss of their previous healthy state and
topic is currently under investigation and progressively accept the reality of a disabling
could add to the understanding of the chronic condition.
autoimmune hypothesis of narcolepsy
(Dauvilliers et al., 2010). Idiopathic hypersomnia (IHS) IHS is a
primary hypersomnia. IHS is a rare and
To date, the treatment of narcolepsy has poorly defined sleep disorder, an essential
been essentially symptomatic, with no feature of which is chronic EDS despite
prospect, at the present time, of a definitive undisturbed nocturnal sleep. IHS is difficult
cure or even remission for subjects who are to diagnose in children and adolescents,
obliged to take psychotropic medication on where the condition seems to fluctuate
a long-term basis. Considering the across time and developmental stages. IHS
repercussion of the disorder and its in children may be defined as fulfilling the
dramatic consequences in children and/or following criteria: chronic EDS for
adolescents, medication is often required at .6 months; absence of cataplexy; no other
a very early stage of the disease and, in evident cause of EDS, such as sleep apnoea,

periodic limb movements (PLMs) and The most frequent sleep-related symptoms
insufficient sleep syndrome; delayed sleep observed in children with ADHD are
phase syndrome; and ADHD. IHS may difficulty falling asleep, bedtime resistance,
initiate during childhood or adolescence and night awakenings, restless sleep and
persist into adulthood, and should therefore difficulty awakening in the morning.
be considered as a disabling condition that Difficulties in settling to sleep and delayed
requires appropriate diagnosis and adequate sleep onset have been investigated in
medication (Janácková et al., 2011). children with ADHD through the use of
parental reports or questionnaires
Recurrent hypersomnia Recurrent (Biederman, 2005; Cortese et al., 2006).
hypersomnia is characterised by periodic Disruptive night awakenings, caused by
hypersomnia episodes that last from a few abnormal activity during sleep, PLM
days to several weeks, and which recur syndrome or SDB, have been reported in
weeks or months apart. Cognitive and studies using actigraphy, video monitoring
behavioural disturbances are common, and PSG. In cases of ADHD where the
including confusion, feelings of unreality, results from a number of PSG tests or other
hallucinations, binge eating, hypersexuality, objective studies remain inconclusive, and
irritability and aggressive behaviour (Arnulf difficulties in sleep maintenance, low sleep
et al., 2008). The best characterised form of efficiency and alterations in sleep
recurrent hypersomnia is the Kleine–Levin architecture do not seem indicative of
syndrome, which is mostly described in specific sleep disturbances, there are reports
adolescent males. In adolescent females, of sleep-onset delays, increased motor
hypersomnia may occur in association with activity and deficits in alertness.
the menstrual cycle, often within the first few
months after menarche. Management of sleep problems may
significantly improve the quality of life of
ADHD and other behavioural disorders
children with ADHD. Indeed, some studies
ADHD ADHD is a common have showed that sleep disturbances worsen
neurodevelopmental disorder, with a high ADHD symptoms, associated mood disorders
prevalence of 3–10% in children or both; therefore, treatment of comorbid
(Lecendreux, 2011; Biederman, 2005). sleep disorders and interventions targeted at
ADHD is typically characterised by ensuring adequate sleep may substantially
developmentally inappropriate symptoms of improve daytime ADHD symptoms.
inattention, hyperactivity and impulsivity,
Restless legs syndrome (RLS) RLS is
with onset before the age of 7 yrs and
characterised by uncomfortable leg
impaired functioning in two or more
sensations with an irresistible urge to move
settings (e.g. at school and at home).
the legs. Because children have limited
Laufer et al. (1957) were the first clinicians to ability to describe their subjective
report that sleep disturbances could symptoms, diagnosis of RLS may be more
represent a significant source of distress for difficult in this age group. A set of criteria
children with ADHD and their parents. specific for this population has been
Wender (1975) further speculated that these proposed by the International Restless Legs
children had ‘an increased frequency of Syndrome Study Group (Allen et al., 2003).
sleep difficulties: difficulty in falling [asleep]
and remaining [asleep], and early awakening’. The relationship between RLS and ADHD
was recently examined (Allen, 2004). Several
Because any sleep disorder that results in hypotheses have been proposed to explain
short sleep duration, fragmented or disrupted such an association with ADHD or ADHD-
sleep, or EDS can cause problems with mood, like symptoms. Indeed, RLS-associated
attention and behaviour, symptoms of sleep sleep disturbance may cause
disturbances may mimic those of ADHD in inattentiveness, moodiness, and
children incorrectly diagnosed with the ‘paradoxical overactivity’, mimicking
condition (Cortese et al., 2006). symptoms of ADHD. Alternatively,

idiopathic ADHD and RLS can be comorbid SDB in this age group, and subsequent
conditions (Allen, 2004); individuals with difficulties in recognition and in management,
RLS, and some of those with ADHD, might should always inform treatment.
share a common dopamine dysfunction.
It is now accepted that the dopamine system Further reading

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Clinical assessment in
children
Maria Pia Villa
Sleep history and clinical assessment of the infant’s sleeping environment, bedtime
an infant routines and parental expectations.
Insomnia due to medical conditions is
Sleep problems during infancy (ranging mainly caused by infant colic; otitis;
from 1 to 12 months of age) are among the gastrointestinal problems, such as
most prevalent problems presented to regurgitations, vomiting, diarrhoea,
paediatricians, in terms of disorders of abdominal cramps and bloating that may be
initiating and maintaining sleep. Insomnia a manifestation of gastrooesophageal reflux;
during infancy may be subdivided into two and cow’s milk allergy or lactose intolerance.
main categories: behavioural insomnia and Information about sleeping arrangements, if
insomnia related to diseases. Behavioural the baby sleeps in the parent’s room or bed,
insomnia commonly occurs in 20–30% of or in an infant crib in a separate room, the
infants, and, if left untreated, bedtime baby’s position while sleeping (on his/her
problems and night awakenings may result back, side or belly) and environmental
in behavioural, emotional, and learning tobacco smoke exposure are very important.
difficulties, persisting into the preschool and Bed routine should be investigated in order
school-aged years. History should focus on to understand if good sleep hygiene is
present. Is it crucial to know the sleep/wake
Key points pattern of the baby, and if the baby has
difficulty falling asleep, or whether frequent
and prolonged night-time awakenings are
N Insomnia during infancy can be
reported by caregivers. Physical examination
classified into: behavioural insomnia
and insomnia related to a specific of an infant with sleep disorders should
medical condition. include an initial visual examination of the
baby, noting any dysmorphic features or
N An ALTE is a frightening and obvious malformations. Height, weight and
unexpected change in an infant’s head circumference measurements should
breathing behaviour that needs a be reported on appropriate growth charts.
careful evaluation. Signs of respiratory infections, or ear and
N PSG is indicated when OSAS or urinary tract infections should be
congenital central alveolar investigated.
hypoventilation syndrome, ALTE,
If a suspected apparent life-threatening
or sleep-related hypoventilation
event (ALTE) has occurred, history should
are suspected.
focus also on the skin colour at the time of
N On physical examination signs the event, duration of the event, sleep
commonly associated with SDB, position and type of sleeping arrangement
such as ‘‘adenoid facies’’, may (chair, lounge, crib, car seat, bed), clothing,
result from oral breathing due to presence of abnormal movements, including
enlarged adenoids. abnormal eye movements, muscle tone,
presence of blood or bloody fluid at the

mouth or nose, vomiting, the relationship of Table 1. Daytime and night-time symptoms suggestive
the event to feeding and the degree of of SDB.
resuscitation required. Finally, relevant past
Night time symptoms
medical history (especially prematurity),
immunisation status, family history of Snoring
sudden unexplained death in infancy or Apnoeas
later, exposure to smoke and metabolic
Nocturnal sweating
disease should be investigated. Heart and
respiratory rate and oxygen saturation must Nightmares
be recorded. Moreover, a careful neurologic Sleep talking
examination and neurobehavioural Bruxism
assessment (e.g. head lag, posturing, motor
Bedwetting
abilities, eye tracking, social smile) should
be performed. Sleepwalking
Restless sleep
Sleep history and clinical assessment of
a child Frequent arousals
Oral breathing
Sleep disturbances such as bedtime
Daytime symptoms
struggles, delayed sleep onset and multiple
night awakenings in children and Sleepiness
adolescents are common and frequently Hyperactivity
associated with both emotional and
Inattention
behavioural difficulties in children and
adolescents (such as anxiety, mood Headache
disorders and attention deficit hyperactivity Learning difficulties
disorders). Sleep disruption affects daytime Oral breathing
functioning, with a significant impact on the
family’s quality of life, and the presence of
SDB needs to be ruled out since the daytime facies’’, characterised by high arched and
consequence and neurobehavioural narrow hard palate, increased facial height
symptoms are the same as paediatric and crossbite, which may result from oral
insomnia (table 1). For this reason, a breathing due to enlarged adenoids. Nasal
detailed clinical history and assessment of a airflow should be assessed by holding a cold
child referred for sleep problems is relevant. spatula or tongue depressor under the nose
Important points in the sleep history should and asking the child to breathe. Misting of
include a complete sleep diary, recording the cold metal indicates airflow. A lack of
sleep patterns (bed-onset and sleep-onset airflow may indicate the presence of
time, number of nocturnal awakenings) on nasopharyngeal obstruction resulting from
weekdays, weekends and changes during enlarged adenoids or nasal obstruction. The
summer. Nocturnal symptoms suggestive of nasal cavity may be examined, using an
gastro-oesophageal reflux, asthma, or pain, appropriate light, for the presence of rhinitis,
presence of snoring or witnessed apnoeas obstructive polyps, enlarged turbinates or
(pauses in breathing) need to be deviated septum. When examining the
investigated. The frequency and patterns of mouth, tonsillar size is usually graded from
snoring, whether it is seasonal or related to 0 (in the case of small tonsils) to 4 (in the
any specific factor, such as upper airway case of enlarged tonsils obstructing at least
infection, are of interest. On physical 75% of the lateral airway dimension).
examination signs commonly associated Moreover, Mallampati score, based on
with SDB need to be evaluated, such as visualisation of the airway on opening of the
obesity or being overweight (assessed by mouth with tongue protruded, is helpful in
elevated age-appropriate BMI) and identifying a small airway, such as the
structural features, known as ‘‘adenoid presence of macroglossia, and of a narrow

and arched palate. Looking at the bite, a cardio-respiratory recording. For the same
crossbite or significant overjet or overbite reasons, even if home oximetry findings may
are signs of maxillary or mandibular be highly specific for OSAS when it is
deficiency. Finally, a patient’s profile may positive, it cannot alone replace PSG
reveal retrognathia or micrognathia. The recordings. When the sleep laboratory is not
presence of glue ear may co-exist with available, appropriate questionnaire,
adenoid hypertrophy. The blood pressure medical examination and home video
should also be taken. Hypertension oximetry is appropriate.
suggests complications of SDB.
Video-PSG recording with an extended EEG
Indications for respiratory and non- channel should be performed if a nocturnal
respiratory investigation seizure is suspected or if parasomnias,
abnormal movements during sleep, are
Further investigation should be performed reported, and/or excessive daytime
on the basis of the history and physical somnolence is not related to a sleep apnoea
examination: sleep questionnaires syndrome. The MSLT (that is used to
(investigating sleep pattern and symptoms measure the time elapsed from the start of a
of several sleep disorders) and sleep diary, daytime nap period to the first signs of
are usually completed by the parents. sleep, also called sleep latency) should be
An objective assessment of sleep may be performed in all cases reporting daytime
obtained using actigraphy, if sleep rhythm hypersomnolence, in particular, when
disorders or restless legs syndrome and/or narcolepsy is suspected.
periodic limb movement disorders are
suspected. An actigraph is an accelerometer
that records motion, generally worn on the Further reading
non-dominant wrist. The actigraph provides N Aurora RN, et al. (2011). Practice para-
a noninvasive means to assess patterns of meters for the respiratory indications for
activity that reflect sleep/wake cycles across polysomnography in children. Sleep; 34:
several consecutive days and nights. 379–388.
N Brodsky L. (1989). Modern assessment of
PSG is indicated when the clinical tonsils and adenoids. Pediatr Clin North
assessment suggests the diagnosis of OSAS Am; 36: 1551–1169.
or congenital central alveolar N Guilleminault C, et al. (2007). Adenoton-
hypoventilation syndrome, ALTE, sleep- sillectomy and obstructive sleep apnoea
related hypoventilation due to in children: a prospective survey.
neuromuscular disorders or chest wall Otolaryngol Head Neck Surg; 136: 169–175.
deformities. At this time, attended PSG is N Hall KL, et al. (2005). Evaluation and
the gold standard for the diagnosis of SDB management of apparent life-threatening
as there is not sufficient evidence to suggest events in children. Am Fam Physician; 71:
the use of other diagnostic tools, such as 2301–2308.
unattended complete PSG or simple

Diagnostic techniques in
children
Stijn Verhulst and Wilfried De Backer
Polysomnography recording should be reviewed using

7 mV?mm-1 to display and recognise low
The following recommendations are made voltage faster frequencies.
according to the American Academy of Sleep N EOG: the recommended EOG derivations
Medicine (AASM) Manual for the Scoring of are E1-M2 and E2-M2. E1 is placed 1 cm
Sleep and Associated Events (Iber et al., 2007). below the left outer canthus and E2 1 cm
Sensors above the right outer canthus. For smaller
children, this distance could be reduced
N EEG: the EEG electrode position is to 0.5 cm. Alternative derivations are E1-
determined by the international 10–20
system. The recommended derivations Fpz and E2-Fpz (the eye electrodes are now
are F4-M1, C4-M1 and O2-M1. Backup placed 1 cm below and lateral to the outer
electrodes should be placed at F3, C3, O1 canthus of the left and right eye). The
and M2 to allow display of F3-M2, C3-M2 alternative derivations record the
and O1-M2 if electrodes malfunction direction of eye movements.
during the study. Alternative acceptable N EMG: three electrodes should be placed
derivations are FZ-CZ, CZ-OZ and C4-M1 to record chin EMG. One is placed in the
with backup electrodes at Fpz, C3 and O1. midline 1 cm above the inferior edge of
An initial EEG sensitivity of 7 mV?mm-1 is the mandible and the other two are
appropriate but the sensitivity often placed 2 cm below the inferior edge of
needs to be adjusted in infants and the mandible 2 cm to the left and right of
younger children to 10 or 15 mV?mm-1. In the midline. For smaller children, this
the last case, portions of the sleep distance should be reduced to 1 cm.
N A thermistor or nasal air pressure
transducer should be used to
Key points detect apnoea.
N A nasal air pressure transducer without
N The scoring of sleep in infants and square root transformation of the signal
children is dependent on age and should be used for detection of
central nervous development. hypopnoeas. A thermistor, end-tidal
N As infants and children express a carbon dioxide tension (PCO2) monitor or
higher breathing rate, adult scoring summed calibrated inductance
rules for respiratory events do not plethysmography can also be used.
apply to children. Specific scoring N Acceptable sensors for detection of
rules need to be used. respiratory effort are oesophageal
manometry or calibrated or uncalibrated
N Full PSG is the gold standard. Limited inductance plethysmography.
data exists on the usefulness of Oesophageal manometry is rarely used in
screening methods such as oximetry daily practice because it is too invasive
and cardiorespiratory monitoring.
for use in children.

N Pulse oximetry should be used with a activity, hypnagogic hypersynchrony or a
maximal signal averaging time of 3 s. diffuse or occipital-predominant, high-
N Transcutaneous or end-tidal PCO2 amplitude rhythmic 3–5 Hz activity.
monitoring is used for assessing Hypnagogic hypersynchrony consists of
alveolar hypoventilation. paroxysmal bursts or runs of diffuse high
amplitude sinusoidal, 75–350-mV,
Scoring EEG in an infant/child These 3–4.5-Hz waves, which begin abruptly and
paediatric sleep scoring rules can be used to are usually widely distributed, but often
score sleep and wakefulness in children maximally expressed, over the central,
aged 2 months post-term and older. Sleep is frontal or fronto-central scalp regions.
divided into the following stages in children: N Stage N2 starts if one or both of the
stages W (wakefulness), N1, N2, N3 and R. following occur during the first half of the
Stages N1, N2 and N3 are sleep stages of epoch or the last half of the previous
NREM sleep. Stage R is a sleep stage of epoch: one or more K complexes not
REM sleep. Sleep is scored according to 30-s associated with arousals or one or more
epochs commencing at the start of the trains of sleep spindles. One can
study. A stage is assigned to each epoch. If continue to score epochs with low-
two or more stages co-exist during a single amplitude, mixed-frequency EEG activity
epoch, the stage that comprises the greatest without K complexes or sleep spindles as
part of the epoch should be assigned. long as it is preceded by K complexes not
associated with arousals or sleep spindles.
N Stage W: .50% of the epoch should have N Stage N3 can be scored when at least
a rhythm or the age-appropriate 20% of an epoch consists of slow-wave
dominant posterior rhythm over the activity. Sleep spindles may persist in
occipital region. The dominant posterior this stage.
rhythm is a dominant reactive EEG N Stage R can be scored in epochs with all
rhythm over the occipital regions in of the following: a low-amplitude, mixed-
relaxed wakefulness with eyes closed, frequency EEG, low chin EMG tone and
which is slower in infants and young rapid eye movements. One can continue
children and attenuates with eye opening to score epochs if the EEG continues to
or attention. The frequency is 3.5–4.5 Hz show low-amplitude, mixed-frequency
when first seen in infants aged activity without K complexes or sleep
3–4 months post-term, 5–6 Hz by age spindles and if the chin EMG remains low.
5–6 months and 7.5–9.5 Hz by 3 yrs of N A major body movement is defined as
age with an amplitude of .50 mV. In movement and muscle artefacts
epochs without visually discernible a obscuring the EEG for more than half of
rhythm or age-appropriate dominant the epoch to the extent that the sleep
posterior rhythm, stage W can be scored stage cannot be determined. An epoch
when there are eye blinks at a frequency with a major body movement should be
of 0.5–2 Hz, reading eye movements or scored as stage W if a rhythm is present,
irregular conjugated eye movements or if no a rhythm is discernible but an
associated with normal or high chin epoch scored as stage W either precedes
muscle tone. or follows the epoch. Otherwise, the
N Stage N1 can be scored if the posterior epoch should be scored as the same
rhythm is attenuated and replaced by low stage as the epoch that follows it.
amplitude, mixed-frequency activity for N An arousal is defined as an abrupt shift of
.50% of the epoch. In subjects who do EEG frequency including a, h and/or
not generate a posterior rhythm, stage N1 frequencies .16 Hz (but not spindles)
is defined with the onset of EEG activity that lasts at least 3 s with at least 10 s of
in the range of 4–7 Hz with slowing of stable sleep preceding the change.
background frequencies by o1 Hz from Scoring of an arousal during REM sleep
those of stage W, vertex sharp waves, requires a concurrent increase in
slow eye movements, rhythmic anterior h submental EMG lasting at least 1 s.

The terms quiet and active sleep are also spindles are present in infants aged
used when scoring infant sleep. Quiet sleep 2–3 months post-term or older, while K
is characterised by tracé alternant or high- complexes are usually present in infants
voltage slow-wave activity. Tracé alternant is aged 4–6 months or older. Slow-wave
an EEG pattern in which 3–8-s bursts of activity usually develops by 4–5 months
moderate-to-high voltage slow waves post-term. On average, NREM sleep can be
intermixed with sharply contoured scored as stage N1, N2 and N3 by
waveforms alternate with 4–8 s intervals of 5–6 months post-term or older. In view of
attenuated mixed-frequency EEG activity. the variability of sleep in infants, four
High-voltage slow-wave activity consists of possible scenarios are described.
continuous moderately rhythmic 50–150-mV,
0.5–4-Hz slow activity without the bursting 1. If all epochs of NREM sleep contain no
activity of tracé alternant. Active sleep recognisable sleep spindles, K
consists of either low-voltage 5–6-Hz EEG complexes or slow-wave activity, score
activity called activité moyenne or a mixture all epochs of NREM sleep as stage N.
of high- and low-voltage activity including d 2. If some epochs of NREM sleep contain
sleep spindles or K complexes, score
activity called mixed. The AASM task force
these epochs as stage N2. If there is
recommends that sleep in infants o2 months
no recognisable slow-wave activity in
post-term should be scored as NREM and
the other epochs, score as stage N.
REM, because all the EEG and PSG features of
3. If some epochs of NREM sleep contain
REM sleep are present at this age and quiet
.20% of slow-wave activity, score
sleep, if not NREM sleep by this age, is at least
these epochs as stage N3. If there are
not REM sleep. This generally holds for most
no recognisable K complexes or sleep
full-term infants as well.
spindles in the other epochs, score as
Sleep is undifferentiated before 32 weeks stage N.
conceptional age (CA). At approximately 4. If NREM is sufficiently developed and
32 weeks CA, rapid eye movements and some epochs contain sleep spindles or
phasic muscle twitches identify active sleep K complexes and other epochs contain
while quiet sleep is associated with the sufficient slow-wave activity, then
presence of far fewer movements. score NREM sleep according to the
Recognisable EEG patterns of active and paediatric rules.
quiet sleep appear around 34 weeks CA. By Scoring breathing in an infant/child The
36 weeks CA, all the EEG and behavioural paediatric rules can essentially be used in
correlates of wakefulness, active and quiet children f18 yrs of age. However, a sleep
sleep are clearly recognisable, although a specialist can decide to use the adult rules
large proportion of sleep is scored as in a child aged 13 yrs or older depending on
indeterminate sleep. This is defined when the clinical context. The following definitions
mixtures of more than two sleep/wake states are used.
are seen within an epoch. The percentage of
indeterminate sleep declines rapidly after N Obstructive apnoea: the event lasts for at
36 weeks CA. Non-EEG correlates are often least two missed breaths or the duration
needed in the distinction between quiet and of two breaths as determined by the
active sleep in young infants. Active sleep is baseline breathing pattern. The event is
typically associated with irregular associated with a .90% fall in the signal
respiration, chin EMG atonia, transient amplitude for o90% of the entire
muscle activity and rapid eye movements. respiratory event compared with the
Regular respiration, no or vertical eye pre-event baseline amplitude, and the
movements and preserved chin EMG are all event is associated with continued or
associated with quiet sleep. increased respiratory effort throughout
the entire period.
The various factors comprising NREM sleep N If an apnoea, as defined previously, is
need to develop over time in infants. Sleep initially associated with absent respiratory

effort followed by resumption of inspiratory day and day–night differentiation appears
effort before the end of the apnoea, then it from the age of 1 month onwards. The
is classified as a mixed apnoea. majority of infants show a longer
N A central apnoea is associated with undisrupted sleep time of 3–4 h at 3 months
absent inspiratory effort throughout the and sleep ‘‘through the night’’ around
entire duration of the event with a period 9 months of age. They also have two naps
of at least 20 s or of at least two missed lasting 2–4 h. During the first months of life,
breaths, but associated with arousal, the various sleep stages develop and sleep
awakening or o3% desaturation. Central can be completely scored at an average age
apnoeas occurring after a snore, sigh, of 6 months. The percentage of REM sleep
respiratory event or arousal are normal reaches 30% at around the age of 1 yr.
phenomena in children and are not
scored unless associated with arousal, In the preschool period, total sleep time
awakening or o3% desaturation. further diminishes to 12 h per day. These
children usually have one nap per day, which
N Hypopnoea is defined as a o50% fall in
disappears between the ages of 3 and 5 yrs.
amplitude of the nasal pressure or
The percentage of REM sleep decreases
alternative signal with the duration of at
(to 20–25%) and stage N3 increases. The
least two missed breaths (or the duration
sleep cycle length slowly increases towards
of two breaths as determined by the
adult levels.
baseline breathing pattern). The fall in
amplitude must last for o90% of the School-age children have an average total
entire respiratory event and the event is sleep time of 11 h and adolescents typically
associated with an arousal, awakening or have 9–10 h of sleep. REM latency
o3% desaturation. increases. The percentage of stage N3
N Respiratory effort-related arousal (RERA): increases until adolescence after which it
there is a discernible fall in the amplitude steadily decreases to adult levels.
of signal from a nasal pressure sensor
but ,50% compared with the baseline In healthy infants, central apnoeas
level with a flattening of the nasal frequently occur but are of short duration
pressure waveform. Furthermore, it is and are not followed by bradycardia or
accompanied by snoring, noisy breathing, oxygen desaturation. REM sleep is
elevation in PCO2 or visual evidence of associated with a higher incidence of central
increased work of breathing which lasts at apnoeas. Obstructive and mixed apnoeas
least two breath cycles. are less frequently seen. The optimal
N Sleep-related hypoventilation is defined definition of an obstructive event,
when CO2 levels are .50 mmHg as particularly hypopnoeas and RERAs has not
measured by transcutaneous or end-tidal been established in infants. Most studies
CO2 sensors for .25% of total sleep time. have reported only obstructive and mixed
N Periodic breathing is defined if there are apnoeas, using thermistor-based studies.
more than three episodes of central Obstructive apnoea or mixed apnoea
apnoea lasting .3 s separated by no appears to be more common in premature
more than 20 s of normal breathing. infants and decreases in frequency over the
first year of life. Studies have shown that, in
Normative data in an infant/child Neonates general, the obstructive apnoea index is
express a high percentage of REM sleep, below 1 event?h-1 in the first year of life both
accounting for 50–60% of total sleep time. in full-term and in pre-term infants
This percentage is even higher in premature Guilleminault et al., 1979; Hoppenbrouwers
infants. Infants can also enter sleep in REM. et al., 1993). Obstructive events are associated
Total sleep time for neonates ranges with a much greater decline in oxygenation
between 16 and 20 h per day and they and heart rate compared with central apnoeas
express no day–night differentiation. A sleep of equal lengths. During the first year of life,
cycle typically lasts 40 min. In the first year the number of central apnoeas decreases.
of life, total sleep time decreases to 14 h per Periodic breathing normally disappears in the

first 6 months of life. The median baseline sometimes use different definitions for the
oxygen saturation during sleep in a term infant various respiratory events. Therefore, sleep
at birth is approximately 98% and the median centres should keep this in mind when
low is 83%. Short desaturations can be selecting their diagnostic criteria. OSA in
observed in infants during periodic breathing, children is commonly diagnosed with an
following normal respiratory pauses and obstructive apnoea index o1 event?h-1 and/
during REM sleep. or an obstructive AHI o2 events?h-1.
During childhood and adolescence, central Cardiorespiratory monitoring in children

apnoeas can still occur although at a lower
frequency that decreases with age. Home-based and portable monitoring
Obstructive and mixed events are rarely studies offer a potentially very interesting
seen. Mean saturation during sleep is approach to study sleep and breathing in
approximately 97% with a mean nadir o90%. children in their home environment.
Although a number of validation studies and
Interpretation and report of PSG in an infant/ a consensus statement have been published
child Studies have shown that a single-night in the adult literature, data are scarce in the
PSG is sufficient to diagnose sleep apnoea paediatric field. The findings in adults
in children. However, when sleep cannot be extrapolated to children because
architecture is the primary outcome, two of the marked differences in frequency and
nights are often necessary to overcome the severity of breathing pauses during sleep.
first-night effect. A PSG report should One pilot study in 11 adolescents with
indicate the equipment and sensors used. Duchenne muscular dystrophy showed that
Furthermore, it should indicate whether the portable monitoring correctly identified the
child is using any medication. It should start three adolescents with an abnormal sleep
at the child’s regular bedtime. Time of study (Kirk et al., 2000). In spite of the lack
waking up in the morning should be of validation studies, several research
indicated so that the total time in bed can be papers have been published that have used
calculated. The reported sleep parameters a portable diagnostic system to study sleep
are: time in bed, total sleep time, sleep and breathing in children. Therefore, no
efficiency, sleep onset latency, wake after clear recommendations can be made on the
sleep onset, REM latency, time and clinical usefulness and cost-benefit ratio of
percentage of total sleep time spent in stage portable monitoring in the diagnosis of SDB
N1, N2, N3 and REM, movement time, in children.
periodic limb movements and arousal index.
Abnormal EEG readings should also be Oximetry
reported. Respiratory variables include
number of central, obstructive and mixed Oximetry is used to detect sleep-related
apnoeas, hypopnoeas, RERAs and the desaturations and hypoxaemia and is a very
presence of snoring. Sleep-stage distribution easy technique suitable for home monitoring.
and position-related distribution of these However, normal sleep oximetry does not rule
respiratory events should be noted. The out OSA, because many obstructive events
number of desaturations with SaO2 nadir are not associated with desaturation in
should be recorded as well as the average children. Therefore, it is only useful for the
saturation during sleep and a saturation identification of the subset of patients with
histogram. Similarly, transcutaneous or end- more severe OSA with marked desaturations
tidal PCO2 levels should also be recorded. during sleep. Furthermore, no large-scale
Average, minimum and maximum heart rate studies have been performed to identify other
and respiratory rate should also be calculated. possible limitations. A validation study
reported a positive predictive value of ,100%
Diagnostic thresholds for OSA in children in children with a history of snoring. However,
are based on normative PSG values in the negative predictive value was very low
children. It is important to note that these (Brouillette et al., 2000). Therefore, in children
studies differ in patient selection criteria and with a suggestive clinical history and physical

examination but with a normal oximetry, a full- last nap effect (increased arousal because of
night PSG is still necessary. Finally, oximetry the anticipation of almost going home) and
does not rule out the contribution of central the influence of patient motivation.
apnoeas or other respiratory diseases to
hypoxaemia. This also requires PSG. In recent The MWT is indicated to assess the efficacy
years, studies have emerged that have of treatment in patients. It can be considered
combined oximetry with ECG signal and as the opposite test of MSLT and measures
derived signals such as the pulse transit time, the ability to stay awake for a defined time. It
which could also allow the detection of consists of four trials of a 40-min test
arousals and showed promising results. protocol performed at 2-h intervals with the
first trial beginning 1.5–3 h after the patient’s
Assessment of daytime sleepiness usual wakeup time. It has an identical
recording montage as MSLT. Normal values
MSLT and MWT: scoring rules and normative
of MWT are .30 min and the test is
data The MSLT is a valid and widely used
abnormal when it is ,12 min. Paediatric
test to measure the tendency to fall asleep
and offers an objective measure of daytime normative values are not available.
sleepiness. MSLT is performed after a full Motivation to stay awake is very important for
night PSG that should show at least 6 h of a reliable interpretation of this test.
sleep. MSLT is performed by allowing five
nap opportunities lasting 20 min each at 2-h
intervals. Sleep stages are scored according Further reading
to standard rules. Parameters of interest N American Thoracic Society. (1996).
include sleep latency defined as the time Standards and indications for cardiopul-
from lights out to stage N1. Sleep-onset monary sleep studies in children. Am J
REM periods (SOREMPs) are defined by Respir Crit Care Med; 153: 866–878.
REM onset within 15 min of sleep onset. The N Brouillette RT, et al. (2000). Nocturnal
mean sleep latency over the five naps is an pulse oximetry as an abbreviated testing
objective index of severity of sleepiness. modality for pediatric obstructive sleep
apnea. Pediatrics; 105: 405–412.
Normative values in children are less well N Gozal D, et al. (2001). Objective sleepi-
defined than in adults, but normal school- ness measures in pediatric obstructive
aged children typically remain awake sleep apnea. Pediatrics; 108: 693–697.
throughout the nap opportunity, or N Grigg-Damberger M, et al. (2007). The
demonstrate mean sleep latency in the visual scoring of sleep and arousal in
15–20 min range. Prepubertal children have infants and children. J Clin Sleep Med; 3:
longer mean sleep latency while adolescents 201–240.
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a mean sleep latency .20 min in obstructive sleep apnea and near miss for
prepubertal children (Gozal et al., 2001; sudden infant death syndrome: 2. Com-
Palm et al., 1989). Therefore, 30-min naps in parison of near miss and normal control
children have been proposed on a research infants by age. Pediatrics; 64: 882–891.
N Hoppenbrouwers T, et al. (1993).
basis. A sleep latency of 5–10 min indicates
Obstructive apnea, associated patterns
moderate daytime sleepiness, whereas
of movement, heart rate, and oxygenation
f5 min indicates severe sleepiness. The in infants at low and increased risk for
presence of two or more SOREMPs SIDS. Pediatr Pulmonol; 15: 1–12.
combined with low mean sleep latency is N Hunt CE, et al. (1999). Longitudinal
considered diagnostic for narcolepsy. assessment of hemoglobin oxygen
However, the physician should remain alert saturation in healthy infants during the
for other factors that might disrupt sleep first 6 months of age. Collaborative
architecture including OSA, periodic limb Home Infant Monitoring Evaluation
movement disorders or insufficient sleep. (CHIME) Study Group. J Pediatr; 135:
Further limitations of MSLT are the lack of 580–586.
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Management of sleep
disordered breathing in
children
Athanasios Kaditis, Maria Pia Villa, Anita K. Simonds and Ha Trang
Untreated OSA may be related to delayed diagnosed and treated in order to prevent
somatic growth, learning problems, daytime the development of complications.
sleepiness, hyperactivity and adverse effects
Apnoeas in infants
from the cardiovascular system such as
hypertension. Thus, it is of importance that Apnoea of prematurity and OSA unrelated to
respiratory disorders during sleep are prematurity are the most common SDB
patterns in infancy that have been described.
Apnoea of prematurity (gestational age
,37 weeks) has been defined as pauses in
Key points
airflow of at least 20 s in duration, or shorter
but accompanied by oxygen desaturation of
N A variety of interventions are used for haemoglobin and bradycardia. Apnoeas may
the treatment of OSA in infancy, such be of the central, obstructive or mixed type
as methylxantines, and they usually disappear by 36–40 weeks
adenotonsillectomy, orthodontic postconceptional age.
appliances, CPAP and tracheostomy.
It is unclear whether apnoea of prematurity
N Adenotonsillar hypertrophy is a
has long-term adverse effects, such as
frequent cause of OSA in otherwise
unfavourable neurodevelopmental
healthy children, but fewer than 30%
outcomes, because of the many other
of them achieve a normal AHI
confounding factors in the early pre-term
(,1 event?h-1) after
period. After secondary causes of apnoea
adenotonsillectomy.
are excluded (i.e. infection, intracranial
N Oral appliances and functional haemorrhage, hypoxaemic-ischaemic
orthopaedic devices are effective in encephalopathy, seizure disorder, anaemia),
cases of maxillary constriction or potential therapeutic interventions are prone
mandibular retrusion with positioning with neck elevation by 15u,
associated OSA. administration of methylxanthine
(theophylline, caffeine), CPAP and nasal
N Long-term home ventilation is required
intermittent positive pressure ventilation
for children with central hypoventilation.
(table 1). Doxapram, kinaesthetic
N NIV in neuromuscular disorders stimulation and red blood cell transfusion in
should be initiated when symptomatic cases of anaemia are among the
nocturnal hypoventilation develops. interventions that have been used for the
treatment of apnoea of prematurity with
N NIV improves quality of life, morbidity
unclear benefit.
and mortality in many stable or
slowly progressive neuromuscular OSA not related to prematurity may be the
disorders, and may be considered to result of a variety of pathogenetic
palliate symptoms in other more mechanisms, i.e. congenital craniofacial
progressive conditions. deformities, nasal or laryngeal obstruction
(choanal atresia, congenital nasal pyriform

Table 1. A stepwise treatment approach for OSA in infants.
1 For history of prematurity (,37 weeks gestational age): exclude infection, intracranial
haemorrhage, hypoxaemic-ischaemic encephalopathy, seizures, anaemia and then use
prone positioning and/or methylxanthine treatment; for mandibular hypoplasia: use prone
positioning or insert a nasopharyngeal tube (e.g. Pierre Robin sequence); for gastro-
oesophageal reflux: antireflux medications.
2 For adenotonsillar hypertrophy (usually age .6 months): adenotonsillectomy (usually age
.12 months).
3 For congenital mandibular hypoplasia (syndromic or non-syndromic): intraoral orthodontic
appliance.
4 CPAP if: 1) history of prematurity (,37 weeks gestational age) and no response to prone
positioning or methylxanthine therapy; 2) OSA and major craniofacial deformities during
the waiting period for a craniofacial procedure; and 3) residual OSA after a craniofacial
procedure.
5 For laryngomalacia: supraglottoplasty; for mandibular hypoplasia: surgical tongue
advancement (i.e. glossopexy via tongue–lip adhesion) or mandibular distraction
osteogenesis; for midface hypoplasia: midface advancement (¡distraction osteogenesis).
6 Tracheostomy if treatment modalities 1–5 are not adequate or to secure the upper airway
while awaiting surgical intervention.
Use nocturnal PSG or oximetry at each step in order to move to the next step if residual
OSA is present.
aperture stenosis, laryngomalacia, vocal old, but most ENT surgeons would operate
cord paralysis, subglottic stenosis), on children older than 1 yr. CPAP may be a
neurological disorders (spinal muscular useful stabilising measure but it is frequently
atrophy, cerebral palsy), gastro-oesophageal tolerated poorly and it is associated with sleep
reflux and adenotonsillar hypertrophy (age disruption. In cases of severe laryngomalacia,
.6 months). Acute viral upper respiratory removal of the lateral edges of the epiglottis
infection may deteriorate the clinical picture and of redundant mucosa covering the
of all the above conditions temporarily. arytenoids along with incision of the
Endoscopic examination of the upper and aryepiglottic folds can relieve upper airway
lower airway is an important diagnostic tool obstruction effectively (supraglottoplasty).
to determine the exact site(s) of obstruction. Tracheostomy is applied to secure the upper
airway while awaiting more permanent
The severity of upper airway obstruction in therapeutic solutions.
infancy requiring treatment has not been
defined. Moreover, there is not always Congenital craniofacial deformities cover a
consensus regarding the type of therapy wide and complex range of diseases, in
indicated in each case, but a stepwise particular affecting newborns and infants
treatment approach moving from the less to and resulting in narrowing of the airway due
the more invasive therapeutic intervention is to midface hypoplasia (e.g.
summarised in table 1 according to the craniosynostosis) and/or mandibular
cause of airway obstruction. hypoplasia (e.g. Pierre Robin sequence).
Adenotonsillectomy for OSA in infants has a Congenital craniofacial deformities can be
higher frequency of post-operative regarded as a model for sleep apnoea in
complications and residual SDB compared infancy, and their high association with OSA
with the same procedure in older children. It suggests that PSG should be performed
is accompanied by appreciable acceleration promptly even if nocturnal symptoms are
in somatic growth. The procedure has been not reported. Cleft lip and/or palate (CL/P) is
performed in infants as young as 5 months a common congenital malformation

affecting approximately two per 1,000 40% of cases, craniosynostosis is part of
newborns worldwide. The Pierre Robin syndromes such as Apert, Crouzon, Pfeiffer,
sequence is a well-defined subgroup of the Muenke or Saethre–Chotzen. Almost 50% of
CL/P population, characterised additionally children with Apert, Crouzon or Pfeiffer
by micrognathia, glossoptosis and upper syndrome develop OSA during the first 6 yrs
airway obstruction and it has a prevalence of of life. Increased risk for OSA is usually the
one per 8,500 newborns. Pierre Robin result of midface hypoplasia, but other
sequence is often part of other Mendelian factors such as adenotonsillar hypertrophy
syndromes such as Stickler’s, or even mandibular hypoplasia may also
velocardiofacial and Marshall’s syndromes, contribute to upper airway obstruction.
or as part of carpomelic dysplasia which is a Surgical procedures for the treatment of
rare skeletal dysplasia. midface hypoplasia are discussed later.
The severity of clinical manifestations in OSA
patients with Pierre Robin sequence may
vary from 1) normal breathing and feeding; The following treatment options are
to 2) normal breathing but with feeding available.
difficulties; and 3) respiratory failure with Tonsillectomy and/or adenoidectomy and other
need for intervention and feeding difficulties
ENT procedures Surgical excision of the
necessitating nutrition via a nasogastric tube.
hypertrophic pharyngeal and palatine tonsils
The most severely affected infants with Pierre
(adenoidectomy and tonsillectomy,
Robin sequence may suffer from intermittent
respectively) is the standard treatment for
hypoxaemia, hypercapnia, cor pulmonale,
OSA in childhood, which reduces upper
failure to thrive, neurodevelopment delay or
airway resistance and the tendency of the
even sudden death.
pharyngeal airway to collapse. It is unknown
Current treatment options for OSA whether adenoidectomy only, tonsillectomy
associated with Pierre Robin sequence only, partial tonsillectomy or total
include: 1) prone positioning; 2) insertion of adenotonsillectomy should be performed to
a nasopharyngeal tube (commonly used achieve complete resolution of OSA. Indeed,
intervention); 3) use of an intraoral no randomised, controlled trials on the
orthodontic appliance; 4) surgical tongue efficacy of adenotonsillectomy have been
advancement (i.e. glossopexy via tongue–lip published, although such studies are in
adhesion); 5) mandibular distraction progress. A retrospective, multicentre study
osteogenesis; and 6) tracheostomy. Infants has used PSG indices as primary end-points
with minor manifestations can be managed to evaluate the efficacy of adenotonsillectomy
by placement in the prone position, taking in children with OSA and without associated
advantage of the effect of gravity on moving anomalies (e.g. genetic syndromes or
the tongue forwards. Use of glossopexy has neuromuscular disorders). Postoperatively,
been declining, since it does not always significant improvements in AHI, respiratory
achieve complete resolution of airway arousal index and oxygen saturation of
obstructive symptoms. An effective, haemoglobin nadir have been demonstrated.
noninvasive and safe treatment modality However, a normal AHI (,1 episode?h-1) was
involves implementation of an intra-oral achieved in fewer than 30% of all studied
orthodontic appliance with velar extension. subjects. Potential reasons for residual OSA
Craniofacial procedures for mandibular (AHI o1 episode?h-1) postoperatively include
hypoplasia are discussed later. nasal mucosa inflammation (e.g. allergic
rhinitis), co-existent obesity, craniofacial
Craniosynostosis is a congenital disorder abnormalities or neuromuscular disorders.
affecting one in 2,500 newborns that is Age greater than 7 yrs is an additional risk
characterised by premature fusion of the factor for postoperative persistence of OSA.
calvarial sutures. Premature fusion restricts
normal growth of the skull, brain and face, The operation may also be accompanied by
necessitating surgical correction. In about beneficial effects on cognition, attention,

behaviour and quality of life. It should be have a significant effect on respiration, while
noted that a subgroup of children exhibit midface advancement appears to be the
rapid weight gain after adenotonsillectomy treatment of choice. Co-existent anatomical
and ultimately partial recurrence of OSA, malformations of the nasopharynx are
most likely due to improved food intake, common, causing functional airway
reduced nocturnal work of breathing or obstruction at this level. Midface
hormonal changes. Adenotonsillectomy is advancement usually improves respiration
not devoid of complications such as in the short term, but long-term efficacy of
anaesthetic risks, postoperative pain, airway the procedure, defined as no need for
compromise and bleeding and in very rare respiratory support for at least 2 yrs
cases even death. postoperatively, is not as clear as was
thought previously. Relapse of OSA after
In addition to adenotonsillectomy, surgery may be due to overcorrection of the
uvulopalatopharyngoplasty has been applied midface hypoplasia with change of
to children with Down syndrome or cerebral malocclusion from class III to class II.
palsy and to subjects with major craniofacial Moreover, collapse of the pharyngeal airway
anomalies. Only case reports and small case is a functional abnormality which does not
series on the efficacy of the procedure have necessarily improve after the anatomic
been published. Therefore, its usefulness in
correction achieved by midface advancement.
the management of paediatric OSA is highly
controversial. Other surgical interventions Orthodontic procedures This section is
that may decrease nasal resistance, such as focused on the management of milder
radio-frequency treatment of the inferior craniofacial abnormalities predisposing to
turbinates, have not been studied OSA compared with the profound
systematically and they are not recommended. congenital craniofacial deformities
discussed previously. A narrow upper airway
Intranasal corticosteroids administered for accompanied by maxillary constriction and
4–8 weeks to children with mild OSA and mandibular retrusion is a common
adenoidal hypertrophy improve symptoms phenotype related to paediatric OSA.
of nasal obstruction and PSG indices. Their Mandibular retroposition predisposes to
use results in reduction of the upper airway collapse of the upper airway during sleep
resistance and severity of obstructive SDB
and it is associated with posterior
via a decrease in adenoidal tissue volume.
displacement of the tongue base which
Topical corticosteroids have also been used
results in further narrowing of the upper
with benefit for those children with residual
airway and a high-arched (ogival) palate
OSA after adenotonsillectomy.
(fig. 1). The reversibility of these craniofacial
Craniofacial procedures Craniofacial abnormalities by means of
procedures are part of the treatment plan for adenotonsillectomy for co-existent
congenital craniofacial deformities (mainly adenotonsillar hypertrophy has yet to be
midface and/or mandibular hypoplasia) established, and orthodontic treatment
which affect respiration and feeding. based on oral appliances is a valid
Mandibular distraction osteogenesis has additional treatment for paediatric OSA.
recently acquired an important position in
the management protocol of mandibular Oral appliances and functional orthopaedic
hypoplasia. With this procedure, the tongue devices have been used in children to shift
and the suprahyoid muscles are moved the mandible forwards, to enlarge the upper
forwards and the size of the pharyngeal airway and to improve respiration. Rapid
airway increases due to gradual lengthening maxillary expansion (RME) is a dento-facial
of the mandible. orthopaedic procedure for the treatment of
constricted maxillary arches and maxillary
In patients with Apert, Crouzon or Pfeiffer transverse deficiencies, commonly used in
syndromes and moderate-to-severe OSA, young patients (.4 yrs of age). Such
neither tonsillectomy nor adenoidectomy patients usually display unilateral or bilateral

Figure 1. Examples of common craniofacial phenotypes of children with OSA. 1: a high-arched palate and
oral breathing; 2: a narrow maxilla, retrognathia; 3: hypotonic lips; and 4: increased lower facial height.
posterior crossbite and anterior dental Oropharyngeal exercises derived from

crowding. The distance between the lateral speech therapy (myofunctional therapy) are
walls of the nasal cavity and the nasal another important treatment modality.
septum is often reduced, leading to Oropharyngeal exercises may be an effective
increased nasal resistance to airflow and treatment option for children with OSA,
consequently to nasal respiratory difficulties. because they adjust physiological breathing
RME may relieve nasal obstruction by and eliminate oral breathing, both of which
increasing the transverse dimensions of the are involved in upper airway muscle function
maxilla, which in turn widens the nasal cavity. and airway patency.
The efficacy of RME has been demonstrated CPAP treatment Children with OSA and
in non-obese children suffering from nasal obesity, those with residual disease after
breathing and OSA, but without enlarged adenotonsillectomy or sleep apnoeic
tonsils or adenoids. 4 months after children with cerebral palsy or craniofacial
completion of the orthodontic treatment, all abnormalities are candidates for CPAP,
children had normal anterior rhinometry and which is usually effective in ameliorating
a significant decrease in AHI. The effects of apnoeas and hypopnoeas. During sleep, the
RME were also evaluated in another group child receives continuous airflow delivered
of non-obese children with OSA and dental by the CPAP ventilator via a mask (nasal
malocclusion i.e. ogival palate associated mask in most cases or facial mask) in order
with deep bite, retrusive bite or crossbite. to maintain positive airway pressure.
RME was applied for 12 months. By the end Compliance with this type of treatment can
of treatment, AHI decreased significantly be improved dramatically by gradual
compared with baseline, reaching normal acclimatisation and introduction of the
values in most patients. An improvement in mask as the child sleeps, as well as by
clinical symptoms was reported by parents, continued gentle and intensive family
such as less snoring, oral breathing, sleep support. The pressure level that is necessary
apnoeas, and daytime sleepiness and to ‘‘stent’’ the pharyngeal airway so as to
tiredness. Beneficial effects of RME persisted prevent the collapse of its walls is determined
even 2 yrs after its completion. In summary, in the sleep laboratory prior to prescribing the
results of these studies suggest that CPAP ventilator. The recommended starting
orthodontic therapy should be encouraged in pressure level during the titration procedure
paediatric OSA, and that its early is 4 cmH2O and the goal of treatment with
implementation may permanently modify CPAP is to lower AHI below 5 episodes?h-1. In
nasal breathing and respiration, thereby patients with OSA and concomitant alveolar
preventing obstruction of the upper airway. hypoventilation due to neuromuscular

disorder or chronic lung disease, noninvasive, 2. Mild OSA (AHI 1–5 episodes?h-1), but
bi-level, positive pressure ventilation can be with OSA-related morbidity (e.g.
used instead of CPAP. enuresis, inadequate somatic growth,
poor academic performance,
Lifestyle management A balanced diet and inattention, hyperactivity, pulmonary
regular physical exercise should be hypertension, or systolic or diastolic
implemented in all children with OSA and blood pressure .95th percentile for
especially in those who are obese. Limited sex, age and height).
evidence indicates that weight loss by as
3. OSA and increasing BMI percentile
much as 35% in children with OSA and
especially in pre-adolescent males
severe obesity can be accompanied by an
(increased risk for persistent OSA).
improvement in the severity of intermittent
4. OSA associated with neuromuscular
upper airway obstruction during sleep.
disorders or craniofacial anomalies
However, it should be noted that such a
(increased risk for development of
degree of weight reduction is difficult to
pulmonary hypertension).
achieve and sustain. Avoidance of exposure
to cigarette smoke and indoor allergens are There are no data supporting the treatment
additional measures that could reduce of children with primary snoring or upper
upper airway inflammation, resistance to airway resistance syndrome.
airflow and the tendency for pharyngeal
airway collapse. Treatment of OSA may be followed by: 1)
improvement in quality of life; 2) appreciable
Indications weight and height gain; 3) resolution or
There are no long-term, prospective studies decrease in the frequency of enuresis; 4)
to evaluate whether OSA symptoms, decrease in systemic blood pressure and
abnormal PSG findings, OSA-related pulmonary artery pressure and reversal of
morbidity or any of their potential cor pulmonale; 5) less daytime sleepiness,
combinations are indications for treatment. hyperactivity and aggression; and 6)
AHI .5 episodes?h-1 in paediatric patients reduction in healthcare utilisation.
that reflects moderate-to-severe intermittent As discussed previously, the available
upper airway obstruction during sleep, treatment options for OSA include: anti-
decreases after adenotonsillectomy in inflammatory medications and weight
subjects with adenotonsillar hypertrophy. control, adenotonsillectomy, orthodontic
Although AHI .5 episodes?h-1 has been devices, CPAP, craniofacial procedures and
clearly related to an increased risk for tracheostomy. If a child with OSA is
morbidity, even an AHI ,1 episode?h-1 with candidate for treatment, therapeutic
no apnoeas or gas-exchange abnormalities interventions should address all
(primary snoring) has been associated with abnormalities predisposing to upper airway
excessive daytime sleepiness and learning dysfunction. For example, a child with
problems. When treatment decisions for mild adenotonsillar hypertrophy and retrusion of
OSA (AHI 1–5 episodes?h-1) are made, it the mandible may benefit from the
should be taken into consideration that SDB combination of adenotonsillectomy and
in certain children may persist in adolescence. application of an orthodontic device. No
Despite the low methodological quality of large, randomised controlled trials have
published evidence on the value of treating been conducted to define the order of
obstructive SDB and the absence of implementation of available treatment
consensus between practitioners, some modalities. At present, a stepwise treatment
indications for therapeutic intervention can approach from the less to the more invasive
be summarised as follows: therapeutic interventions is proposed
(table 2). After completion of one step, the
1. Moderate-to-severe OSA (AHI patient should be re-evaluated and the next
.5 episodes?h-1) irrespective of the therapeutic option should be applied to treat
presence of morbidity. residual OSA.

Table 2. A stepwise management approach for children with OSA who have indications for treatment.
1 Nasal corticosteroids for adenoidal hypertrophy and AHI ,5 episodes?h-1; may also be used
for residual OSA following adenotonsillectomy
2 Adenotonsillectomy for adenotonsillar hypertrophy
3 Orthodontic devices for craniofacial abnormalities (e.g. oral appliances for mandibular
retroposition or rapid maxillary expansion for constricted maxillary arches and maxillary
transverse deficiencies). Orthodontic treatment may be used for residual OSA after
adenotonsillectomy (AHI .5 episodes?h-1)
4 Nasal CPAP if AHI .5 episodes?h-1 and: 1) residual OSA after adenotonsillectomy; 2) OSA
related to obesity; 3) OSA related to neuromuscular disorders or craniofacial abnormalities
and unresponsive to measures 1–3; 4) major congenital craniofacial deformities while
awaiting a craniofacial procedure
5 Craniofacial surgery if treatment modalities 1–4 are not adequate. Craniofacial procedures
include mandibular distraction osteogenesis for micrognathia and midface advancement
(¡ distraction osteogenesis) for midface hypoplasia
6 Tracheostomy if treatment modalities 1–5 are not adequate or to secure the upper airway
while awaiting surgical intervention
Weight control based on a balanced diet and regular exercise is recommended for all
children with OSA and especially for those who are overweight.
Use nocturnal PSG or oximetry at each step in order to move to the next step if residual
OSA is present.
Sleep hypoventilation syndromes Management of tracheostomy should be

carefully carried out at initial presentation
Treatment options Either due to central or to
and during regular follow-up at least
peripheral causes, hypoventilation is always
annually at a centre with extensive
most severe during sleep (see ‘‘Sleep-
experience in the care of these children. It is
disordered breathing in children’’).
recommended to use a tracheostomy
Ventilatory support aims to provide optimal
cannula smaller than the airway diameter in
ventilation, i.e. normal PaO2 and normal
order to avoid traumatic lesions of the
PaCO2. Long-term home setting ventilatory
airway wall, but enable adequate mechanical
support allows children to live and grow up
at home with families. Positive pressure ventilation during sleep.
ventilation via tracheostomy, bi-level Noninvasive bi-level positive pressure
positive pressure ventilation via nasal or ventilation Noninvasive bi-level positive
facial mask and respiratory pacing are the pressure ventilation (NIV) is delivered via a
main options for these patients. Negative nasal mask or facial mask using bi-level
pressure ventilation is rarely used. positive pressure ventilators. These
Positive pressure ventilation via tracheostomy ventilators use a blower to produce a
Commercially available positive pressure variable continuous flow and can
ventilators are adequate for a long-term compensate for leaks occurring around the
home setting, equipped with battery security mask or in case of infection-related reduced
and easily portable. However, not all lung compliance. The timed mode ensures a
positive pressure ventilators are fitted for minimal number of breaths delivered to
infants and young children who require infants and young children who are unable
delivery of small tidal volumes. Particular to trigger the ventilator. Some ventilators are
attention should be paid to maintain a now equipped with a volume preset-
ventilator circuit appropriate for the child’s pressure mode. Mask ventilation has been
size and able to deliver heated and associated with mid-face hypoplasia when
humidified air to the patient. used in infants or young children. Close

follow-up by a multidisciplinary team, recommended in the first several years of
including a paediatric orthodontist or life, allowing early discharge to home
maxillofacial surgeon is highly recommended. (American Thoracic Society). After 6–8 yrs
of age, most children with CCHS who
Negative pressure ventilation Negative require sleep ventilation only can be
pressure ventilators apply a negative successfully transitioned from positive
pressure outside the chest and abdomen pressure ventilation via tracheostomy to
with a shell or a cuirass, allowing expansion NIV. It should be noted that direct
of the chest and effective ventilation in comparisons between noninvasive positive
children and adolescents. pressure and invasive (trachestomy-
Respiratory pacing Respiratory pacing delivered) ventilation have not been carried
generates breathing by electrically out in CCHS.
stimulating the patient’s diaphragm. A NIV has been reported as an initial
battery-operated external device produces treatment performed in some infants with
trains of electrical pulses that are CCHS. However, again there are no data or
transformed into a radiofrequency signal systematic studies on the long-term
and transmitted to internally implanted outcome in patients receiving NIV as initial
receivers. The latter are connected to and sole mode of ventilation.
electrodes either inserted around the
phrenic nerves (phrenic nerve pacing) or One must keep in mind that oxygen
directly implanted into the diaphragm administration without ventilatory support is
muscle (diaphragm pacing). Phrenic nerve inadequate in patients with central
pacing requires a normally functioning hypoventilation as it increases oxygen
phrenic nerve-diaphragm axis. This saturation, but worsens hypoventilation,
technique has been shown to provide subsequently producing pulmonary
efficient ventilator support. In contrast, hypertension or coma.
direct diaphragm pacing is a newer
technique that needs to be more extensively Respiratory pacing may be recommended to
assessed in adults and is still scarcely used active children with central hypoventilation
in children in a research setting at this time. who require ventilatory support day and night.
The surgical process and initiation of the These children may combine different modes
pacing system should be made by a of ventilatory support, receiving positive
multidisciplinary paediatric team with extensive pressure ventilation during night-time and
expertise in diaphragm pacing in children. using their respiratory pacers during daytime,
so that they are totally free from the ventilator
Indications during their diurnal activities.
Central hypoventilation Ventilatory support Regardless of the mode of ventilation,
is a life support in patients with congenital patients with central hypoventilation require
central hypoventilation syndrome (CCHS) or continuous monitoring with pulse oximetry
central hypoventilation secondary to and end-tidal carbon dioxide tension
different causes (see ‘‘Sleep-disordered during nighttime.
breathing in children’’). Hypoventilation is
most severe during sleep, but may occur Neuromuscular disorders The probability of
also during daytime in some patients developing nocturnal hypoventilation in
severely affected. neuromuscular diseases depends on the
diagnosis, age and extent of respiratory
The main objective of ventilatory support in muscle weakness. For example, in type 1
central hypoventilation is to provide optimal spinal muscular atrophy (SMA), respiratory
ventilation 24/7 beginning in the first days of insufficiency is likely in the first few months
diagnosis of these patients in order to of life, whereas in Duchenne muscular
preserve optimal neurocognitive outcome. dystrophy, SDB is not usually seen until the
In patients with CCHS, use of positive late teenage years. Sleep studies should be a
pressure ventilation via tracheostomy is part of the regular follow-up, and for most

authorities the indication is to start NIV in References
the presence of symptomatic nocturnal
N Arens R, et al. (2010). Sleep, sleep
hypoventilation, even if daytime PaCO2 is
disordered breathing, and nocturnal
near normal. Successful NIV use is
hypoventilation in children with neuro-
associated with resolution of symptoms
muscular diseases. Paediatr Respir Rev; 11:
such as poor sleep, headaches, 24–30.
concentration/cognitive difficulties, and N Anderson IC, et al. (2010). Prevalence and
importantly results in decreased morbidity severity of obstructive sleep apnea and
and increased survival. In children with snoring in infants with Pierre Robin
severe progressive respiratory failure (e.g. sequence. Cleft Palate Craniofac J; 48:
due to type I SMA) NIV may be used to 614–618.
palliate symptoms and facilitate discharge N Bhattacharjee R, et al. (2011).
home. The choice of ventilator is important. Adenotonsillectomy outcomes in treat-
As indicated above, bi-level pressure ment of obstructive sleep apnea in
support is most commonly used, but children: a multicenter retrospective
attention to ventilator performance such as study. Am J Respir Crit Care Med; 182:
trigger function is critical. The risk of 676–683.
midfacial hypoplasia induced by NIV use N Chen ML, et al. (2005). Diaphragm
can be reduced by the use of customised pacers as a treatment for congenital
masks, rotation of interfaces and application central hypoventilation syndrome. Expert
of nasal plug interfaces. Many children with Rev Med Devices; 2: 577–585.
N Kaditis A, et al. (2012). Algorithm for the
neuromuscular disease can be managed
diagnosis and treatment of pediatric
with NIV throughout the course of their
OSA: a proposal of two pediatric sleep
illness. Ventilator settings should be centers. Sleep Med; 13: 217–227.
checked regularly with overnight monitoring N Katz ES, et al. (2012). Obstructive sleep
including SpO2 and PCO2 control, plus the apnea in infants. Am J Respir Crit Care
use of ventilator downloads to assess Med; 185: 805–816.
optimal synchrony with the ventilator. The N Villa MP, et al. (2011). Mandibular
combination of NIV with cough assistance advancement devices are an alternative
using mechanical in-exsufflation to control and valid treatment for pediatric obstruc-
bronchial secretions can help reduce chest tive sleep apnea syndrome. Sleep Breath;
infections and their complications. The [Epub ahead of print DOI: 10.1007/s11325-
cough in-exsufflator has not been subject to 011-0595-9].
randomised controlled trials but clinical N Villa MP, et al. (2011). Efficacy of rapid
benefit is evident from case series. The use maxillary expansion in children with
of cough assistance and NIV has reduced obstructive sleep apnea syndrome: 36
the need for tracheostomy ventilation in months of follow-up. Sleep Breath; 15:
neuromuscular disease. 179–184.
N Weese-Mayer D, et al. (2010). An official
Current indications for tracheostomy ATS clinical policy statement: congenital
ventilation include: central hypoventilation syndrome. Am J
Respir Crit Care Med; 181: 626–644.
N Severe bulbar weakness leading to N Zhang L, et al. (2008). Intranasal corti-
aspiration costeroids for nasal airway obstruction in
children with moderate to severe adenoi-
N Upper airway problems
dal hypertrophy. Cochrane Database Syst
N Near 24-h ventilator dependency
Rev; 3: CD006286.
N Failure to control ventilation with N Zhao J, et al. (2011). Apnea of prematur-
noninvasive mode ity: from cause to treatment. Eur J Pediatr;
N Intractable interface problems 170: 1097–1105.
N Patient/family choice

Index
A
accidents
ANS (autonomic nervous system) 13
sleep-related changes see under sleep
anticonvulsant drugs, insomnia treatment 180, 182
motor vehicle see motor vehicle accidents (MVAs) antidepressants
workplace, increased risk in OSA patients 191 cataplexy management 70, 71, 185
acetazolamide therapy insomnia management 180, 181, 182
central sleep apnoea 165 OSA treatment 154
obstructive sleep apnoea 154 antihistaminics 182
acetylcholine sweat-spot test 14 antihypertensives 155
achondroplasia 206 antipsychotics, insomnia treatment 180, 182
acid maltase deficiency 50 APAP (autotitrating positive airway pressure) devices 139,
acromegaly, SDB association 96, 98 141, 157, 158
actigraphy 143 Apert syndrome 206, 230, 231
in children 220 apnoea
circadian rhythm evaluation 74, 75 central see central apnoea
free-running circadian disorder 76 definition 21
insomnia assessment 57 in infants see under infants
active sleep (AS) 200 obstructive see obstructive apnoea
polysomnography 223 presentation 22
acute insomnia 55 apnoea of prematurity 228
adaptive servo ventilation (ASV) 162, 165, 166–167 apnoea threshold 97
“adenoid facies” 219 central sleep apnoea 43
adenoid hypertrophy 219, 220, 229 apnoea–hypopnoea index (AHI) 21
adenotonsillectomy 152, 230–231 upper airway anatomy and 7, 8
infants 229 apparent life-threatening events (ALTEs) 203–204
ADHD see attention deficit hyperactivity disorder (ADHD) definition 203
adherence, CPAP therapy 160–161 sleep history 218–219
adipose tissue 37 appetite regulation, sleep and 18
adjustment insomnia 55 arousal disorders 63–64
advanced sleep phase syndrome (ASPS) 75, 76 classification 63
age diagnosis 64
effect on sleep cycle 3–4 epidemiology 63
as obstructive sleep apnoea risk factor 26, 95 pathophysiology 63
algorithms treatment 64, 187
diagnostic 100–105 arousals
nocturnal hypoventilation management central sleep apnoea pathophysiology 43–44
neuromuscular/skeletal disorders 172 EEG 126
obese patients 169, 171 in children 222
Oxford 160 arterial blood gas (ABG) sampling 143, 144
for setting CPAP level 159–160 arterial hypertension see hypertension
allergic rhinitis, in children 211 asphyxia, infants 201
Alzheimer’s disease 62, 64 ASPS (advanced sleep phase syndrome) 75, 76
ambulatory blood pressure monitoring (ABPM) 115–116 asthma, in children 210
American Academy of Sleep Medicine (AASM) ASV (adaptive servo ventilation) 162, 165, 166–167
electrode placement 120, 121 atherosclerosis, assessment in OSA patients 117, 118, 155
home diagnosis recommendations 100, 137 atrial fibrillation
hypopnoea scoring 141 CSA patients 40
manual for scoring of sleep 120, 126 OSA patients, assessment 116–117, 118
sleep disordered breathing definitions 21, 23 attention deficit hyperactivity disorder (ADHD) 213, 215
aminophylline 154 restless legs syndrome and 215–216
amitriptyline 180, 182 sleep disordered breathing and 216
amphetamines autonomic nervous system (ANS) 13
hypersomnia treatment 183–184 sleep-related changes see under sleep
narcolepsy 71 autonomic ‘stress tests’ 14
side-effects 184 autotitrating positive airway pressure (APAP) devices 139,
amyotrophic lateral sclerosis (ALS) 50, 144, 170, 172 141, 157, 158
anaesthesia risk assessment, obstructive sleep apnoea 111–113
237
B
bariatric surgery
C
CAD see coronary artery disease (CAD)
OSA patients 111, 112, 152–153 Calgary Sleep Apnea Quality of Life Index (SAQLI) 109
beneficial effect 153 capnography, nocturnal 143–144
techniques 153 carbon dioxide application, central sleep apnoea 165
Beck Depression Inventory (BDI) 109 carbon dioxide sensitivity, infants 201
behavioural disorders, paediatric OSA patients 208 cardiac function, assessment in OSA patients 116–117, 118
behavioural insomnia, infants 218 cardiac hypertrophy, assessment in OSA patients 116, 118
benzodiazepine therapy cardiac resynchronisation therapy 165
arousal disorders 64 cardiac structure, assessment in OSA patients 116–117, 118
effect on sleep structure 179 cardiorespiratory monitoring
insomnia 179–181 children 225
restless legs syndrome 186 OSA patients see under obstructive sleep apnoea
Berger, Hans 1 syndrome (OSAS)
Berlin Questionnaire 32–33, 92, 93, 112, 113 cardiorespiratory polygraphy 137
bi-level positive airway pressure ventilation 157, 158, 162 interpretation 140–142, 143
central sleep apnoea treatment 165, 166 scoring 138–140
nocturnal hypoventilation management in obstructive cardiovascular changes, sleep-related see under sleep
lung disease 173, 174 cardiovascular disease (CVD)
sleep hypoventilation syndrome management central sleep apnoea and 40, 46–47, 98
neuromuscular/skeletal disorders 171–173 obstructive sleep apnoea and 35–37, 98, 155
obesity hypoventilation syndrome 169, 171 cataplexy, narcolepsy with 67, 68, 69, 70, 86
sleep hypoventilation syndrome management in children management 70, 71, 183, 184–185
234–235 prevalence 213
central hypoventilation 235 symptoms 213–214
neuromuscular disorders 236 see also narcolepsy
biliopancreatic derivation technique 153 central apnoea
blood pressure monitoring 14–15 in childhood/adolescence 225
ambulatory 115–116 definition 224
breathing healthy infants 224
control of see breathing, control of see also central sleep apnoea (CSA)
monitoring 120 central hypoventilation syndromes 7, 48–49
periodic see periodic breathing management 235
during sleep see under sleep see also congenital central hypoventilation syndrome
sleep history 85 (CCHS)
at wake/sleep transition see wake/sleep transition central respiratory event, definition 124
see also entries beginning respiratory central sleep apnoea (CSA) 21, 22–23, 39–47
breathing, control of 6–7 clinical aspects 22–23, 45
development 201–202 consequences 46–47
asphyxia and 201 cardiovascular 46–47
breathing and sleep 202 neurobehavioural 46
carbon dioxide and 201 definition 21, 39
hypoxia and 201 obstructive sleep apnoea vs 39
plasticity 202 pathophysiology 21, 42–44
sleep and 202 apnoea threshold 43
upper airway 201–202 arousals 43–44
obstructive sleep apnoea syndrome pathophysiology 30 hyperventilation 42
during sleep 6–7 hypoventilation 42
at wake/ sleep transition 7 hypoxic and hypercapnic ventilatory response 43
breathing, sleep disordered see sleep disordered breathing loop gain 42–43
(SDB) prevalence 40
bronchiectasis 174 risk factors 40
bronchopulmonary dysplasia (BPD) 212 see also sleep disordered breathing, predisposing factors
Brouillette questionnaire 207 symptoms 22–23, 45
treatment 164–167
adaptive servo ventilation 162, 165, 166–167
238
carbon dioxide 165 irregular sleep/wake syndrome see irregular sleep/wake
CSA associated with hyperventilation 164–165 syndrome (ISWS)
CSA associated with hypoventilation 164 treatment 74, 76
oxygen 165 circadian rhythmicity 74
pharmaceutical options 165 effect on metabolic regulation 17, 18
positive airway pressure treatment 47, 165–166 Circadian Type Inventory (CTI) 75
cephalometry 8 CLOCK gene 74
cerebrospinal fluid (CSF) analysis, narcolepsy 68, 69 clomipramine, cataplexy management 71
chemosensitivity 6, 7 clonazepam therapy
sleep-related reduction 10, 11 arousal disorders 64
chest wall disorders 50, 170 REM behaviour disorder (RBD) 63
see also neuromuscular/skeletal disorders sleep-related movement disorders 186, 187
Cheyne–Stokes respiration (CSR) 23, 39, 40, 98 codeine therapy, sleep-related movement disorders 187
see also central sleep apnoea (CSA) cognitive behavioural therapy, CPAP compliance and 148
children cognitive behavioural therapy for insomnia (CBT-I) 82,
clinical assessment 218–220 178, 196
child 219–220 cognitive performance, OSA patients 191
indications for further investigation 220 paediatric 207–208
infant 218–219 comorbid insomnia see under insomnia
physical examination 218, 219 congenital central hypoventilation syndrome (CCHS) 7,
development 48–49, 208–209
control of breathing see under breathing, control of management 235
sleep development in first years of life 200–201, continuous positive airway pressure (CPAP) therapy
224–225 157–162
diagnostic techniques 221–226 adherence 160–161
assessment of daytime sleepiness 226 algorithms for setting level 159–160
cardiorespiratory monitoring 225 alternatives 162
oximetry 207, 220, 225–226 central sleep apnoea 47, 165–166
polysomnography see polysomnography (PSG) adaptive servo ventilation vs 162, 166, 167
nonrespiratory sleep disorders 213–216 children 232–233
ADHD 215 assessment of facial development 159
hypersomnias of central origin 213–215 infants 229
restless legs syndrome 215–216 comorbidity and 161
SDB and 216 interfaces 158–159
sleep disordered breathing see sleep disordered breathing machines 157–158
in children obesity hypoventilation syndrome 169
see also infants obstructive sleep apnoea syndrome 102
chloral hydrate 182 alternatives 162
cholinergic neurons 1, 2 cardiovascular effects 36, 116
chronic kidney disease 98 children 232–233
chronic lung disease, in children 212 cost-effectiveness 193–194
chronic obstructive pulmonary disease (COPD) infants 229
assessment in OSA patients 117, 118 metabolic effects 37, 118
nocturnal hypoventilation 51, 174 neurobehavioural effects 35
indications for initiation of nocturnal NIV 172, 174 patient education 148
chronic respiratory insufficiency, nocturnal hypoventilation positional therapy vs 149
and 48 quality of life effects 108, 109
management 174 surgical patients 112, 113
circadian rhythm disorders 74–78 weight effects 148
evaluation tools 74, 75 principles 157
jet lag see jet lag disorder (JLD) problem solving 161
shift work disorder see shift work disorder (SWD) titration 159–160
sleep/wake rhythm disorders 76–77 unattended autotitrating device 159–160
advanced sleep phase syndrome 75, 76 COPD see chronic obstructive pulmonary disease (COPD)
delayed sleep phase syndrome 75, 76 core body temperature, circadian rhythm evaluation 74, 75
free-running circadian disorder see free-running coronary artery disease (CAD), OSA patients 35–36
circadian disorder (FRD) assessment 117, 118
239
corticosteroids, intranasal, OSA management in children drug treatment
231 central sleep apnoea 165
cortisol 17, 18 hypersomnias of central origin 183–185
cortisol levels, circadian rhythm evaluation 75 narcolepsy 70, 71, 183–185, 214
cost-effectiveness insomnia 178–182, 195
CPAP therapy 193–194 obstructive sleep apnoea 153–154
restless legs syndrome treatment 195 restless legs syndrome 65, 185–187, 195
costs, sleep disorders 189 see also specific drugs
see also healthcare costs Duchenne muscular dystrophy
costs, healthcare see healthcare costs cardiorespiratory monitoring 225
CPAP therapy see continuous positive airway pressure hypoventilation 48, 50, 162, 170, 209
(CPAP) therapy treatment 171–172, 235–236
craniofacial disorders
congenital 229–230, 232
obstructive sleep apnoea syndrome and 29, 34, 205–206
management 230, 231
E
ECG (electrocardiography) 120
craniofacial procedures 231 evaluation of ECG traces 127
craniosynostosis 229, 230 OSA patients 116, 118
critical closing pressure see under upper airway echocardiography, OSA patients 116, 118
Crouzon syndrome 206, 230, 231 economic impacts
cystic fibrosis (CF) 174, 211 insomnia 195–196
obstructive sleep apnoea 192–194
D
daytime dysfunction, insomniacs 53, 54
restless legs syndrome 195
education see patient education
elderly
daytime sleepiness central sleep apnoea risk 40
assessment in children 226 sleep cycle 4
see also excessive daytime sleepiness (EDS) electrocardiography see ECG (electrocardiography)
daytime symptoms, sleep history 85–86 electroencephalography see sleep EEG
delayed sleep phase syndrome (DSPS) 75, 76, 187 EMG (electromyography) 121
treatment 187–188 paediatric 221
depression sleep stages 122, 123
Beck Depression Inventory 109 emotions, sleep and 82
insomnia and 80–81 endocrine disorders, SDB-associated 98
psychological intervention 82–83 diabetes see diabetes
obstructive sleep apnoea syndrome and 35 endoscopy, sleep 151
assessment 117 EOG (electrooculography) 120–121
treatment 156 paediatric 221
development sleep stages 122, 123
control of breathing see under breathing, control of epiglottoplasty, obstructive sleep apnoea 152
sleep 200–201, 224–225 epilepsy 64
dextroamphetamine 184 Epworth Sleepiness Scale (ESS) 33, 84, 91–92
diabetes, SDB association 98 paediatric 207
assessment in OSA patients 117, 118 ergot preparations, restless legs syndrome management 186
diagnostic algorithms 100–105 excessive daytime sleepiness (EDS) 182
dietary interventions, obstructive sleep apnoea 147–148, 152 assessment 88–90, 131–135
difficulties initiating sleep (DIS) 53 in children 226
difficulties maintaining sleep (DMS) 53 MSLT see multiple sleep latency test (MSLT)
dim light melatonin onset (DLMO) 74, 75 MWT see maintenance of wakefulness test (MWT)
diurnal sleep, young children 200–201 OSLER test 90, 133, 134
dopamine agonists, restless legs syndrome management test limitations 135
65, 186 causes 87, 88, 131
dopaminergic neurons 1 CSA patients 46
Down’s syndrome 96, 97–98, 231 differential diagnosis 87–90
driving licence regulations OSA patients 35, 87, 88
insomnia patients and 197 assessment 33, 89
OSA patients and 191 treatment 185
240
presentation 88 restless legs syndrome 195
questionnaires 91–92 heart failure
Epworth Sleepiness Scale see Epworth Sleepiness Scale central sleep apnoea and 40, 43, 46, 47, 98
(ESS) CPAP vs adaptive servo ventilation 162
Stanford Sleepiness Scale 92 obstructive sleep apnoea and 36
sleep history 85–86 heart failure with preserved ejection fraction (HFprEF) 36
see also hypersomnias of central origin heart rate variability (HRV) analysis 14, 15
expiratory positive airway pressure (EPAP) 162 high spinal injuries 50
obesity hypoventilation syndrome management 169 histaminergic neurons 1, 2
HLA DQB1*0602, narcolepsy association 68, 70, 214
F
facial development, assessment in children on long-term
home monitoring, obstructive sleep apnoea 100
in children 207
human leukocyte antigen gene complex, narcolepsy associa-
CPAP therapy 159 tion 68, 70, 214
failure to thrive, OSA patients 208 hyoid bone displacement 96
fatigue, excessive daytime sleepiness vs 88 hyoid bone surgery, obstructive sleep apnoea 152
fluoxetine, cataplexy management 71 hyperarousal 55
flurazepam 180 hypercapnic ventilatory response
free-running circadian disorder (FRD) 76 central sleep apnoea 43
evaluation 74, 75, 77 obesity hypoventilation syndrome 50
full-face CPAP mask 158, 159 during sleep 10, 11
Functional Outcome of Sleep Questionnaire (FOSQ) hypersomnias of central origin 67–72
108–109 in children 213–215
idiopathic see idiopathic hypersomnia (IHS)
G
GABAergic neurons 2, 3
narcolepsy see narcolepsy
primary 67, 68
recurrent see recurrent hypersomnia
gabapentin therapy secondary 67, 68
insomnia 180, 182 sleep disordered breathing and 216
sleep-related movement disorders 186, 187 treatment 182–185
galanin 3 nonpharmacological 183
gastric bypass 153 pharmacological 183–185
see also bariatric surgery see also excessive daytime sleepiness (EDS)
gastro-oesophageal reflux disease (GERD) 98 hypertension
Gélineau, Jean-Baptise-Edouard 67 OSA patients 18, 25, 32, 36
gender see sex assessment 115–116, 118, 155
genioglossus, reduced activity 11 paediatric 208
ghrelin 17, 18 treatment 155
glossopexy 230 pulmonary 48, 50
glucose metabolism hyperventilation, central sleep apnoea
OSA patients 37 pathophysiology 42
assessment 117, 118 treatment 164–165
sleep and 18 hypnogram
glutaminergic neurons 2 typical overnight sleep pattern 3
growth hormone (GH) 17, 18 see also polysomnography (PSG)
Guillain–Barré syndrome 51, 62 hypnotics 178–182
contraindications 179
H
health-related quality of life (HRQoL)
effect on sleep structure 179
hypocapnia 40, 43, 97, 144
hypocretin (orexinergic) neurons 1, 2
definition 107 hypocretins, narcolepsy and 67–68, 69, 70, 183, 214
questionnaires 107–109 hypopharynx 7
disease-specific 108–109 hypopnoea
generic 108 definition 21, 124, 224
healthcare costs periodic limb movement disorder vs 186–187
insomnia 195–196 presentation 22
obstructive sleep apnoea 192–194 hypothyroidism, SDB association 98
241
hypoventilation syndromes 21, 23, 48–51 nonorganic 56–57
central see central hypoventilation syndromes nosological classification 55–57
characteristics 23, 48 organic 56–57
in children see under sleep disordered breathing in paradoxical 55–56
children pathophysiology 55, 56
neuromuscular/skeletal disorders see neuromuscular/ perpetuating factors 55, 56
skeletal disorders precipitating factors 55, 56
obesity hypoventilation syndrome see obesity predisposing factors 55, 56
hypoventilation syndrome (OHS) prevalence 54, 195
treatment see under nocturnal hypoventilation primary 54, 55–56
see also nocturnal hypoventilation psychiatric disorders and 54, 56, 80–83
hypoxaemia, post-operative 113 depression 80–81
hypoxic ventilatory response psychological intervention 82–83
central sleep apnoea 43 psychophysiological 55
infants 201 rebound 178
SDB and 54, 58–59
I
idiopathic hypersomnia (IHS) 71–72, 183
secondary 54, 56
Spielman (3P) model 56
treatment 58, 177–182
in children 214–215 comorbid OSA and 182
narcolepsy vs 72 economic impact 196
treatment nonpharmacological 82–83, 177–178, 196
nonpharmacological 183 pharmacological 178–182, 196
pharmacological 183–185 work disability 196
see also hypersomnias of central origin insulin resistance 117, 118
idiopathic insomnia 56 insulin sensitivity, effect of sleep deprivation 18
imipramine, cataplexy management 71 intermittent hypoxia, effect on sympathetic activity 17
infants International Classification of Functioning, Disability and
apnoea 202–203 Health (ICF) 108
aetiology 202 International Classification of Sleep Disorders (ICSD-2)
clinical aspects 203 hypersomnia 68
diagnosis 202 idiopathic 71
management 228–230 insomnia 55–57
see also apparent life-threatening events (ALTEs); parasomnias 63
obstructive sleep apnoea syndrome in children sleep disordered breathing 21
clinical assessment 218–219 interstitial lung disease, in children 211–212
periodic breathing see periodic breathing intranasal corticosteroids, OSA management in children 231
sleep cycle 200, 201, 224 iron deficiency, restless legs syndrome and 65, 185–186, 216
sleep development 200–201, 224–225 irregular sleep/wake syndrome (ISWS) 76–77
sleep problems 218 evaluation 75
see also children; sleep disordered breathing in children
inflammation, airway 9, 97
insomnia 52, 53–59, 80, 195
adjustment (acute) 55
J
jet lag disorder (JLD) 78
assessment 57–58 evaluation 75
behavioural, in infants 218 treatment 78
comorbid 54, 56
therapeutic aspects 182
daytime dysfunction 53, 54
diagnosis 53–54, 195
K
K complexes 17, 122, 123
due to drug/substance 56 in children 222, 223
economic consequences 195–196 Kleine–Levin syndrome 67, 68, 215
emotions and 82
epidemiology 195
idiopathic 56
L
lateral sleeping position, obstructive sleep apnoea therapy
legal aspects 196–197 148–149
medical consequences 195 legal aspects
242
increased motor vehicle accident risk in OSA patients 191 narcolepsy 71
insomnia patients and vehicle accidents 196–197 OSA patients 185
leptin 17, 18 Morningness–Eveningness Questionnaire (MEQ) 75
levodopa therapy, restless legs syndrome 186 motor neurone disease (MND) 170, 172
Lewy body disease 62 motor symptoms, sleep history and 86
lifestyle management, OSA patients 147–148, 152, 155 motor vehicle accidents (MVAs)
children 233 increased risk in OSA patients 189, 190, 191–192
liver function, assessment in OSA patients 118 economic impact 193
loop gain 97 legal aspects 192
central sleep apnoea pathophysiology 42–43 insomnia patients and 196–197
lormetazepam 180 movement disorders, sleep-related
lung disease periodic limb movement disorder see periodic limb move-
chronic, in children 212 ment disorder (PLMD)
interstitial, in children 211–212 restless legs syndrome see restless legs syndrome (RLS)
obstructive, nocturnal hypoventilation 174 treatment 185–187
see also specific diseases movements
lung volumes, influence on upper airway geometry 8 scoring in sleep 127
sleep history 85
M
macroglossia 96
Muenke syndrome 230
multi-system atrophy 62
multiple sleep latency test (MSLT) 89, 131, 133, 134
magnesium sulfate 186 in children 220, 226
maintenance of wakefulness test (MWT) 89–90, 131, 133 disadvantages 131
in children 226 guidelines 132
Mallampati score 219 idiopathic hypersomnia 72
mandibular advancement devices (MADs) 149–150, 162, narcolepsy 68, 69, 70, 133, 134
231 technique 131
mandibular distraction osteogenesis 231 Munich Chronotype Questionnaire (MCTQ) 75
mandibular plane–hyoid (MP–H) distance, measurement 8 muscle sympathetic nerve activity (MSNA), effect of inter-
Marshall syndrome 230 mittent hypoxia 17
maxillofacial surgery, obstructive sleep apnoea 152 MWT see maintenance of wakefulness test (MWT)
MCTQ (Munich Chronotype Questionnaire) 75 myasthenia 50
Medical Outcomes Study 36-item short-form health survey myotonic myopathy 50
(SF-36) 108
melatonin therapy
jet lag 78
REM behaviour disorder (RBD) 63
N
naltrexone 154
metabolic disorders narcolepsy 67–71, 183
assessment in OSA patients 117–118, 155 with cataplexy see cataplexy, narcolepsy with
see also specific disorders in children 213–214
metabolic syndrome diagnosis 68–70
definition 37 multiple sleep latency test 68, 69, 70, 133, 134
diagnosis 116 idiopathic hypersomnia vs 72
obstructive sleep apnoea syndrome and 37–38 pathogenesis 67, 214
assessment 116, 118 hypocretins 67–68, 69, 70, 183, 214
methadone therapy, sleep-related movement disorders 187 prevalence 67, 213
methylphenidate, side-effects 184 secondary 67, 69
methylphenidate therapy, hypersomnia 183, 184 symptoms 67, 69, 213–214
narcolepsy 71 treatment 70–71, 214
micrognathia 96 nonpharmacological 183
microneurography 16 pharmacological 70, 71, 183–185, 214
midazolam 180 see also hypersomnias of central origin
midface advancement 231 nasal CPAP mask 158, 159
Milijeteig–Hoffstein method 159, 160 nasal obstruction 96
mirtazapine 154, 180, 182 clinical assessment in children 219
mixed apnoea, definition 124, 223–224 nasal plugs, CPAP interface 158, 159
modafinil, hypersomnia treatment 183, 184 nasal pressure, measurement 22, 137–138, 142
243
in children 221, 224 in children see under children
nasal surgery, obstructive sleep apnoea 151, 152 see also specific disorders
nasopharyngeal surgery noninvasive ventilation (NIV)
obstructive sleep apnoea 152 negative pressure ventilation, sleep hypoventilation
see also adenotonsillectomy syndrome management in children 234, 235
nasopharynx 7 positive pressure see positive airway pressure (PAP)
NBBRAs (non-benzodiazepine receptor agonists) 179, 181 therapy
negative pressure ventilation, sleep hypoventilation nonorganic insomnia 56–57
syndrome management in children 234, 235 nonrestorative sleep (NRS) 53
neural regulation noradrenergic neurons 1, 2
breathing during sleep 6–7 Nottingham Health Profile (NHP) 108
NREM and REM sleep 1, 2, 3 NREM sleep
wakefulness 1, 2 abnormal behaviour see arousal disorders
neurobehavioural sequela neural regulation 1, 2, 3
central sleep apnoea 46 normal vs abnormal events 61, 62
obstructive sleep apnoea 35 polysomnography 122, 123
neurobiology, sleep 1–4 in children 222, 223
neurokinin-1 receptor (NK1R) 6 respiratory mechanics and ventilation 10, 11
neuromuscular/skeletal disorders 50–51 stages 3
in children 209 see also wake/sleep transition
management 235–236 NREM–REM cycle see sleep cycle
management 170–174
algorithm 172
in children 235–236
newborns
O
obesity
sleep cycles 200 adipocyte activity 37
see also infants obstructive sleep apnoea and 26, 27, 32, 98, 152
NHP (Nottingham Health Profile) 108 assessment 117–118
‘night owl’ pattern of sleep 76, 78 surgical considerations 111, 112
night terrors 63–64 upper airway effects
nitrazepam 180 anatomy 7, 8
nocturnal capnography 143–144 critical closing pressure 9
nocturnal hypoventilation see also bariatric surgery; metabolic syndrome
central sleep apnoea associated with obesity hypoventilation syndrome (OHS) 23, 49–50
pathophysiology 42 treatment 169–170, 171
treatment 164 obstructive apnoea
in children 208, 209 definition 21, 124, 223
chronic respiratory insufficiency and see chronic respira- infants 224
tory insufficiency see also obstructive sleep apnoea syndrome (OSAS)
identification of high-risk cases 170 obstructive lung disease
in obstructive lung disease 174 nocturnal hypoventilation 174
COPD see under chronic obstructive pulmonary see also specific diseases
disease (COPD) obstructive sleep apnoea syndrome (OSAS) 21–22, 25–38,
cystic fibrosis 174, 211 190
treatment 169–174 cardiorespiratory monitoring 136–144
algorithms 169 actigraphy 143
in children 234–236 interpretation of cardiorespiratory polygraphy 140–142
evaluation 173, 174 nocturnal capnography 143–144
management plan 170 polygraphy scoring 138–140
in neuromuscular/skeletal disorders 170–172, 174 portable devices 137, 138, 139, 140, 141
in obese patients 169–170, 171 pulse oximetry see oximetry
in obstructive lung disease 174 central sleep apnoea vs 39
see also hypoventilation syndromes in children see obstructive sleep apnoea syndrome in
nocturnal seizures 64 children
nocturnal symptoms, sleep history 85, 86 clinical aspects 32–34, 103
non-benzodiazepine receptor agonists (NBBRAs) 179, 181 comorbid insomnia see under insomnia
nonrespiratory sleep disorders 52 comorbidity assessment 115–118, 155
244
cardiac structure and function 116–117, 118 questionnaires 92–93
chronic obstructive pulmonary disease 117, 118 Berlin Questionnaire see Berlin Questionnaire
coronary artery disease and peripheral arterial disease Epworth Sleepiness Scale see Epworth Sleepiness Scale
117, 118 (ESS)
depression 117, 118 pre-operative screening 112, 113
obesity and metabolic disorders 117–118 quality of life assessment see under health-related qual-
systemic hypertension 115–116, 118 ity of life (HRQoL)
comorbidity management 154–156 STOP-Bang questionnaire 92–93, 112, 113
consequences 25, 32, 35–38, 189 STOP questionnaire 92
cardiovascular 35–37 risk factors 26–27
in children 207–208 age 26, 95
metabolic 37–38 obesity 26, 27, 32, 98, 152
neurobehavioural 35 sex 26, 27
definition 21 upper airway abnormalities 27, 96–97
diagnosis 21, 23, 100–105 see also sleep disordered breathing, predisposing factors
in children 206–207, 220 surgical and anaesthesia risk assessment 111–113
steps 101–103 symptoms 32–33, 103
strategies 104–105 in children 206
epilepsy and 64 see also excessive daytime sleepiness (EDS)
hypertension and see under hypertension “typical” vs actual patients 100, 101
management 147–156 upper airway anatomical abnormalities and 7–8, 27, 29,
ambulatory 139–140, 141 96–97
bariatric surgery 111, 112, 152–153 as predictor of therapeutic interventions 9–10
comorbidities 154–156 surgery 150–152
CPAP see continuous positive airway pressure (CPAP) upper airway and 96–97
therapy critical closing pressure 9, 30, 97
drug treatment 153–154 inflammation 9, 97
economic impact 193 influence of lung volumes on geometry 8
network system 101 reflex activation responses 8
oral devices 149–150, 162 obstructive sleep apnoea syndrome in children 205–208
patient education 147–148 associated complications 207–208
perioperative 112–113 clinical presentation 206
positional 148–149 diagnosis 206–207, 220
reference hospitals 100, 101 epidemiology 205
upper airway anatomy as predictor of response to infants 228–230
therapy 9–10 management 230–234
upper airway surgery 150–152 indications 233
weight loss 147–148, 152, 155 in infants 228–230
medicolegal and economic aspects 190–194 stepwise approach 229, 233, 234
economic consequences 192–194 pathophysiology 205–206
increased motor vehicle accident risk 189, 190, occupational accidents, OSA patients 191
191–192 oesophageal pressure, measurement 22
professional performance and work disability 190–191 children 221
pathophysiology 21, 25, 29–30, 205–206 Ondine’s curse see congenital central hypoventilation
autonomic nervous system assessment and 17 syndrome (CCHS)
central respiratory control mechanisms 30 opioids
craniofacial morphology 29, 205–206 central sleep apnoea risk and 40, 112, 113
see also craniofacial disorders effect on respiratory rhythm-generating neurons 6
function/dysfunction of upper airway muscles 30 restless legs syndrome treatment 186, 187
upper airway morphology 29, 206 oral devices, obstructive sleep apnoea treatment 149–150
see also sleep disordered breathing, predisposing factors in children 231–232
perioperative complications 111–112 orexinergic neurons 1, 2
perioperative management 112–113 orexins (hypocretins), narcolepsy and 67–68, 69, 70, 183,
physical examination 33–34 214
pre-operative screening 112, 113 organic insomnia 56–57
prevalence 26, 190 orlistat 155
in children 205 oronasal CPAP mask 158, 159
245
oropharyngeal exercises 232 PHOX2B gene, mutations 49
oropharyngeal surgery physical examination
obstructive sleep apnoea 152 children with sleep disorders 219
see also tonsillectomy infants with sleep disorders 218
oropharynx 7 obstructive sleep apnoea 33–34
orthodontic procedures, OSA management in children Pickwickian syndrome 49
231–232 see also obesity hypoventilation syndrome (OHS)
orthopnoea, amyotrophic lateral sclerosis 50 Pierre Robin syndrome 34, 96, 97, 205–206, 230
OSLER test 90, 133, 134 Pittsburgh Sleep Quality Index (PSQI) 93
otolaryngological surgery, obstructive sleep apnoea 151, 152 plasticity, development of breathing control 202
Oxford algorithm 160 poliomyelitis 50
oximetry 124, 137, 142 polyalanine repeat mutations (PARMs) 49
in children 207, 220, 225–226 polycystic ovary syndrome, SDB association 98
oxygen therapy polygraphy (PG)
central sleep apnoea 165 cardiorespiratory see cardiorespiratory polygraphy
cystic fibrosis 211 insomnia 59
obesity hypoventilation syndrome 169–170 polysomnography (PSG) 120–129
arousal disorders 64
P
PAP see positive airway pressure (PAP) therapy
in children 220, 221–225
interpretation and reporting 225
normative data 224–225
paradoxical insomnia 55–56 obstructive sleep apnoea 206–207
parafacial respiratory group (pFRG) 6, 7 scoring breathing 223–224
parasomnias 61–65 scoring EEG 222–223
definition 61 sensors 221–222
diagnosis 61 circadian rhythm disorders 75
primary 61 ECG evaluation 127
non-REM-related see arousal disorders EEG see sleep EEG
REM-related see REM behaviour disorder (RBD) EMG see EMG (electromyography)
secondary 61 EOG see EOG (electrooculography)
nocturnal seizures 64 hypersomnia
treatment 187 idiopathic 72
trigger factors 61 narcolepsy 68, 69
see also restless legs syndrome (RLS) instruction series 121, 126
Parkinson’s disease 62, 69, 88, 103, 109 interpretation 127–129
PARMs (polyalanine repeat mutations) 49 in infants/children 225
paroxetine 154 limitations 136
patient education measurement techniques 124, 126
obstructive sleep apnoea treatment 147–148 nocturnal seizures 64
sleep hygiene 82 normal PSG 128
Period genes 74 obstructive sleep apnoea 100, 102, 104–105, 128
periodic breathing 202, 203, 224–225 in children 206–207
definition 224 portable monitoring vs 138, 139–140, 142, 143
periodic limb movement disorder (PLMD) 65, 85, 86, 185 REM behaviour disorder 62
hypopnoeas vs 186–187 restless legs syndrome 65
treatment 185, 186, 187 scoring
perioperative complications, obstructive sleep apnoea EEG arousals 126
patients 111–112 movement in sleep 127
perioperative management, obstructive sleep apnoea patients respiratory events see respiratory events
112–113 sleep EEG see sleep EEG
peripheral arterial tonometry (PAT) 15–16, 138 SDB-plus patients 59
peripheral artery disease (PAD), assessment in OSA patients sensors and associated monitoring 121–122, 124
117, 118, 155 in children 221–222
Pfeiffer syndrome 230, 231 portable monitoring devices, obstructive sleep apnoea 137,
pharmacological treatment see drug treatment 138, 139, 140, 141
Phox2b 6, 7 positional treatment, obstructive sleep apnoea 148–149
246
positive airway pressure (PAP) therapy 157–162 Epworth Sleepiness Scale see Epworth Sleepiness Scale
adherence 160–161 (ESS)
autotitrating devices 139, 141, 157, 158 Stanford Sleepiness Scale 92
bi-level see bi-level positive airway pressure ventilation quetiapine 180, 182
central sleep apnoea 165–166 quiet sleep (QS) 200
continuous see continuous positive airway pressure breathing and 202
(CPAP) therapy polysomnography 223
expiratory see expiratory positive airway pressure (EPAP)
interfaces 158–159
machines 157–158
principles 157
R
race, as SDB predisposing factor 95
titration 159–160 ramelteon 180, 182
positive pressure ventilation via tracheostomy 234, 235, 236 rapid maxillary expansion (RME) 231–232
post-operative hypoxaemia 113 rebound insomnia 178
pramipexole, restless legs syndrome treatment 186, 187 recurrent hypersomnia 67, 69, 88, 183
cost 195 in children 215
pre-ejection systolic period (PEP) 15 see also hypersomnias of central origin
preBötzinger Complex (preBötC) 6, 7 reflex activation, upper airway dilator muscles see under
primary insomnia 54, 55–56 upper airway
see also insomnia relaxation training, insomnia treatment 178
professional performance, OSA patients 190–191 REM behaviour disorder (RBD) 61–63
protriptyline classification 62
adverse effects 154 diagnosis 62
cataplexy treatment 71 pathophysiology 62–63
OSA treatment 154 presenting features 62
PSQI (Pittsburgh Sleep Quality Index) 93 prevalence 62
psychiatric disorders, insomnia and see under insomnia treatment 63, 187
psychological interventions, insomnia 82–83, 177–178 REM sleep
psychophysiological insomnia 55 neural regulation 1, 2, 3
psychosomatic disorders, treatment of sleep disturbances normal vs abnormal events 61, 62
188 polysomnography 123
pulmonary congestion 43 in children 222
pulmonary hypertension 48, 50 respiratory mechanics and ventilation 10–11
pulse oximetry see oximetry see also sleep
pulse transit time (PTT) 15, 129 resistant hypertension 116
pulsus paradoxus 15 respiration
monitoring 120
Q
quality-adjusted life-year (QALY) 189–190
sleep history 85
see also breathing
respiratory disturbance index (RDI) 92, 141, 143, 151
CPAP therapy 193–194 respiratory drive, instability 97
restless legs syndrome treatment 195 respiratory effort-related arousals (RERAs) 22, 224
quality of life 107–109 respiratory events
assessment see health-related quality of life definitions 124
definition 107 scoring 125–126, 127
Quebec Sleep Questionnaire (QSQ) 109 in children 223–224
questionnaires 84, 91–93 respiratory mechanics, during sleep 10–11
circadian rhythm assessment 75 respiratory pacing 235
OSAS screening 92–93 respiratory polygraphy (RP), obstructive sleep apnoea 100,
Berlin Questionnaire see Berlin Questionnaire 102, 104, 105
STOP-Bang questionnaire 92–93, 112 in children 207
STOP questionnaire 92 respiratory rhythm, developmental aspects 202
paediatric 207 restless legs syndrome (RLS) 64–65, 85, 86, 185, 194
quality of life assessment see under health-related quality attention deficit hyperactivity disorder and 215–216
of life (HRQoL) in children 215–216
sleep quality assessment 93 classification 65, 194
sleepiness assessment 91–92 diagnosis 64–65, 185
247
economic consequences 195 peripheral arterial tonometry 15–16, 138
epidemiology 65, 194 pulse transit time 15
iron deficiency and 65, 185–186, 216 breathing during 6–11
medical consequences 194 control of 6–7
pathophysiology 65, 216 developmental aspects 202
treatment 65, 185–187 pathophysiology of ventilatory changes 48
economic impact 195 respiratory mechanics and ventilation 10–11
nonpharmacological 185 development in first years of life 200–201, 224–225
pharmacological 65, 185–187, 195 diaries see sleep logs/diaries
retrotrapezoid nucleus (RTN) 6, 7 disorders see sleep disorders
rhinitis, in children 211 emotions and 82
RME (rapid maxillary expansion) 231–232 history see sleep history
ropinirole, restless legs syndrome treatment 186, 187 hygiene see sleep hygiene
Roth, Bedrich 71 logs see sleep logs/diaries
rotigotine, restless legs syndrome treatment 186, 187 metabolic changes 17–18
Roux-en-Y gastric bypass 153 appetite regulation 18
R–R interval analysis 14, 153 glucose metabolism 18
neurobiology 1–4
S
Saethre–Chotzen syndrome 230
non-REM see NREM sleep
questionnaires see questionnaires
REM see REM sleep
SAQLI (Calgary Sleep Apnea Quality of Life Index) 109 requirements 3, 4
Scopinaro technique 153 Sleep Apnea Quality of Life Index (SAQLI) 109
SDB see sleep disordered breathing sleep apnoea
secondary insomnia 54, 56 central see central sleep apnoea (CSA)
see also insomnia obstructive see obstructive sleep apnoea syndrome
seizures, nocturnal 64 (OSAS)
selective serotonin re-uptake inhibitors sleep attacks 88
cataplexy treatment 71, 185 sleep cycle 3
OSA treatment 154 effect of ageing 3–4
‘selfish brain’ theory 37 infants 200, 201, 224
sensory symptoms, sleep history and 86 sleep deprivation, effects 3
serotonergic neurons 1, 2 appetite regulation 18
sex, as SDB predisposing factor 95 glucose metabolism 18
central sleep apnoea 40 sleep disordered breathing (SDB)
obstructive sleep apnoea 26, 27 in children see sleep disordered breathing in children
SF-36 (Medical Outcomes Study 36-item short-form health CSA see central sleep apnoea
survey) 108 definitions 21–24
shift work disorder (SWD) 77–78 diagnostic algorithms 100–105
evaluation 75 insomnia and 54, 58–59
health impacts 78 OSA see obstructive sleep apnoea
management 78 predisposing factors see sleep disordered breathing,
SIDS (sudden infant death syndrome) 204 predisposing factors
skeletal disorders see neuromuscular/skeletal disorders quality of life and see health-related quality of life
sleep (HRQoL)
arousal from 1 SDB-plus 59
autonomic and cardiovascular changes 13 sleep-related hypoventilation see hypoventilation
obstructive sleep apnoea 17 syndromes
physiological data 16–17 sleep disordered breathing in children 205–209
autonomic and cardiovascular changes, assessment 13–16 clinical assessment 219–220
autonomic ‘stress tests’ 14 comorbid nonrespiratory disorders 216
blood pressure monitoring 14–15 comorbid respiratory disorders 210–212
heart rate variability analysis 14, 15 allergic rhinitis 211
methodological issues 13–14 asthma 210
microneurography 16 bronchopulmonary dysplasia 212
OSA patients 17 chronic lung disease 212
248
cystic fibrosis 211 in infant/child 222–223
interstitial lung disease 211–212 see also polysomnography (PSG)
obstructive sleep apnoea see obstructive sleep apnoea sleep endoscopy 151
syndrome in children Sleep Heart Health Study (SHHS) 108
sleep hypoventilation syndromes 208–209 sleep history 84–86
congenital central hypoventilation syndrome see children 219–220
congenital central hypoventilation syndrome daytime symptoms 85–86
(CCHS) infants 218–219
management 234–236 insomnia assessment 57
neuromuscular and related conditions see nocturnal symptoms 85, 86
neuromuscular/skeletal disorders questionnaires see questionnaires
see also children sleep/wake pattern 85
sleep disordered breathing, predisposing factors 95–98 sleep hygiene
age 95 inadequate 56
anatomical abnormalities 95–97, 96 recommendations for insomnia patients 88, 177, 178
congenital syndromes 97–98 sleep hygiene education (SHE) 82
hyoid bone displacement 96 sleep logs/diaries 84
hypertrophy of uvula, soft palate and tonsils 96 circadian rhythm evaluation 74, 75
macroglossia 96 insomnia assessment 57, 58
micrognathia 96 sleep monitoring devices, classification 136–137
nasal obstruction 96 sleep-onset REM periods (SOREMPs) 89
upper airway shape/length 96–97 definition 89
associated diseases 96, 97–98 idiopathic hypersomnia 72
chronic kidney disease 98 narcolepsy 69
endocrine disorders 98 sleep quality, questionnaires 93
gastro-oesophageal reflux disease 98 sleep questionnaires see questionnaires
heart failure 98 sleep-related hypoventilation
obesity 98 definition 224
stroke 98 see also hypoventilation syndromes; nocturnal
functional factors 96, 97 hypoventilation
airway inflammation 97 sleep-related movement disorders
increased upper airway collapsibility 97 periodic limb movement disorder see periodic limb
instability of respiratory drive 97 movement disorder (PLMD)
race 95 restless legs syndrome see restless legs syndrome (RLS)
sex 95 treatment 185–187
sleep disorders sleep requirements 3, 4
medicolegal and economic aspects 189–197 sleep restriction
costs 189 effects 4
see also healthcare costs insomnia treatment 177–178
QALY assessment see quality-adjusted life-year (QALY) sleep spindles 122, 123
nonrespiratory 52 in children 222, 223
in children see under children sleep stages
psychiatric aspects 80–83 normative data across lifespan 127
depression 80–81 polysomnography 122, 123, 126
psychological interventions 82–83 sleep state misperception 56
role of emotions 82 sleep/wake rhythm disorders see circadian rhythm disorders
in somatoform disorders, treatment 188 sleepiness, daytime
see also sleep disordered breathing (SDB); specific disorders assessment in children 226
‘sleep drunkenness’ 71 see also excessive daytime sleepiness (EDS)
sleep EEG 120 sleepwalking 63
arousals 126 snoring 32, 85, 86
in children 222 in children 205, 207
electrode placement 120, 121 clinical assessment 219
historical aspects 1 sodium oxybate 70, 71, 184–185
paediatric 221 soft palate, hypertrophy 96
scoring 222–223 somatoform disorders, treatment of sleep disturbances 188
scoring 122, 123, 126 somnambulism 63
249
Spielman model of insomnia 55, 56
spinal injuries 50
stage 1 sleep, polysomnography 122
U
upper airway 7–10
in children 222 anatomy 7–8, 9
stage 2 sleep, polysomnography 122, 123 in obstructive sleep apnoea see under obstructive sleep
in children 222 apnoea
stage 3/4 sleep, polysomnography 123 as predictor of therapeutic interventions 9–10
in children 222 critical closing pressure 8–9
stage R sleep obstructive sleep apnoea syndrome 9, 30, 97
polysomnography 123 in development of breathing control 201–202
in children 222 effect of mandibular advancement 150
see also REM sleep examination, obstructive sleep apnoea 34
stage W (wake stage), polysomnography 122, 123 inflammation 9, 97
in children 222 influence of lung volumes on geometry 8
Stanford Sleepiness Scale (SSS) 92 reflex activation of dilator muscles 8
Stickler’s velocardiofacial syndrome 230 in obstructive sleep apnoea 30
stimulants, hypersomnia treatment 183–184 surgery, in obstructive sleep apnoea 150–152
narcolepsy 70, 71 three-dimensional reconstruction 8, 9
stimulus control, insomnia treatment 177 volume, men vs women 8
STOP-Bang questionnaire 92–93, 112, 113 upper airway resistance syndrome (UARS) 22, 205
STOP questionnaire 92 uvula, hypertrophy 96
stroke 98 uvulopalatopharyngoplasty 152, 231
central sleep apnoea and 40, 98
obstructive sleep apnoea and 35, 36, 98
sudden infant death syndrome (SIDS) 204
surgery, bariatric see bariatric surgery
V
valerian 182
surgical risk assessment, obstructive sleep apnoea 111–113 valsartan 155
α-synucleinopathy 62 venlafaxine 71
systemic hypertension see hypertension ventilation
during sleep 10–11
T
temazepam 180
see also breathing
ventilatory response (VR)
hypercapnic see hypercapnic ventilatory response
tetraplegia 50 hypoxic see hypoxic ventilatory response
theophylline therapy infants 201
central sleep apnoea 165 ventrolateral pre-optic area (VLPO) neurons 3
obstructive sleep apnoea 154 ventrolateral respiratory column (VRC) 6, 7
thermistors 122, 142, 221 video-polysomnography, in children 220
3P (Spielman) model of insomnia 55, 56
tongue size
measurement 8
sleep apnoea and 29, 96
W
wake/sleep transition 3
tongue surgery, obstructive sleep apnoea 152 breathing
tonsillectomy 152, 230–231 changes in lung mechanics 10
in infants 229 control of 7
tonsils, hypertrophy 96, 229 wake stage see stage W (wake stage)
Total face mask 158 wakefulness, neural regulation 1, 2
tracheostomy ‘wakefulness drive to breathe’ 7
obstructive sleep apnoea 152 weight loss, OSA patients 147–148, 152, 155
in infants 229 work disability
sleep hypoventilation syndromes in children 234, 235, 236 insomnia patients 196
trazodone 180, 182 OSA patients 190–191
triazolam 181
tricyclic antidepressants
cataplexy treatment 185
insomnia treatment 180, 182
Z
zaleplon 179, 181
OSA treatment 154 zolpidem 179, 181
250 zopiclone 179, 181

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Chapter 1 - Physiology and anatomy of sleep and breathing

Neuroanatomy and neurobiology of sleep 1

Chapter 2 - Respiratory conditions

Definitions of sleep disordered breathing 21

Chapter 3 - Nonrespiratory conditions

Nonrespiratory sleep disorders 52

Chapter 4 - Clinical assessment

Chapter 5 - Diagnostic techniques

Treatment of obstructive sleep apnoea 147

Chapter 7 - Medicolegal and economic aspects of sleep disorders

Medicolegal and economic aspects of sleep disorders 189

Chapter 8 - Paediatric respiratory sleep medicine

Development of breathing and sleep and physiopathology of 200

Ferrán Barbé Maria R. Bonsignore

An Boudewiyns Gary Cohen

Viliam Donic Athanasios Kaditis

Eric Konofal Michel Lecendreux

Patrick Levy Marie Marklund

Juan Fernando Masa Walter T. McNicholas

Josep M. Montserrat Mary J. Morrell

Paolo Palange Dirk Pevernagie

Winfried Randerath Dieter Riemann

Renata L. Riha Daniel Rodenstein

Silke Ryan Zoltan Tomori

Stijn Verhulst Maria Pia Villa

Anita K. Simonds, Wilfried de Backer

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2 ERS Handbook: Respiratory Sleep Medicine

ERS Handbook: Respiratory Sleep Medicine 3

● ● presence of delta waves. Alternatively,

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Mary J. Morrell, Paolo Palange, Patrick Levy and Wilfried De Backer

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Nostrils Oropharynx (OP)

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Stage 3/4 sleep-disordered breathing. J Biomech;

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Mary J. Morrell, Paolo Palange, Patrick Levy and Wilfried De Backer

Autonomic and cardiovascular regulation system. Pre-ganglionic cell bodies originate

Key points Methodological issues In view of the

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