Diagnosis and Treatment

of

Disorders

SPONSORED BY NEUROSCIENCE EDUCATION INSTITUTE

Released: November, 2007

CME Credit Expires: October, 2010
Diagnosis and Treatment
of Sleep/Wake Disorders
Every effort has been made in preparing this book to provide accurate and up-to-date
information that is in accord with accepted standards and practice at the time of
publication. Nevertheless, the author, editors, and publisher can make no warranties
that the information contained herein is totally free from error, not least because
clinical standards are constantly changing through research and regulation. The
authors, editors, and publisher therefore disclaim all liability for direct or consequen-
tial damages resulting from the use of material contained in this book. Readers are
strongly advised to pay careful attention to information provided by the manufacturer
of any drugs or equipment that they plan to use.

PUBLISHED BY NEI PRESS, an imprint of NEUROSCIENCE EDUCATION INSTITUTE

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Library of Congress Cataloging-in-Publication Data

ISBN 1-4225-0017-9
3-5 CME Information
7-18 Neurobiology of Sleep/Wake
8 Excessive Sleepiness
9 Sleep and Arousal Pathways and Brain Regions
10 Hypothalamic Regulation of Sleep and Arousal
11 Circadian Rhythms and Wake Propensity
12 The Arousal Spectrum
13 Disordered Sleep Affects Executive Function
14 Consequences of Sleep Deprivation
15 Consequences of Untreated Symptoms: Vehicular Accidents
16 Consequences of Untreated Symptoms: Medical Errors and School Achievement
17 Summary

19-32 Diagnosing Sleep/Wake Disorders

20 Polysomnography (PSG)
21 Tests of Wakefulness and Sleepiness
22 Epworth Sleepiness Scale
23 Neurobiological Causes of Sleep/Wake Disorders: Narcolepsy
24 Diagnosis of Narcolepsy
25 Diagnosis of Obstructive Sleep Apnea
26 Consequences of Obstructive Sleep Apnea
27 Factors Underlying Shift-Work Sleep Disorder
28 Shift-Work Sleep Disorder
29 Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLMs)
30 Neurobiology of RLS and PLMs
31 Summary

33-47 Treatment of Sleep/Wake Disorders

34 Sleep/Wake Hygiene
35 Treatment Guidelines
36 Treating Excessive Sleepiness: Methylphenidate
37 Treating Excessive Sleepiness: Amphetamine
38 Treating Excessive Sleepiness: Modafinil
39 Treating Excessive Sleepiness: Sodium Oxybate
40 Treating Excessive Sleepiness: Caffeine
41 Treatment for Disturbed Sleep: Sleep Aids
42 Modulating the Circadian Rhythm: Melatonin
43 Treatment Guidelines: Narcolepsy
44 Treatment Guidelines: OSA
45 Treatment Guidelines: Shift-Work Sleep Disorder
46 Restless Legs Syndrome/Periodic Limb Movements
47 Summary

48-49 Reference List

50 Posttest
 CME Information

CME Information

Overview
Sleep/wake disorders can cause significant impairment in social and work functioning due to
their daytime effects on alertness, cognitive functioning, and mood. In this booklet we examine
the underlying neurobiological causes of sleep/wake disorders as well as the current evidence
and guidelines for diagnosis and treatment of patients presenting with these disorders.
Target Audience
This activity was designed for healthcare professionals, including psychiatrists, neurologists,
primary care physicians, clinical psychologists, pharmacists, psychotherapists, nurses,
nurse practitioners, addiction counselors, social workers and others, who treat patients with
psychiatric conditions.
Statement of Need
The content of this educational activity was determined by rigorous assessment, including
activity feedback, expert faculty assessment, and literature review, which revealed the
following unmet needs:
• The neural circuitry implicated in the pathophysiology of sleep disorders is
beginning to be understood
• Despite the well-established significant mental and physical health consequences of
sleep disorders, they are under-recognized and under-treated
• Appropriate treatment options can differ depending on the cause of disordered
sleep; in addition, for each sleep disorder there are multiple treatment options
including pharmacological, behavioral, and others
Learning Objectives
Upon completion of this activity, you should be able to:
• Recognize underlying causes of sleep/wake disorders
• Identify patients for whom direct treatment of sleep/wake problems is necessary
• Effectively implement treatment plans for patients with sleep/wake disorders
Accreditation and Credit Designation Statements
The Neuroscience Education Institute is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians.
The Neuroscience Education Institute designates this educational activity for a maximum of
2.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate
with the extent of their participation in the activity.
Activity Instructions
This CME activity is in the form of a printed monograph and incorporates instructional
design to enhance your retention of the information and pharmacological concepts that are
being presented. You are advised to go through this activity from beginning to end and then
complete the posttest and activity evaluation. The estimated time for completion of this
activity is 2.5 hours.
Instructions for CME Credit
To receive your certificate of CME credit or participation, please complete the posttest (you
must score at least 70% to receive credit) and activity evaluation found at the end of the
monograph and mail or fax them to the address/number provided. Once received, your
posttest will be graded and a certificate sent if a score of 70% or more was attained.
Alternatively, you may complete the posttest and activity evaluation online and immediately
print your certificate. There is no fee for this activity.
NEI Disclosure Policy
It is the policy of the Neuroscience Education Institute to ensure balance, independence,

3
Diagnosis and Treatment of Sleep/Wake Disorders

objectivity, and scientific rigor in all its educational activities. The Neuroscience Education
Institute takes responsibility for the content, quality, and scientific integrity of this CME activity.
All faculty participating in any NEI-sponsored educational activity and all individuals in a
position to influence or control content development are required by NEI to disclose to the
activity audience any financial relationships or apparent conflicts of interest that may have a
direct bearing on the subject matter of the activity. Although potential conflicts of interest are
identified and resolved prior to the activity, it remains for the audience to determine whether
outside interests reflect a possible bias in either the exposition or the conclusions presented.

Individual Disclosure Statements

Authors/Developers
Meghan Grady
Director, Content Development
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Eleanor Roberts, MSc, PhD
Medical Writer
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Content Editor
Stephen M. Stahl, MD, PhD
Adjunct Professor, Department of Psychiatry
University of California, San Diego School of Medicine, San Diego, CA
Board Member: Cypress Bioscience; NeuroMolecular; Pierre Fabre; Tetragenix
Grant/Research: Alkermes; AstraZeneca; Bristol-Myers Squibb; Cephalon; Cyberonics; Eli
Lilly; GlaxoSmithKline; Janssen; Jazz; Neurocrine Biosciences; Novartis; Organon; Pfizer;
Sepracor; Shire; Somaxon; Takeda; Wyeth
Consultant/Advisor: Acadia; Amylin; AstraZeneca; Avera; Azur; Biovail; Boehringer
Ingelheim; Bristol-Myers Squibb; Cephalon; CSC; Cyberonics; Cypress Bioscience; Eli
Lilly; Epix; Forest; GlaxoSmithKline; Janssen; Jazz; Labopharm; Neurocrine Biosciences;
NeuroMolecular; Neuronetics; Novartis; Organon; Pamlab; Pfizer; Pierre Fabre;
sanofi-aventis; Schering-Plough; Sepracor; Shire; Solvay; Somaxon; Tethys; Tetragenix;
Vanda; Wyeth
Speakers Bureau: AstraZeneca; Cephalon; CSC; Eli Lilly; Pfizer; Wyeth

Peer Reviewers
Meera Narasimhan, MD
Professor, Department of Psychiatry
Director of Biological Research, Office of Biological Research
Department of Neuropsychiatry and Behavioral Science
University of South Carolina School of Medicine, Columbia, SC
Grant/Research: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Forest
Laboratories, Inc.; Janssen Pharmaceutica Inc.
Consultant/Advisor: Bristol-Myers Squibb Company; Eli Lilly and Company
Speakers Bureau: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Eli Lilly
and Company; Janssen Pharmaceutica Inc.
Electa Stern, PharmD
Clinical Supervisor
Sharp Grossmont Hospital, La Mesa, CA
Attended Advisory Board: Aventis Pharmaceuticals Inc.; Johnson & Johnson; Novartis

4
 CME Information

Editorial & Design Staff

Rory Daley, MPH
Program Development Associate
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Stacey L. Hughes
Director, Program Development
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Nancy Muntner
Director, Medical Illustrations
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose
Steve Smith
President and COO
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Jahon Jabali
Interactive Designer
Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.
Disclosed financial relationships have been reviewed by the Neuroscience Education
Institute CME Advisory Board to resolve any potential conflicts of interest. All faculty and
planning committee members have attested that their financial relationships do not affect
their ability to present well-balanced, evidence-based content for this activity.

Disclosure of Off-Label Use

This educational activity may include discussion of unlabeled and/or investigational uses of
agents that are not approved by the FDA. Please consult the product prescribing information
for full disclosure of labeled uses.

Disclaimer
Participants have an implied responsibility to use the newly acquired information from
this activity to enhance patient outcomes and their own professional development. The
information presented in this educational activity is not meant to serve as a guideline
for patient management. Any procedures, medications, or other courses of diagnosis or
treatment discussed or suggested in this educational activity should not be used by clinicians
without evaluation of their patients’ conditions and possible contraindications or dangers
in use, review of any applicable manufacturer’s product information, and comparison with
recommendations of other authorities. Primary references and full prescribing information
should be consulted.

Grantor Information
This activity is supported by an educational grant from Cephalon, Inc.

5
 Neurobiology of Sleep/Wake

Objectives

Apply an understanding of neurobiological and neurochemical

mechanisms of arousal and sleep to the diagnosis of sleep/wake
problems

Recognize that there is a spectrum of arousal, from hyperarousal to

hypoarousal, which has been shown in a number of disorders but may
stem from the same brain mechanisms

Recognize the role of the hypothalamic-pituitary-adrenal (HPA) axis in

disorders of arousal and sleep

Identify the relationship between excessive sleepiness and problems

such as vehicular accidents, medical errors, and work/school
productivity

7
Diagnosis and Treatment of Sleep/Wake Disorders

Figure 1.1 In 2005, the National Sleep Foundation conducted a “Sleep in America Poll”
that involved 1506 random telephone interviews with adults within the continental United
States. Questions asked included the circumstances leading to excessive sleepiness (ES).
These involved incidences of sleep disturbances such as getting less sleep than needed during
the week, taking 30 minutes or more to fall asleep, and having to stay up later than wanted
during the week. They found that one- to two-thirds of those who had these problems suffered
from ES. For instance, of the 26% who said that they only got a good night’s sleep a few
nights a month, 62% also reported they had ES.

Problems with ES can affect a person’s work and/or social life. Of the 28% who had missed
work/events or made an error at work, half of them also suffered from ES. Of the physical
factors examined, 62% considered themselves obese and of these over a third suffered from
ES at least 3 days a week. A number of these factors will be considered in this booklet.
[National Sleep Foundation, 2005]

8
 Neurobiology of Sleep/Wake

Arousal
Circuits

Thalamus
Basal
Hyp Forebrain

N
BA

Figure 1.2 Most wake circuits originate in the brainstem arousal nuclei (BAN), which stimulate
the thalamus, hypothalamus (Hyp) and basal forebrain. The hypothalamus itself stimulates
the thalamus and basal forebrain, and these areas arouse the cortex. These projections also
inhibit sleep centers such as those discussed below.

Sleep
Circuits

Thalamus

Basal
VLPO
Forebrain
N
BA

Figure 1.3 The ventrolateral preoptic nucleus (VLPO) in the hypothalamus inhibits the BAN
and the parts of the hypothalamus involved in wakefulness. This leads to inhibition of other
wake-centers including the thalamus, basal forebrain, and the cortex, and thus the initiation
and maintenance of sleep. [Stenberg, 2007]

9
Diagnosis and Treatment of Sleep/Wake Disorders

The Hypothalamus
and Control
SCN PVN
Suprachiasmatic nucleus SPZ
SPZ
Supraventricular zone
Lateral
DMN SCN Hyp
Dorsomedial nucleus
PVN
Paraventricular nucleus DMN
Lateral Hyp VLPO
Lateral hypothalamus
VLPO
Ventrolateral preoptic nucleus

Figure 1.4 The sleep/wake cycle is controlled by distinct hypothalamic neurons. The SCN
is the circadian “pacemaker” and is influenced by light, activity, and melatonin to promote
either wake or sleep. Signals from the SCN are amplified by the SPZ and the DMN, which
project to the VLPO (promotes sleep), the lateral hypothalamus (promotes wakefulness), and
the PVN (controls pineal melatonin release).

From SCN

SCN
PVN CRF

Pit
ACTH

Cortisol
To/from adrenal glands via bloodstream

Figure 1.5 In the normal hypothalamic-pituitary-adrenal (HPA) axis, the PVN is stimulated by
the SCN, in a circadian fashion, to produce corticotrophin-releasing factor (CRF). This acts
on the pituitary gland (Pit), which in turn produces adrenocorticotrophic hormone (ACTH).
ACTH is then released into the bloodstream where it initiates the release of cortisol from the
adrenal glands. Cortisol is one of the factors involved in the sleep/wake cycle through a
feedback system whereby it can then influence activity in the hypothalamus. Thus the HPA axis
is important to regulation of sleep and arousal.

10
 Neurobiology of Sleep/Wake

Wake Wake
propensity

Sleep

Body Wake
temperature

Sleep

Circadian rhythm: Wake

response
to light

Sleep

Wake
Cortisol

Sleep

6am 9am 12pm 3pm 6pm 9pm 12am 3am 6am 9am 12pm 3pm

Figure 1.6 Several factors involved in the rhythmic control of sleep and wake are shown here.
Circadian arousal is largely influenced by ocular exposure to light; thus it rises in the morning,
declines with a gradual slope throughout the day, and then declines further beginning in the
late evening. Body temperature is also at its lowest in the early morning, rising throughout
the morning and then staying fairly steady until it begins to decline again in the late evening.
Combined with this, a morning pulse of cortisol, which binds to circadian hypothalamic
receptors, stimulates arousal from sleep with levels declining throughout the day. In addition,
certain brain chemicals (e.g., adenosine, a byproduct of energy metabolism), accumulate
during waking time and decline during sleep. The varying levels of these chemicals affect one’s
wake propensity, with wake propensity declining as they accumulate and then increasing as
the sleep debt is paid. [Saper et al., 2005; Dijk and Lockley, 2002]

11
Diagnosis and Treatment of Sleep/Wake Disorders

Insomnia, Sleepiness,
executive dysfunction executive dysfunction
Hyperarousal Normal Hypoarousal
Arousal

Hallucinations Sleep

Figure 1.7 Whether we are asleep or awake depends on the interaction between many key
players: circadian rhythms, ultradian cycles, and homeostatic drive. However, “awake” and
“asleep” are not the only states of arousal; rather, arousal is akin to a dimmer switch that
affects a person’s behavior depending on how high or low the switch is turned.

Hyperarousal is considered an underlying cause of insomnia and may be related to

dysfunction of the HPA axis. Specifically, HPA dysfunction can lead to increases in CRF and
cortisol release. These factors feed back to cause additional activation of both the HPA axis
and arousal systems, such as the locus coeruleus, during the night. Thus, during hyperarousal
arousal circuits fail to turn off, and whole-brain metabolism remains more akin to the waking
than the sleeping state. Problems arising from this hyperarousal include sleep fragmentation
and a decrease of the more “refreshing” slow-wave sleep. In extreme cases of hyperarousal,
individuals may even experience hallucinations.

With hypoarousal, there is thought to be reduced basal ACTH secretion and a reduction of
central CRF. Extreme hypoarousal underlies excessive sleepiness present in numerous sleep/
wake disorders, which is the focus of this booklet and is discussed in more detail later.

Ailments along the trajectory connecting both extremes are more intriguing and their
treatment can be controversial. Mild sleepiness, regardless of cause, may lead to executive
dysfunction. Similarly, being in a state of hyperarousal, even mild hyperarousal, can impair
cognitive functioning. Thus the question remains, is there a relationship between sleep/wake
disorders and cognitive disorders? Sleep circuits overlap with many neurobiological circuits
underlying cognitive functioning, as discussed in more detail on the following page. [Buckley
and Schatzberg, 2005]

12
 Neurobiology of Sleep/Wake

Circuit Function Lesion

DLPFC Problem Solving Working Memory
Cognitive Flexibility Attention
Self Monitoring Organizational Skills
Planning
OFC Sensory Integration Impulsivity
Response Inhibition Distractibility
Emotional Regulation Disordered Behavior
ACC Goal-Directed Behavior Error Monitoring
Error Processing Stroop Performance
Emotional Output
Attention

Figure 1.8 Symptoms of sleepiness can affect daily life, including our higher executive
functions. This is because circuits involving sleep centers can overlap with those controlling
attentional processes. The main pathways involved in attention are the ascending projections
from catecholaminergic nuclei in the brainstem, and from cholinergic cells of the basal
forebrain to the prefrontal cortex. These are the same nuclei that are important in maintaining
cortical arousal.

In general, the dorsolateral prefrontal cortex (DLPFC) is involved in problem solving, cognitive
flexibility, self monitoring and planning. Lesions here can lead to problems with working
memory, attention, and organization skills.

The orbitofrontal cortex (OFC) is involved in the mediation of information about the internal
environment, including sensory signals, as well as inhibiting inappropriate responses and
regulating emotional behavior. Lesions here can lead to impulsivity, distractibility, disordered
behavior, and difficulties in responding appropriately to social cues.

The anterior cingulate cortex (ACC) mediates goal-directed behavior, partly by aiding the
selection of internally relevant cues to environmental situations; monitors conflict situations;
helps control emotional output; and is involved in the voluntary allocation of attention. Studies
of lesion here show sufferers responding less to errors and performance deficits on cognitive
tests. [Arnsten, 2005; Heyder, 2004; Shipp, 2004]

13
Diagnosis and Treatment of Sleep/Wake Disorders

M L
a o
n n
y g

Performance Lapses

Sleep Latency
Right cerebellum Cingulate cortex N S
o h
Inferior frontal gyrus n o
Inferior parietal lobe e r
Dorsolateral prefrontal cortex Baseline 1 2 3 4 5 6 7 t
Days with Restricted Sleep

Figure 1.9 In the short-term, sleep deprivation Figure 1.10 In the “real world” it is more
can be compensated for and people who often the case that sleep is below average
have had little to no sleep can function (not totally deprived) over an extended
somewhat normally in everyday tasks. period of time. Dinges et al. (1997) restricted
sleep to an average 4.98 hours per night
As an example, Drummond et al. (2005) over 7 days. The results were that cumulative
used a word memorizing task and showed sleep debt produced significant problems
that when recalling easy to learn words, with fatigue, confusion, tension, and total
sleep deprived subjects reported finding the mood disturbance; in addition, psychomotor
task slightly more difficult but showed no vigilance generally decreased day by
difference in brain activation compared to day. Interestingly, overall changes in these
after a normal night’s sleep. However, when measures were great during the first 2 days,
asked to memorize and recall hard to learn recovered slightly during the next 3 days,
words there were significant increases in and then fell again during the last 2 days.
brain activation in the regions shown in color
above. This shows that it is possible for the body and
brain to compensate for sleep deprivation in
As performance levels did not change it was the short-term, but that if this continues it can
thus shown that to be able to complete a task “run out” of resources. In addition, sleepiness
at the same level as normal the sleep deprived and performance problems continued for
brain has to both increase activation in the around 2 days after the end of the study,
regions usually utilized in this task and recruit despite participants having a normal sleep
additional brain regions. It is of note that time. The graph above combines the results
activation and recruitment during the harder of this study showing performance deficits
task was found in many of the brain regions with the effect of sleep deprivation on
previously discussed as being involved in sleep latency during the day. [Dinges et al.,
executive functioning. [Drummond et al., 1997]
2005]

14
 Neurobiology of Sleep/Wake

6 5.9

Odds Ratio
4

3
2.3
2
1
1

0
Signs that a person may have After Non- MVC After Near Misses
fallen asleep at the wheel include Extended Extended After Extended
the absence of skid marks (<24h) Shift (>24h) Shift (>24h) Shift

Figure 1.11 In the 2005 Sleep in America Poll, 37% of the respondents who “drive or have
a license” said that they have, at some point in their lives, nodded off or fallen asleep while
driving. 5% said that this occurs at least once a month and 4% said they have had an accident
or near accident in the past year because of dozing or being too tired while driving.

During accident investigations a key sign that someone has drifted off behind the wheel is the
absence of tire skid marks or signs of hard braking such as could be shown on a truck driver’s
tachograph. Many drivers who have had a sleep-related vehicle accident (SRVA) cannot
recollect falling asleep, and, indeed, it has been found in sleep studies that people who fall
asleep for less than two minutes generally do not recall it.

The peak time of SRVAs is 02:00–06:00 and 14:00–16:00, coinciding with the circadian
lows. The biggest sector of people who have SRVAs are those who drive company cars and
trucks, especially at night; drivers who are on call for extended periods; people who have
long work hours; and those driving home from a night shift.

A study of medical interns showed that the odds ratio of having a “near miss” during the
commute home from work was 5.9 times higher following a shift lasting more than 24
hours, and having an actual motor vehicle crash (MVC) was 2.3 times higher. It was also
found that for every extra extended shift per month the risk of a crash on the commute from
work increased by 16.2%. Additionally, the odds ratios for falling asleep behind the wheel
significantly increased with the number of extended shifts worked per month. [Horne and
Reyner, 1999; Barger, 2005]

15
Diagnosis and Treatment of Sleep/Wake Disorders

18
Significant linear trend p<0.01

16
Sleepiness (Mean)

14

12

10
Mostly As Mostly As All Bs Mostly Bs All Cs or
and Bs and Cs less

Figure 1.12 Excessive sleepiness can significantly impair performance and increase the risk
of errors. When a child or adolescent’s grades start slipping, parents and teachers often
overlook sleep problems as a causative factor. Drake et al. (2003) looked at 442 students
(aged 11 to 15 years) and found a significant linear relationship between ES and total
sleep time as well as between Pediatric Daytime Sleepiness Scale (PDSS) scores and school
achievement, anger towards self and others, and more frequent illness.

Adolescents’ circadian rhythms can be shifted such that they cannot get to sleep until late, and
want to wake up later as well. This study also showed that over two-thirds of eighth graders,
compared to just over one-third of sixth graders, reported bedtimes of 11:00pm or later, and
that over double the percentage of eighth graders (40%) reported getting less than 7 hours
sleep on school nights. Accordingly, PDSS score increased with grade level. This circadian
shift and an adolescent’s need for more than 8 hours sleep a night is now being recognized
by some schools who are experimenting with later school start times.

Increased work errors as a result of excessive sleepiness can be a safety concern. Suzuki
(2005) surveyed hospital nurses about occupational accidents due to excessive sleepiness
(ES). Over a quarter of nurses answered “yes” to the question, “Do you feel excessively sleepy
during the daytime?” and nearly half said that their sleep sufficiency was “very insufficient”
or “insufficient.”

For those who had an error when administering a drug, the incident was associated with
ES, sleep medication use, age, and night or irregular shift work, the last being significantly
correlated. Incorrect operation of medical equipment also showed significant associations
with ES and age (those over 50). This study suggests that there is a correlation between
medical errors and ES, especially for nurses working irregular shifts and/or night shifts.
[Drake et al. 2003; Suzuki, 2005]

16
 Neurobiology of Sleep/Wake

People can suffer from excessive sleepiness for a number of reasons.

During the day arousal circuits normally inhibit sleep circuits, with a
role reversal during the night.

Many sleep-related problems involve and affect the same neurobiological

systems even if they do not stem from the same neurobiological
systems.

There is a “spectrum of arousal” from hyperarousal to sleep which can

all be associated with sleep-related problems.

The HPA axis is intimately involved in arousal and sleep and disruptions
can lead to either hyperarousal or hypoarousal.

Problems with hyper- and hypoarousal can affect executive functions

and, therefore, performance.

While short-term sleep deprivation may be compensated for, long-term

sleep restriction can affect psychomotor and cognitive performance.

Consequences of untreated excessive sleepiness can include vehicular

accidents, medical errors, decreased work productivity/school
achievement, and/or increased psychiatric symptoms.

17
 Diagnosing Sleep/Wake Disorders

Objectives

Gain knowledge of the tests for investigation of sleep/wake problems

to help in diagnosis

Understand the underlying biological factors involved in narcolepsy,

obstructive sleep apnea, shift-work sleep disorder, restless legs
syndrome, and periodic limb movements of sleep

Diagnose and distinguish sleep/wake disorders in order to provide

effective treatment and improve patient outcomes

19
Diagnosis and Treatment of Sleep/Wake Disorders

Electroencephalogram (EEG)

Electroocculogram (EOG)

Electromyogram (EMG)

Figure 2.1 PSG may be used when certain sleep/wake disorders are suspected, such as
periodic limb movement disorder (PLMD), narcolepsy, or obstructive sleep apnea (OSA).
During PSG, an EEG is used to determine which sleep stage a person is in, an EOG measures
eye movement to identify rapid eye movement sleep, and an EMG measures muscle movement
via electrodes on the chin, jaw bone, and calf muscles.

Thermistor
Electrocardiogram (ECG)

Piezo crystal effort sensor

Pulse oximeter

Figure 2.2 In addition, an electrocardiogram (ECG) is used to measure heart rate and rhythm,
and breathing is measured with a piezo crystal effort sensor, which utilizes two Velcro bands
around the chest and abdomen to measure movements and effort. Airflow is measured with
a “thermistor” secured under the nose and oxygen saturation can be measured by a “pulse
oximeter” on the finger or ear lobe. Finally the patient may also be videotaped. [Meir et al.,
2005]

20
 Diagnosing Sleep/Wake Disorders

Maintenance of Wakefulness Test (MWT)

• Quiet, secure, comfortable temperature, low light that allows patient to
focus on objects in the room, but not too bright
• Patient in a comfortable sitting position, with a back support
• Patient in daytime clothing
• Instructed to
- “Sit and remain still, try and stay awake for as long as you can
without extreme measures”
• Four attempted naps at 2-hour intervals beginning around 10:00am
• Sleep latency measured as time from beginning of trial to the first epoch
at any sleep stage
• Nap is terminated as soon as sleep onset is recognized

Multiple Sleep Latency Test (MSLT)

• Dark, comfortable room at an ambient temperature
• Smoking, stimulants and vigorous physical activity avoided during the
day, only light breakfast and lunch given
• Instructions are to
- “Lie quietly in comfy position, keep eyes closed, try to fall asleep”
• Five nap opportunities at 2 hour intervals—initial nap opportunity 1.5–3
hours after termination of usual sleep
• Between naps patient out of bed and awake
• Sleep onset determined by time from “lights out” to first epoch of any
sleep stage
• To assess occurrence of REM sleep the test continues for 15 minutes
from first sleep epoch
• Session terminated if sleep does not occur after 20 minutes

Figures 2.3 and 2.4 The Maintenance of Wakefulness Test and the Multiple Sleep Latency Test
are carried out in sleep laboratories, often after a night of PSG and a week filling in a sleep
diary. As there are different mechanisms for arousal maintenance and sleep induction, these
tests can measure different aspects of excessive sleepiness. Association between scores on
these two measures is not uniform across disorders, and thus sleep studies should involve both
measures. [Sangal et al., 1992]

21
Diagnosis and Treatment of Sleep/Wake Disorders

Likelihood of falling asleep or dozing off when: Chance of

Dozing
Sitting and reading 0 1 2 3

Watching television 0 1 2 3

Sitting inactive in a public place—theatre, meeting 0 1 2 3

As a car passenger for an hour without a break 0 1 2 3

Lying down to rest in the afternoon 0 1 2 3
Sitting and talking to someone 0 1 2 3
Sitting quietly after lunch without alcohol 0 1 2 3
Stopped for a few minutes while driving a car 0 1 2 3
Total Score

Likelihood scale—rate each from 0–3 and total score

0—Would never doze
1—Slight chance of dozing
2—Moderate chance of dozing
3—High chance of dozing
Score over 11 indicates abnormal sleepiness

Figure 2.5 The Epworth Sleepiness Scale (ESS) is a self-rating tool to enable patients and
physicians to easily investigate problems with excessive sleepiness. For the most part it can
be used both for looking at a day as a whole or for various times throughout a person’s wake
time to chart their circadian changes. As a self-rating tool, it is of course subjective, and may
not correlate well with objective test measures.

For the general population, the average score on the ESS may be approximately 5.9; scores
over 11 indicate excessive sleepiness. Interestingly, those with insomnia may have scores
lower than the general population, lending further weight to the theory that insomnia is a
disorder of the arousal mechanisms that, as well as keeping someone awake at night, can
leave someone in a state of hyperarousal during the day. [Stahl, in press]

22
 Diagnosing Sleep/Wake Disorders

Thalamus
Basal
LH Forebrain

Figure 2.6 Orexin/hypocretin (Orx) is released predominantly while awake and is impor-
tant in general arousal. Orexin is thought to suppress REM sleep and increase the excitatory
tone of arousal circuits. Although orexin neurons are only found in a small population of
cells in the lateral hypothalamus (LH), they have wide ranging projections.

To Basal Forebrain

Orx
HA GABA

A N
B
Motor
Neurons

Figure 2.7 Orexin neurons have reciprocal projections to hypothalamic histamine (HA)
neurons, as well as to the brainstem arousal neurons (BAN), motor neurons, and the basal
forebrain. In narcolepsy there is a deficiency in orexin leading to rapid destabilization of the
arousal circuits and thus extreme and sudden sleepiness. In addition, there may be a lack of
stimulation to motor neurons, which can cause cataplexy, or loss of muscle tone. [Scammell,
2003]

23
Diagnosis and Treatment of Sleep/Wake Disorders

/
Figure 2.8 Narcolepsy is estimated to occur in 0.03–0.16% of the general population, with
its development mostly beginning in the teens. Narcoleptic sleep attacks usually occur for
10–20 minutes and, on awakening, the patient can be refreshed for 2–3 hours before feeling
the need to sleep again. Although sleep attacks occur most often in monotonous situations,
they can also occur when a person is actively conversing or eating. Symptoms of narcolepsy
may include frightening hypnagogic hallucinations and sleep paralysis, which are usually
coincident with SOREMPs. Not everyone with narcolepsy will have cataplexy but it is a unique
feature of this disorder. An attack normally lasts a few seconds to minutes, during which the
person is conscious. Some people have only minimal muscle involvement, while others can
have “full-body” attacks; however, the respiratory and ocular muscles are never involved.
Excessive sleepiness is the main symptom to continue with age, and it may worsen alongside
the development of periodic limb movements and obstructive sleep apnea. In addition, sleep
may be disrupted and include frequent awakenings. [ICSD rev, 2001]

24
 Diagnosing Sleep/Wake Disorders

Figure 2.9 Obstructive sleep apnea (OSA) is most common in middle-aged people with a
high BMI, a large neck circumference, and/or an underlying upper airway obstruction. It
has an estimated prevalence of 4% for men and 2% for women. The diagnostic criteria
for OSA include complaints of excessive sleepiness and/or difficulty sleeping as well as
frequent episodes of obstructed breathing during sleep that may lead to awakening with
breath holding, gasping or choking. Associated features include snoring, morning headache,
and dry mouth on wakening.

Diagnosis of OSA should be carried out in a sleep laboratory using PSG. Detailed above
is a number of readings that would be expected to be seen. A) The pharyngeal muscles
collapse at the beginning of an apneic event (effort), leading to B) zero airflow (flow) and
C) a drop in oxygen saturation (SaO2) (which can be to below 50%). This is followed by
D), an increase in respiratory effort, E) an arousal reaction, as shown on the EEG, and
F) an increase in pharyngeal muscle tone, leading to the upper airways opening again,
hyperventilation, accompanied by G) snoring (microphone), and tachycardia. These events
lead to a recovery period as can be seen with H) a return to normal oxygen saturation. Apneic
episodes normally last for 20–40 seconds, most often during REM sleep and sleep stages 1
and 2. They can be followed by loud snores and vocalizations, as well as whole-body move-
ments and microarousals.

Upon awakening patients can feel unrefreshed, disoriented, groggy, and uncoordinated.
These problems can be accompanied by a severe dry mouth and a dull, generalized
headache. The presenting complaint of those found to have OSA is predominantly excessive
sleepiness, although unexplained depression, anxiety, and irritability often accompany OSA.
Mild hypotension with an elevated diastolic pressure is also commonly associated with OSA
and bradytachycardia can accompany an apneic event and can increase the risk of sudden
death. [ICSD rev, 2001; Gilmartin et al., 2005]

25
Diagnosis and Treatment of Sleep/Wake Disorders

Healthy
Normal
Response

OSA
Limited
Response
Even After
Say “yes” when you see
OSA
the same letter that
appeared two letters ago

Figure 2.10 Occurrence of OSA can interfere with prefrontal cortical executive functions
including attention, concentration, alertness, and memory, as well as physical measures such
as reaction time. These may be due not only to the consequences of sleep fragmentation from
an apneic episode, but also to the intermittent hypoxemia and hypercarbia that the apnea
can cause. Other problems that may stem from these factors include poor motivation and
increased chances of developing an affective disorder.

Thomas et al. (2005) used the ‘n-back’ test where subjects are shown a series of items/
numbers/letters and are told to respond whenever an item matches another item shown ‘n’ (in
this case 2) items ago. This task was used to investigate working memory, specifically through
activation of the DLPFC, in patients with OSA compared to a group of control subjects.

The study showed that while in the control group there was activation of the DLPFC during
the n-back test, there was almost an absence of activation in this area in the patients with
OSA. This was regardless of whether the OSA patients suffered from nocturnal hypoxia,
and despite the fact that the percentage of correct responses was high. Although, clinically,
patients recovered following the use of continuous positive airway pressure (CPAP) therapy
(which will be discussed later), the decrease in DLPFC activation remained. [Thomas et al.,
2005]

26
 Diagnosing Sleep/Wake Disorders

Melatonin
Pineal SCN PVN

Figure 2.11 The main factors controlling the circadian rhythm of arousal are light, melatonin,
and activity. Retinal receptors project to the SCN, which also receives information from the
pineal gland, mostly via melatonin. This release of melatonin is indirectly controlled by the
SCN through the PVN and via the brainstem.

Activity
DMN
SCN
N
BA

Figure 2.12 Information about the body’s activity state is conveyed to the SCN through indirect
projections from the brainstem arousal nuclei (BAN). There is also local feedback inhibition
from other hypothalamic areas, such as the dorsomedial nucleus (DMN). [Saper et al., 2005;
Mistlberger, 2005]

27
Diagnosis and Treatment of Sleep/Wake Disorders

Normal sleep/wake cycle

Awake Asleep Awake

9am 3pm 9pm 3am 9am

Melatonin Level
9am 3pm 9pm 3am 9am

Asleep Awake Asleep

Shifted sleep/wake cycle
Figure 2.13 Up to 5% of adults are thought to suffer from shift-work sleep disorder and this can
lead not only to reduced work productivity, errors, and vehicular accidents, but also to mood
problems such as irritability, malaise, hostility, and depression.

While some people find that their circadian rhythm shifts to match their daily/nightly activity,
those who suffer from shift-work sleep disorder are not able to adjust to the mismatch
between their normal circadian sleep-wake pattern and the pattern required by that person’s
environment. This can lead to daytime insomnia, due to the arousal centers being normally
activated by light, and nighttime excessive sleepiness.

The diagnosis of shift-work sleep disorder generally begins with a detailed patient history
including questions such as:

Do you . . .

Feel irritable or sleepy during your shift?

Fall asleep sometimes while driving?
Have difficulty paying attention, concentrating, and/or working to your full potential?
Get told by others that you look tired?
Have emotional outbursts?
Feel like taking a nap while working?
Require caffeinated beverages throughout the night to keep yourself going?

This should be followed by a 7-day sleep diary and may include the wearing of a sleep
actigraph, a watch-like device that records gross activity. [Schwartz, 2006]

28
 Diagnosing Sleep/Wake Disorders

Figure 2.14 Patients with RLS experience an urge to move their legs to rid themselves of
unpleasant sensations (prickling, tingling, burning, or tickling; numbness; “pins and needles”;
or cramp-like sensations ). This movement typically relieves the sensations, which can occur at
any time but are most disruptive when one is trying to fall asleep.

Arousal
EEG Reading

PLM
Leg Actigraph Reading

Seconds

0 5 10 15 20 25 30

Figure 2.15 PLMs are involuntary movements that can occur during sleep or when awake.
Muscle activation usually occurs in a sequence of 0.5–15 second contractions at intervals
of 5–90 seconds and may arouse a person from sleep. Up to 87% with RLS will have PLMs
but not everyone with PLMs has RLS. Diagnosis must involve an overnight electromyogram to
distinguish PLM from other involuntary sleep movements [ICSD rev, 2001; Gilmartin et al.,
2005]

29
Diagnosis and Treatment of Sleep/Wake Disorders

To cortex 4 Knee
Flexion
A11 DA DRN
neurons +
1

DH
3
Muscle afferents + IML
- +
+
Motor neurons +
+ Big Toe
2
Ankle Extension
NE
Leg muscles Adrenaline Adrenal glands Dorsiflexion

Figure 2.16 The prevalence of RLS ranges Figure 2.17 Although around 80% of people
from 3–15% and increases with age. It is two with RLS also have PLMs, it is thought to arise
times greater in women and is also familial. from a separate mechanism and can be
experienced with or without RLS.
The proposed cause is shown above: 1)
inhibitory actions of A11 dopamine (DA) The action of PLMs consists of extension of the
neurons are compromised, allowing the big toes, ankle dorsiflexion and, occasionally,
excitatory serotonergic dorsal raphe nucleus flexion of the knee and hip, occurring every
(DRN) projections to dominate in the spinal 20–40 seconds. It predominantly occurs
cord. 2) An increase in sympathetic drive can at the beginning of the sleep cycle, where
result in increased norepinephrine (NE) and general periodic arousals are most common,
adrenal gland released adrenaline, which and mostly disappears during deep sleep
leads to aberrant activation of high-threshold and REM sleep. PLMs are associated with
muscle afferents. 3) Loss of DA inhibitory tachycardia, tachypnoea, and increases in
controls in the region relaying high-threshold systemic blood pressure, all of which can lead
deep afferent input to the brain also leads to arousal from sleep and thus disruptions in
to enhanced and aberrant signaling of daytime functioning.
ascending transmission of HTMAs. 4) The
resulting focal akathisia may be exacerbated Although it is unclear whether PLMs start in
by a compromised A11 modulatory control the limbs or are generated within spinal cord
of higher order sensory processing. neurons, it is known that the timing of PLMs
are modulated by descending influences and
It is thought that the proximity of A11 cells the current view is that the brainstem is the
to the hypothalamus explains the circadian common trigger. [Vetrugno et al., 2007]
nature of RLS and that, as dopamine
production requires ferritin, inadequate iron
stores/abnormal metabolism may decrease
brain dopamine production and contribute to
RLS. [Meir et al., 2005]

30
 Diagnosing Sleep/Wake Disorders

There are a number of measures designed to identify sleep/wake

problems which may involve a simple rating scale or a visit to a sleep
clinic.

Narcolepsy is a disorder involving lack of hypothalamic orexin, which

affects motor and brainstem neurons.

Narcolepsy diagnosis, which does not necessarily include cataplexy,

should involve assessment at a sleep clinic.

OSA follows a characteristic series of events that can lead to multiple

awakenings; consequences of OSA include excessive sleepiness,
depression, irritability, and cognitive dysfunction.

Our circadian rhythm is most influenced by daylight, which can be

counteractive in those with SWSD.

Diagnosis of SWSD is generally through a detailed patient history and

a sleep diary.

RLS and PLMs both have unelucidated etiologies.

31
 Treatment of Sleep/Wake Disorders

Objectives

Advise patients on appropriate sleep hygiene practices in order to

alleviate symptoms associated with sleep deprivation

Differentiate mechanisms of action for medications used in the treatment

of sleep/wake disorders

Implement appropriate management strategies for patients with sleep/

wake disorders in order to improve patient outcomes

33
Diagnosis and Treatment of Sleep/Wake Disorders

Dark room No stimulants

Cool environment before bed

No
disturbances Sleep Time

Figure 3.1 Difficulty falling or staying asleep can often be caused or exacerbated by poor
sleep hygiene. Using caffeine, exercising, working, or doing stimulating things late in the
evening; having a room that is too hot/cold or too light; having outside disturbances (e.g.,
noisy neighbors, disruptive pets); or keeping an inconsistent sleep/wake schedule should
always be examined first.

Wake Time

Activity

Natural light

Figure 3.2 During a person’s wake time excessive sleepiness can be exacerbated by being
inside, without natural light, and being sedentary. Therefore both sunlight and activity can
help relieve or prevent excessive sleepiness.

34
 Treatment of Sleep/Wake Disorders

(d)
Methylphenidate
Modafinil
(d,l)
Methylphenidate

Amphetamines

Caffeine

Sodium oxybate

Melatonin

Sleep aids

Ropinirole

Pramipexole

Antidepressants
Narcolepsy: sleepiness X X X X X X
Narcolepsy: cataplexy X X
OSA: sleepiness X X X X X
Shift-work sleep disorder
Shift- X X X X X X X
RLS/PLM X X X X X X X
Idiopathic hypersomnia X X X X X

Figure 3.3 For the most part, the same pharmacologic options can be used to treat ES
regardless of a patient’s diagnosis, as shown in the chart above (green denotes FDA approval
for the specified indication). Thus, methylphenidate, amphetamines, or modafinil can be used
to treat ES in narcolepsy, OSA, circadian rhythm disorders, restless legs syndrome, periodic
limb movement disorder, or idiopathic hypersomnia, as well as to treat ES associated with
medical or psychiatric conditions. Sodium oxybate, though it is efficacious for ES, has a
difficult dosing schedule and would likely not be a preferred choice for patients who do not
also have cataplexy. Each of these medications is examined in turn on the following pages,
focusing on mechanism of action, dosing, and side effects.

Beyond ES, treatment for sleep/wake disorders will likely vary based on the underlying
neurobiological basis for the symptoms, as indicated in the chart above. More specific
treatment recommendations for the sleep/wake disorders shown here are covered later in this
chapter. [Erman, 2006]

35
Diagnosis and Treatment of Sleep/Wake Disorders

VMAT

dopamine

A methylphenidate B

Figure 3.4 Psychostimulant-induced arousal is dependent on the actions of dopamine, along

with norepinephrine, within both the prefrontal cortex, the limbic areas, and a network of
subcortical regions. Following dopamine release, this neurotransmitter is taken back into
the neuron by the dopamine transporter (DAT) and once inside the cell can be stored again
in synaptic vesicles via the actions of the vesicular transporter (VMAT) (A). Methylphenidate
prevents dopamine reuptake by binding to the DAT (B).

Functional imaging studies have shown that methylphenidate can increase frontal activation in
people with intact functioning. Activation induced by methylphenidate here, as well as in the
cerebellum and frontal temporal cortex, is significantly correlated with dopamine D2 receptor
availability, thus responses to psychostimulants are determined in part by the working of the
dopamine system.

Methylphenidate is available in a racemic form (d,l), of which there are many formulations
which vary in terms of release (immediate release Ritalin, Methylin, generic; sustained
release Ritalin SR, Methylin SR, Metadate ER, generic; time release beads Metadate CD;
SODAS microbeads Ritalin LA; OROS Concerta). Methylphenidate is also available as the
d-enantiomer (immediate and extended release Focalin). Immediate release formulations are
recommended for excessive sleepiness, dosed 2–3 times per day for a total daily dose of
20–60 mg (racemic) or 5–20 mg (d-enantiomer). Notable side effects include insomnia,
headache, nervousness, irritability, overstimulation, tremor, and dizziness. Methylphenidate
has high abuse potential and is Schedule II, with greater risk for immediate release formulations,
although methylphenidate may be less reinforcing than amphetamines. [Stahl, in press; Stahl,
2005]

36
 Treatment of Sleep/Wake Disorders

VMAT

amphetamine A B

Figure 3.5 Amphetamine, like methylphenidate, binds to the DAT and prevents it from taking
up dopamine. However, it is also itself taken up into the neuron where it binds the vesicular
transporter (VMAT) (A). Competitive inhibition of amphetamine with dopamine at the VMAT
leads to transport of amphetamine into the synaptic vesicles, which in turn causes displacement
of dopamine from synaptic vesicles, intracellular dopamine accumulation, channel opening,
and dopamine release into the synapse. It also causes a reversal of DAT function, so that
dopamine is pumped out of the neuron instead of into it (B).

Amphetamines are available as the d-enantiomer (immediate and sustained release Dexedrine)
and as the racemic (immediate and extended release Adderall). Like methylphenidate, dosing
of amphetamines for excessive sleepiness is recommended at 20–60 mg/day divided into
2–3 doses. The side effects are also similar and include insomnia, headache, nervousness,
irritability, overstimulation, tremor, and dizziness. Like methylphenidate, amphetamines
are Schedule II drugs. There is a subtly greater dopamine release by amphetamines than
methylphenidate in the prefrontal cortex, which is thought to account for the subtle differences
in effects of these drugs on behavioral tolerance. [Stahl, in press; Stahl, 2005]

37
Diagnosis and Treatment of Sleep/Wake Disorders

modafinil

Alpha-adrenergic
receptors

dopamine

Figure 3.6 The precise mechanism of action of modafinil (Provigil) is yet to be fully elucidated.
It binds to the DAT and requires its presence as well as that of alpha adrenergic receptors,
especially alpha 1. In contrast, modafinil does not appear to require the norepinephrine
transporter or postsynaptic dopamine receptors. Modafinil’s low affinity for the dopamine
transporter has led some to question whether its binding there is relevant; however, because
plasma levels of modafinil are high, this “compensates” for the low binding affinity. It is
believed that the increase in synaptic dopamine following blockade of DAT leads to stimulation
of alpha receptors and thus downstream effects on neurotransmitters including glutamate and
histamine in wake-promoting regions.

Modafinil can also decrease GABA release in the nucleus accumbens of rats, which can lead
to a weak dopaminergic increase, and has also been shown to modulate orexin release,
which, in turn, can induce release of both glutamate and histamine in the hypothalamic areas
involved in arousal.

Modafinil is typically dosed between 200 and 400 mg/day in a single dose, with a starting
dose of 100 mg/day. The most common side effects are headache, nausea, nervousness,
anxiety, and insomnia. Despite having some actions on the dopamine system, modafinil does
not seem to have much abuse potential and is a Schedule IV drug. [Ballon and Feifel, 2006,
Stahl, 2005; Wisor and Eriksson, 2005]

38
 Treatment of Sleep/Wake Disorders

GABA

GABA B
GABA A
receptor
receptor

Cataplexy
Slow wave sleep
Excessive daytime sleepiness

Figure 3.7 Sodium oxybate (Xyrem) is the sodium salt of the endogenous neurochemical
gamma-hydroxybutyrate (GHB). It mediates most of its effects at the GHB and GABAB receptors.
GHB can further affect the GABA receptor system through its metabolism to GABA and
subsequent actions at GABAA and GABAC receptors. Sodium oxybate is also associated with
increased serotonin turnover, interactions with endogenous opioids, and possible modulation
of dopaminergic activity.

Low-dose sodium oxybate can increase levels of glutamate and dopamine, but at higher doses
it reduces levels of these neurotransmitters and increases levels of striatal and mesolimbic
serotonin. This is thought to reflect the activation of GHB receptors at low dose and the GABAB
receptors—for which sodium oxybate has only weak affinity—at higher doses.

Sodium oxybate can induce sleep without radically changing the natural sleep pattern and
was previously used in general anesthesia. It can consolidate disrupted sleep in people with
narcolepsy and also improves the occurrence of cataplexy and other daytime symptoms,
however the precise mechanism that is operating to help reduce cataplexy is not fully
understood. Sodium oxybate is available as a liquid (0.5 g/mL) and has to be dosed twice
nightly: starting dose is 2.25 g/4.5 mL diluted in 2 ounces of water immediately before
lying down and again 2.5–4 hours later. Therapeutic total daily dose is generally 6–9 g.
Side effects include headache, nausea, dizziness, pain, and somnolence. Sodium oxybate is
contraindicated in patients taking sedative hypnotics and in those with succinic semialdehyde
dehydrogenase deficiency. For medical use sodium oxybate is Schedule III, although for illicit
use it is Schedule I [Maitre, 1997; Lemon et al., 2006]

39
Diagnosis and Treatment of Sleep/Wake Disorders

Caffeine Antagonizes Adenosine Binding

and Enhances DA Actions

caffeine
adenosine

Figure 3.8 The well known effects of caffeine include enhanced psychomotor vigilance
and decreased propensity to sleep, normally at a “dose” of over 150 mg (large cup of
coffee). Caffeine works by blocking adenosine -1 (A1) and -2A (A2A) receptors in the basal
forebrain, leading to cortical arousal. While the almost ubiquitous A1 receptors are highest
in the hippocampus, cerebellum, and some thalamic nuclei, A2A receptors are concentrated
in the dopaminergic regions of the brain. A2A and D2 receptors colocalize on GABAergic
neurons in the striatum, and stimulation of the A2A receptors by adenosine reduces the
affinity of D2 receptors for dopamine, thus, blockade of these receptors by caffeine restores
the normal affinity of dopamine for the receptor. Through A1 receptor blockade caffeine
can increase levels of cortical acetylcholine release. Caffeine can also increase levels of
serotonin, glutamate, and norepinephrine, but the role these actions have in caffeine’s effects
is not thought to be major.

Wyatt et al. (2004) put a group of 16 subjects on a ‘forced desynchrony’ protocol where
they underwent 28.57-hour wake episodes and 14.28-hour sleep episodes. During the
wake condition subjects received either caffeine capsules or a placebo every hour. In the
placebo group there were a large number of unintentional sleep onsets especially at the
end of wake episodes and following the normal core temperature and melatonin high. In
contrast, during the wake episodes the caffeine group showed attenuation of the wake- and
circadian-dependent modulation of unintentional sleep onset. The caffeine group also had
significantly better results on an addition task, the Digit Symbol Substitution Task, and the
Psychomotor Vigilance Task. However, the sleep chances taken by the placebo group meant
that on subjective scales of sleepiness this group actually fared better than the caffeine group
and, using slow eye movements during wake time as another sign of sleepiness, there was no
difference between the groups. Interestingly the caffeine group also showed more impaired
sleep during times of normal wakefulness. [Stahl, 2005; Wyatt et al., 2004]

40
 Treatment of Sleep/Wake Disorders

zolpidem and zaleplon

12 3
9
6

benzodiazepines

1 2 3 5

Figure 3.9 There are a number of medications, both prescription and over-the-counter (OTC),
that can help improve sleep and thus in turn may reduce excessive sleepiness during waking
hours. The classic benzodiazepines bind non-selectively to any of the α-subunit isoforms of
GABAA receptors. This means that, along with their sedative effects, they can also be used
for anxiety problems, as muscle relaxants, and as hypnotics. Although these are added
benefits for some people, they can lead to problems with next day sedation and psychomotor
slowness. In addition, benzodiazepine actions at α5 can lead to memory problems.

The GABAA modulators zolpidem (Ambien, Ambien CR) and zaleplon (Sonata) show
selective affinity for only those GABAA receptors that include α1 subunits. Thus, although
GABAA modulators and benzodiazepines both act on the same receptors, the newer drugs
specifically activate receptors involved in sleep-promoting effects. This more restrictive binding
is proposed to be why the drugs have a better safety profile and less tolerance over long-term
use. The GABAA modulators zopiclone (not available in the U.S.) and eszopiclone (Lunesta)
may have slightly different mechanism of action, as it is not yet known if they are selective
for α1 subunits.

Although sleep aids can be used to improve sleep in some sleep disorders, as well as in
psychiatric and medical illnesses, they may not be recommended in all of these disorders.
Specific treatment guidelines for several sleep disorders are given on the following pages.
[Stahl, in press]

41
Diagnosis and Treatment of Sleep/Wake Disorders

Melatonin
Pineal SCN PVN
RHT

NE

SCG

Figure 3.10 Melatonin, an endogenous neurohormone, is a tryptophan/serotonin derivative

that is secreted by the pineal gland in increased levels as darkness sets in. It is intimately involved
in feelings of tiredness and initiation of sleep. Its synthesis is predominantly controlled by the
retinohypothalamic tract (RHT), via the suprachiasmatic nucleus (SCN). From here, the pineal
gland can be stimulated either via the paraventricular nucleus (PVN) of the hypothalamus, or
via norepinephrine release from the superior cervical ganglion (SCG) in the brainstem/spinal
cord, initiated when the SCN is inhibited. The receptors MT1 and MT2 control the relevant
actions of melatonin, suppressing neuronal firing and inducing phase shifts respectively. The
presence of MT1 receptors in the SCN suggests these mediate sleep-promoting mechanisms.

The general action of melatonin is to reduce sleep onset latency as opposed to maintaining
sleep. Although touted as a general sleep-promoting factor, studies show that ingestion of
melatonin may only be effective in people whose melatonin levels are low, e.g., night-shift
workers or people with insomnia. As such, it can also be used at times when there is not
normally melatonin, such as when someone with jet-lag is trying to advance their endogenous
circadian rhythm. It has been used additionally to help ‘train’ people who may be suffering
from free-running circadian rhythms such as has been shown in people who are blind.

Synthetic MT1/MT2 agonists, such as ramelteon (Rozerem), have been developed that
are around ten times as effective as ingested melatonin for reducing sleep onset latency.
Slow-release tablets are being investigated which are able to improve sleep maintenance
and duration as well. The effects of these tablets may not be as immediate as other sleep-aids,
with several nights administration needed before the full potential is reached. [Pandi-Perumal
et al., 2006; Pandi-Perumal et al., 2007]

42
 Treatment of Sleep/Wake Disorders

Drug Clinical Use Dose

modafinil excessive sleepiness 200–400 mg/day
amphetamines excessive sleepiness 5–60 mg/day*
methylphenidate (d,l) excessive sleepiness 20–60 mg/day*
sodium oxybate excessive sleepiness Initially 2.25 g taken just before
cataplexy lying down and again 2.5–4 hours
later; usual total daily dose 6–9 g
venlafaxine cataplexy 37.5–150 mg/day
clomipramine cataplexy 10–200 mg/day
fluoxetine cataplexy 20–80 mg/day
protriptyline cataplexy 5–30 mg/day

*Dosing schedule varies by formulation

Figure 3.11 Management of narcolepsy falls mostly into two categories: drugs for treating
excessive sleepiness and drugs for treating cataplexy. Treatment of excessive sleepiness has
been discussed in general on previous pages; pharmacologic options and their doses are
listed here.

Sodium oxybate has proved useful in the treatment of cataplexy and is the only agent
approved for such use. Sodium oxybate is also effective for reducing excessive sleepiness,
and additionally may reduce sleep disturbances and improve daytime alertness and
concentration.

A number of antidepressants have been used clinically for cataplexy, including tricyclic
antidepressants (TCAs), venlafaxine, and fluoxetine, although they have not been studied in
large controlled trials. The mechanism for anticataplectic effects is not known, but may be
related to their ability to suppress REM sleep. Clomipramine is the most frequently used
antidepressant for cataplexy and may also reduce sleep paralysis and hypnagogic
hallucinations. Protriptyline is also frequently used, and more recently venlafaxine and
fluoxetine as well. Newer antidepressants may not be as efficacious as TCAs, but may be
more tolerable.

Although nearly all patients with narcolepsy will require pharmacologic intervention,
behavioral management is nonetheless an important part of treatment. It is particularly
important for narcolepsy patients to practice good sleep hygiene. These patients should avoid
work or lifestyle situations that can cause sleep deprivation or dysregulation, such as shift
work, and should not work in hazardous situations. Patients with narcolepsy may benefit from
taking brief naps at specified times, which could require coordination with their employers.
[Billiard et al., 2006; Stahl, 2005; Thorpy, 2007]

43
Diagnosis and Treatment of Sleep/Wake Disorders

First-Line Treatment Other Options

Nosemask
Airflow Expiratory
Resistance

Rx
Mouth is
Unobstructed

Figure 3.12 The first-line treatment for moderate to severe OSA is continuous positive airway
pressure (CPAP). This treatment delivers oxygen through a nose mask while the patient is
sleeping so that the upper airway can be kept open. CPAP is very effective at improving sleep
quality and reducing sleepiness when used correctly and has the benefit of being effective
from the first night’s use. However, the apparatus can be uncomfortable for some patients
and can lead to problems such as nasal congestion, chest and sinus discomfort, and skin
abrasions or rashes where the mask contacts the face. Because of these factors, compliance
may be a problem and 20–35% of patients cannot put up with these side effects. Currently
in development is a much less irritating nasal cannula which uses warm, humidified air to
increase pharyngeal pressure.

Some drug therapies have been used to treat apneas, but are of only marginal benefit. These
include protriptyline, which may help by suppressing REM sleep (most apneas occur during
REM sleep) as well as by increasing genioglossus muscle tone.

Many patients with apnea experience residual excessive sleepiness, and thus adjunct drug
therapy is sometimes necessary. Treatments for excessive sleepiness include modafinil, which
is approved for this use, as well as off-label use of methylphenidate and amphetamines. In
addition, patients may use caffeine during the day. Sleep aids are not recommended unless the
respiratory symptoms are well under control, although Kryger et al. (2007) recently showed
in a small study that the melatonin agonist ramelteon reduces sleepiness without negative
respiratory effects. Benzodiazepines can exacerbate OSA and are not recommended.

Surgery is an option for people who cannot tolerate CPAP, but may only be successful for
those who have obvious anatomical abnormalities in their upper airway. Surgery can include
removal of the tonsils, uvula, distal margin of the soft palate, and excessive pharyngeal tissue.
More extreme surgery can include tongue reduction or oromaxillofacial surgery. [McGinley et
al., 2007; Hirshkowitz and Black, 2007]

44
 Treatment of Sleep/Wake Disorders

Rx

Figure 3.13 Optimizing sleep hygiene for night shift workers is vital. One of the major
factors inhibiting sleep is exposure to bright light, which should be counteracted by wearing
dark sunglasses on returning home and sleeping in a dark, quiet room. As it is important to
try and retrain the core body temperature to the shifted time, the bedroom should be kept
cool. A person should refrain from stimulants in the second half of a shift, or a cycle can
develop whereby a person who relies on caffeine/tobacco can experience insomnia and
then subsequent excessive sleepiness on the next shift. However, strategic use of caffeine early
in the shift may be helpful. As light entering the eyes directly affects the hypothalamus, the
use of artificial daylight bulbs, known as bright light therapy (BLT), can also be very helpful
during the work shift.

Melatonin is useful to help someone phase shift but the degree and direction of shift depends
on the time of day it is administered, as melatonin receptor levels are high during the evening
and low during the night. When melatonin is administered in the evening the circadian
rhythm advances to allow a person to sleep earlier. However, melatonin given early in the
morning can cause a phase delay, so that a person will not feel sleepy until later. Hence,
against popular thought, it is better to use melatonin for shift-work sleep disorder during the
night, at around the normal circadian low of 03:00. Sleep aids can also help with retraining
the body to match the shift-work time.

Many of those with shift-work sleep disorder suffer from excessive sleepiness during their wake
time. Modafinil is the only currently approved medication for this indication; methylphenidate
or amphetamines may be used off-label. [Pandi-Perumal et al., 2006; Czeisler et al., 2005]

45
Diagnosis and Treatment of Sleep/Wake Disorders

Figure 3.14 For mild RLS, daytime activity and complete abstinence of coffee, alcohol and
nicotine is indicated. RLS may also be aggravated by medications including antihistamines,
antidopaminergics, and antidepressants, thus the use of these should be investigated and
possibly stopped. Various forms of physiotherapy can help, including mild stretching exercises,
massage, biofeedback, and leg vibration. RLS, a physical anomaly which may have roots
in the brain, may be counteracted by mental activity such as crosswords, video games,
stimulating conversation, or painting.

As RLS is thought to involve problems with iron storage/metabolism, long-term supplementation

can be very effective, more so than one high dose of iron dextran.

Ropinirole and pramipexole significantly reduce motor and sleep disturbances and are both
approved to treat RLS. Their side effects can include nausea, dizziness, vomiting, constipation,
fatigue and somnolence. Ropinirole is given 1–3 hours before bedtime at an initial dose of
0.25 mg, which can be increased up to 4 mg/night on a slow titration schedule. Pramipexole
is given 2–3 hours before bedtime at an initial dose of 0.125 mg, which can be increased
after 4–7 days to 0.25 mg and then again to 0.5 mg.

Also effective may be the dopamine precursor l-dopa, which is approved in some European
countries in combination with benserazide, a dopa decarboxylase inhibitor that prevents
conversion of l-dopa to dopamine in the periphery.

For PLMs, anticonvulsants such as gabapentin or benzodiazepines including clonazepam

may reduce muscle contractions in some people, the latter being the most widely used drug
for this condition. Also used is the GABA agonist baclofen, which can inhibit release of
neurotransmitters that stimulate muscle contractions. [Vignatelli et al., 2006; Silber et al.,
2004]

46
 Treatment of Sleep/Wake Disorders

One of the easiest, earliest ways to try and help a patient with excessive
sleepiness is to investigate if poor sleep/wake hygiene is adding to
excessive sleepiness problems.

Medications can be used both to treat excessive sleepiness during

waking hours and help alleviate sleep problems which can also lead
to excessive sleepiness.

Wake-promoting agents include modafinil, amphetamines, and

methylphenidate.

Specific treatments for specific disorders include sodium oxybate for

narcolepsy, CPAP for OSA, and dopamine agonists for RLS/PLMs.

47
Diagnosis and Treatment of Sleep/Wake Disorders

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49
Diagnosis and Treatment of Sleep/Wake Disorders

To receive your certificate of CME credit or participation, please complete the posttest and
activity evaluation answer sheet found on the next page and return by postage-paid mail or
fax it to 760-931-8713. Upon receipt, your posttest will be graded and, along with your
certificate (if a score of 70% or higher was attained), returned to you by mail. Alternatively,
you may complete these items online and immediately print your certificate at www.neiglobal.
com/pt/07sleepwakemonograph.

1. Most wake circuits originate in the 6. Melatonin is released from the

A. Thalamus brainstem.
B. Brainstem arousal nuclei (BAN) A. True
C. Hypothalamus B. False
D. Basal forebrain
7. Which statement is right?
2. Increases in cortisol release can A. All of those with restless legs
lead to syndrome have concurrent
A. Hyperarousal periodic limb movements
B. Hypoarousal B. All of those with periodic limb
movements have concurrent
3. The peak time for sleep-related restless legs syndrome
vehicular accidents is: C. People with periodic limb
A. 02:00–06:00 movements do not necessarily
B. 14:00–16:00 have restless legs syndrome
C. 10:00–12:00 D. Periodic limb movements and
D. A and B restless legs syndrome never
E. B and C occur together

4. The instruction, “Lie quietly in a 8. Sodium oxybate can be converted

comfortable position, keep your into:
eyes closed, and try to fall asleep” A. Dopamine
is part of the: B. Glutamate
A. Maintenance of Wakefulness C. Norepinephrine
Test D. GABA
B. Multiple Sleep Latency Test
9. CPAP for obstructive sleep apnea is
C. Epworth Sleepiness Scale
an acronym that stands for:
5. Orexin/hypocretin neurons are only A. Concentrated positive airway
found in a small population of cells pressure
in the: B. Continuous positive airway
A. Thalamus pressure
B. Hypothalamus C. Continuous positive alveolar
C. Hippocampus pressure
D. Locus coeruleus D. Concentrated pressure and
presence

50
Diagnosis and Treatment of Sleep/Wake Disorders
Posttest
To receive your certificate of CME credit or participation, please complete the posttest and activity
evaluation answer sheet found on this page and return by postage-paid mail or fax it to 760-931-
8713. Upon receipt, your posttest will be graded and, along with your certificate (if a score of 70%
or higher was attained), returned to you by mail. Alternatively, you may complete these items online
and immediately print your certificate at www.neiglobal.com/pt/07sleepwakemonograph. (Circle the
correct answer)
Answer Sheet
1. A B C D 6. A B
2. A B 7. A B C D
3. A B C D E 8. A B C D
4. A B C 9. A B C D
5. A B C D

Activity Evaluation: Please rate the following, using a scale of:

1-poor 2-fair 3-good 4-very good 5-excellent

1. The overall quality of the content was… 1 2 3 4 5

2. The relevance of the content to my professional needs was… 1 2 3 4 5

3. The level at which the learning objective was met of teaching me to 1 2 3 4 5

recognize underlying causes of sleep/wake disorders

4. The level at which the learning objective was met of teaching me to 1 2 3 4 5

identify patients for whom direct treatment of sleep/wake problems
is necessary

5. The level at which the learning objective was met of teaching me to 1 2 3 4 5

effectively implement treatment plans for patients with sleep/wake
disorders

6. The level at which this activity was objective, scientifically balanced, 1 2 3 4 5

and free of commercial bias was…

7. The overall quality of this activity was… 1 2 3 4 5

8. Based on my experience and knowledge, the level of this activity was:

Too Basic Basic Appropriate Complex Too Complex

9. Based on the information presented in this activity, I will:

A. Change my practice
B. Seek additional information on this topic
C. Do nothing as current practice reflects activity’s recommendations
D. Do nothing as the content was not convincing

10. What barriers might keep you from implementing changes in your practice you’d like to make as
a result of participating in this activity?

11. The following additional information about this topic would help me in my practice:

12. How could this activity have been improved?

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