Neurol Clin 24 (2006) 267–289
Sleep Disorders: Case Studies
Mark W. Mahowald, MDa,b,*,
Michel A. Cramer Bornemann, MDa,b
a
Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center,
701 Park Avenue, Minneapolis, MN 55415, USA
b
Department of Neurology, University of Minnesota Medical School, 420 Delaware Street SE,
Minneapolis, MN 55455, USA
Case 1: ‘‘Passing-Out’’ Spells
A 23-year-old man was referred to the sleep clinic for evaluation of a
3-year history of progressively severe, inappropriate excessive daytime sleepiness (EDS). He stated: ‘‘I can fall asleep any time, anywhere, any place.’’
He had fallen asleep during noisy social events and had even fallen asleep
standing up. He also complained of ‘‘short faints,’’ which were described
as episodes of muscle weakness, particularly involving the knees, triggered
by any type of emotion. He stated: ‘‘With laughter, I go out.’’ His first episode of weakness occurred when he was working as a busboy; he dropped
an entire tray of dishes he was carrying when he laughed at a joke. He has
hypnagogic hallucinations, described as perceiving a ‘‘presence in my room’’
once weekly. There was no history of sleep paralysis. His past history was
remarkable for remote head injuries without neurologic sequellae. The physical examination was normal.
Questions
What Is the Differential Diagnosis?
The practical differential diagnosis of EDS is short: volitional sleep deprivation, obstructive sleep apnea, narcolepsy, or idiopathic CNS hypersomnia. In this case, narcolepsy would be likely, in view of a history suggestive
of cataplexy.
* Corresponding author. Minnesota Regional Sleep Disorders Center, Hennepin County
Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA.
E-mail address: mahow002@umn.edu (M.W. Mahowald).
0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2006.01.010
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What Studies Should Be Performed?
A formal polysomnogram (PSG) should be performed to evaluate the
quality and quantity of sleep the night before a multiple sleep latency test
(MSLT) is performed. The PSG would rule out other causes of EDS,
such as obstructive sleep apnea. The MSLT is a standardized and well-validated measure of physiologic sleepiness. The MSLT is designed to quantitate sleepiness by measuring how quickly an individual falls asleep on
sequential naps during the day and to identify the abnormal occurrence of
sleep-onset REM (SOREM) during a nap. For each nap, the latency between lights out and sleep onset is recorded. Pathologic ranges of sleep latency have been carefully defined. A mean latency of 5 minutes or less
indicates severe excessive sleepiness. The number of naps during which episodes of SOREM appears is also noted. Patients with narcolepsy often display REM sleep on two or more naps. REM sleep during daytime naps in
nonnarcoleptics is uncommon. Many factors can affect sleep latency during
the daytime: prior sleep deprivation, sleep continuity, age, time of day, physiological arousal before nap opportunities, meals, and medications [1]. From
a technical standpoint, early termination of PSGs such that patients are not
allowed to wake up spontaneously may contribute to sleep deprivation, resulting in false-positive MSLTs. Nonetheless, the MSLT is a most useful
tool in quantifying daytime sleepiness and in differentiating the subjective
complaints of sleepiness, tiredness, and fatigue.
This patient’s formal PSG was unremarkable. The total sleep time was
343 minutes with a sleep efficiency of 95%. A urine toxicology screen was
negative for recreational drugs. A multiple sleep latency test the following
day revealed a mean sleep latency of 2.4 minutes, with REM sleep occurring
on four of five naps. This confirmed the complaint of severe hypersomnia.
The appearance of REM sleep on two or more naps is highly suggestive
of narcolepsy. For perspective, a nonnarcoleptic would have to miss an entire night’s sleep to obtain a similar mean sleep latency.
MSLTs may be falsely negative. Therefore, telling a patient that he or she
does not have a sleep disorder because the MSLT is normal is similar to telling a patient with chest pain that the pain cannot be cardiac in origin because the ECG is normal. All sleep studies must be interpreted in light of
the entire clinical picture.
What Is the Diagnosis?
The combination of a clinical history of EDS with cataplexy along with
an MSLT that has short mean sleep latency and two episodes of SOREM
confirms that diagnosis of narcolepsy. Narcolepsy is a frequent disorder,
with a prevalence of 0.09%, affecting at least 250,000 Americans. There is
a clear genetic component, with over 90% of individuals with narcolepsy
carrying the HLA-DR2/DQ1 (under current nomenclature HLA-DR15
and HLA-DQ6) gene (found in less than 30% of the general population)
[2]. This association is present in the different ethnic populations to varying
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degrees, and represents the highest disease-HLA linkage known in medicine.
Clearly, there is a genetic component; however, that component is neither
necessary nor sufficient to cause narcolepsy.
Hypocretin-1, also known as orexin, plays an important role in narcolepsy. Hypocretin-1 is a neuropeptide of hypothalamic origin. It appears
that patients with narcolepsy have lost the hypocretin-producing cells, possibly via an immune-mediated mechanism [3]. Undetectable CSF levels of
hypocretin-1 are specific for patients with narcolepsy who have cataplexy
and who are HLA DQB1*0602 positive, and absent CSF hypocretin-1 levels
have not been found in any other conditions that could be confused with
narcolepsy [4].
EDS is the primary symptom of narcolepsy. Ancillary symptoms include
the classic ‘‘narcolepsy triad’’ of cataplexy, hypnagogic hallucinations, and
sleep paralysis. Cataplexy occurs in 65% to 70% of patients with narcolepsy
and is the sudden loss of muscle tone, typically triggered by emotion, such as
laughter, anger, excitement, delight, or surprise. In many people with narcolepsy, the hypersomnia precedes the appearance of the ancillary symptoms,
often by decades. Clearly, the absence of a history of cataplexy does not rule
out the diagnosis of narcolepsy. Sleep paralysis and hypnagogic (occurring
at sleep onset) or hypnopompic (occurring at sleep offset) hallucinations are
also common in narcolepsy, but may also occur in nonnarcoleptics, particularly in the setting of sleep deprivation.
The underlying pathophysiology of narcolepsy results in impaired control
of the boundaries that normally separate the states of wakefulness from
REM and NREM sleep. The total sleep time per 24 hours in people with
narcolepsy is similar to that in those without narcolepsy [5]. However, the
control of the onset/offset of REM and non-REM sleep is impaired. Moreover, there is a clear dissociation of various components of the individual
wake and sleep states. Cataplexy and sleep paralysis simply represent the
isolated and inappropriate intrusion or persistence of REM sleep related
atonia (paralysis) into wakefulness. The hypnagogic or hypnopompic hallucinations are (REM sleep-related) dreams occurring during wakefulness [2].
How Should This Be Managed?
Stimulant medications, such as amphetamine-based agents, amphetamine
salt derivatives, such as methylphenidate, and modafinil are used to treat hypersomnolence. Though modafinil alone is FDA approved in the treatment
of EDS associated with narcolepsy, there is no evidence that any of these
agents are more or less effective than the other. Furthermore, no pharmacokinetic studies have been performed, rendering stated ‘‘maximum doses’’ arbitrary and without scientific basis. Many practitioners will titrate the
medications to maximally control the symptoms [6]. The abuse potential
for these agents in the bona-fide patient populations for which they are therapeutic has been greatly overrated, as have the cardiovascular and psychiatric consequences [6–10].
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Treatment of cataplexy includes tricyclic antidepressants, serotoninspecific reuptake inhibitors, and gamma-hydroxy butyrate [11–13]. Venlafaxine, which inhibits the reuptake of norepinephrine, serotonin, and to
a lesser extent dopamine, is often effective [14].
Case 2: Idiopathic Central Nervous System Hypersomnia Initially
Misdiagnosed as Obstructive Sleep Apnea
A 32-year-old married Caucasian man, employed as an operations manager, was referred to the sleep disorders center for a second opinion. Since
adolescence he has suffered from severe excessive daytime sleepiness. Regardless of how much sleep he obtained at night, he routinely fell asleep during periods of inactivity and reduced environmental stimulation. This
reduced his effectiveness at work and compromised his safety, as well as
others, while driving. Twelve years ago he had a fall-asleep motor vehicle
crash. He stated: ‘‘At times, I feel that there is nothing that I can do to
stay awake, no matter what I try.’’ He had a history of automatic behavior,
but no cataplexy, sleep paralysis, or hypnagogic hallucinations. He was
known to snore and also had observed respiratory pauses during sleep. A
review of systems and his past medical history were otherwise unremarkable. On examination, he stood 5’10’’, carried a weight of 230 pounds,
and had a corresponding body mass index of 33.
Four years earlier the patient had been evaluated at an outside sleep clinic
for the same complaint of EDS and was found to have, at worst, mild sleep
apnea (respiratory disturbance index of four events per hour). He was
placed on a nasal continuous positive airway pressure (CPAP) device with
which he was staunchly compliantdwith no improvement in his daytime
sleepiness.
Questions
What Is the Differential Diagnosis?
There are few causes of EDS. The most common is volitional sleep deprivation for social or economic reasons. In the absence of sleep deprivation,
the only other common causes of EDS are obstructive sleep apnea, narcolepsy, or idiopathic CNS hypersomnia. Although he had a history of snoring
and observed apnea, the initial sleep study revealed trivial sleep apnead
clearly insufficient to explain his long-standing complaint of severe EDS.
This leaves either narcolepsy or idiopathic CNS hypersomnia.
What Diagnostic Tests Should Be Performed?
A repeat formal polysomnographic (PSG) study followed by a (MSLT)
the next day would be indicated. The PSG again revealed trivial sleep apnea
with an apnea-hypopnea index of seven events per hour associated with negligible hemoglobin oxygen desaturation. The total sleep time was 489 minutes
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with a sleep efficiency of 90%. The MSLT revealed a mean sleep latency of 1.1
minutes without any episodes of SOREM occurring on any of five naps.
What Is the Diagnosis?
The MSLT provides objective evidence of severe daytime sleepiness. (For
perspective, a normal individual would have to have remained awake all
night to obtain a similar mean latency valuedthis means that this patient
feels all day, every day, the way those without this condition feel after being
up all night). The diagnosis is either monosymptomatic narcolepsy (narcolepsy without the ancillary symptoms of cataplexy, sleep paralysis, or hypnagogic hallucinations) or idiopathic CNS hypersomnia. Many individuals
with narcolepsy do not have ancillary symptoms initially, and some may
never develop cataplexy. Idiopathic CNS hypersomnia (IHS) may represent
a number of different conditions that present as unexplained EDS. This condition characterized by EDS in the absence of sleep deprivation or other
identifiable abnormality during sleep, such as obstructive sleep apnea [15].
The pathophysiology is unknown.
The diagnosis may be suspected by the history of unexplained EDS in the
absence of symptoms suggestive of obstructive sleep apnea, narcolepsy, or
sleep deprivation. Formal studies are mandatory to confirm the absence
of unsuspected sleep-related pathologies and to confirm the subjective complaint of EDS. Chronic sleep deprivation must be aggressively ruled out as
an explanation for EDS. Severe chronic sleep deprivation may affect the
MSLT for several days, despite ad-lib sleep [16]. It is anticipated that further
study of CSF hypocretin levels will likely aid in the proper classification of
patients with various forms of hypersomnia.
How Should This Be Treated?
The treatment of the EDS in idiopathic hypersomnia is identical to the
treatment of sleepiness in narcolepsydstimulant medications, including
methylphenidate, methamphetamine, dextroamphetamine, or modafinil [15].
What Is the Moral of This Story?
Sleep studies must be interpreted in light of the entire clinical picture.
Clearly, although this patient did have mild (and clinically insignificant)
sleep apnea, the observed degree of apnea would in no way explain either
the severity of either the subjective complaint or objective degree of sleepiness. He responded better to stimulant medication than to CPAP.
Case 3: Insomnia
A retired 69-year-old married man was referred to the sleep clinic for
evaluation of long-standing insomnia. He reported that for many years he
had difficulty falling asleep, and on some nights stated that he did not sleep
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at all. The insomnia worsened following a surgical procedure a few months
before the clinic visit. He had been prescribed a number of benzodiazepine
and nonbenzodiazepine sedative-hypnotic agents with little benefit. He took
occasional naps but had no symptoms of true excessive daytime sleepiness.
He admitted to some depression that he attributed to his wife’s serious medical problems. He states that he retires between 9 and 9:30 pm, and may or
may not sleep at all during the night.
Questions
What Is the Differential Diagnosis?
Insomnia is by far the most common of all sleep-related complaints,
probably exceeded only by pain in frequency of complaints to primary
care physicians. Like pain, insomnia is a constitutional symptom and not
a single diagnostic entity. It may also be the presenting symptom of other
primary sleep disorders. A clear understanding of the probable cause of insomnia in a given case is essential before rational and effective treatment can
be made.
Contrary to popular opinion, insomnia is often not due to psychiatric or
psychological problems. Although there are numerous studies indicating
that patients with insomnia have coexisting psychiatric problems, the causality dilemma associating insomnia with psychiatric problems, such as depression, remains unresolved. There is growing evidence that insomnia
initially not associated with psychiatric problems, if untreated, is a significant
risk factor for the development of psychiatric disorders [17].
It is well established that insomniacs differ from noninsomniacs in their
perception of having been awake or asleep. The perception of having been
asleep is inexact even in normal subjects, and is even worse in patients complaining of insomnia, who tend to overestimate the sleep latency and underestimate the total sleep time. There is growing evidence that many
insomniacs may be in a constant state of hyperarousal. Many are less sleepy
during the day than noninsomniacs as measured by MSLT, and they also
have an increase in metabolic rate across the 24-hour period [18]. It has
been proposed that chronic insomniacs may suffer from a more general disorder of hyperarousal that may be responsible for the daytime symptoms
and poor nocturnal sleep [19].
Insomnia is not defined by the total sleep time but, rather, by the inability
to obtain sleep that is sufficiently long or ‘‘good enough’’ to result in feeling
rested or restored the following day. The total sleep requirement ranges between 4 and 10 hours. Therefore, a 4-hour sleeper who awakens rested and
restored does not have insomnia but rather is simply a ‘‘short sleeper.’’ Conversely, a 10-hour sleeper may have insomnia despite obtaining 8 hours of
sleep nightly. Insomnia is a constitutional symptom, like pain, fever, or
weight loss, and not a disorder in and of itself. In general, the complaint
of insomnia requires a search for the underlying cause. Medical, psychiatric,
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and psychological conditions are only a few of the myriad of factors that
may cause or worsen insomnia. One must also remain mindful to other factors, including environmental triggers, undiagnosed sleep disorders, and
drug-induced influences. The most likely diagnostic possibilities in this particular case are conditioned (psychophysiological) or sleep state misperception (paradoxical) insomnia [20].
What Is the Diagnostic Approach to Insomnia?
A careful history and physical examination should rule out obvious underlying medical or psychiatric problems. All drugs (prescription, supplements, or recreational) should be identified. Prolonged (2–3 weeks) sleep/
wake diaries completed by the patient or observer may give an at-a-glance
overview of wake/sleep patterns not obviously apparent by clinical history.
Analysis of sleep diaries may be insufficient to verify a tentative diagnosis
in patients with reported insomnia or suspected wake/sleep cycle abnormalities. In such cases, definitive objective data may be obtained by actigraphy,
a recently developed technique to record activity during wake and sleep that
supplements the subjective sleep log. An actigraph is a small wrist-mounted
device that records the activity plotted against timedusually for 1 to 3
weeks. When data collection has been completed, the information is transferred to a personal computer for software analysis with the output displayed as a graphic plot of activity versus time. There is direct correlation
between the rest/activity recorded by the actigraph and the wake/sleep pattern as determined by polysomnography [21]. Indications for the use of actigraphy include insomnia, wake/sleep schedule disorders, and monitoring
treatment process. Without actigraphy, it may be nearly impossible to objectively evaluate particularly bizarre sleep complaints (as in the case of a
patient who claims to sleep only 1 or 2 hours per night). In such cases,
actigraphy is mandatory to confirm or refute the perceived sleep pattern before a treatment plan can be developed.
Formal sleep studies are rarely indicated in the evaluation of insomnia
complaints. Exceptions include (1) a history of unexplained EDS (patients
with insomnia complain of fatigue or lack of energy but uncommonly experience true excessive daytime sleepiness), (2) the suspicion of a coexisting
sleep disorder, such as obstructive sleep apnea, or (3) lack of response to aggressive management of the insomnia.
What Should Be Done in This Case?
In view of this patient’s subjective report of frequent nights of absolutely
no sleep, an actigraphic study would be invaluable to confirm or refute this
history. Without actigraphy, the physician has no way of knowing whether
this patient has severe insomnia or paradoxical insomnia. Figure 1 shows
the actigraphic pattern. Simultaneously recorded subjective sleep diaries indicated that he perceived receiving little sleep. On three of the nights, he
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subjectively recorded absolutely no sleep at all. Clearly, he is obtaining
nearly normal amounts of sleep every night, and yet perceives that he sleeps
little, if at all. This confirms the clinical suspicion of sleep-state misperception (paradoxical) insomnia.
What Is the Management?
Though time-intensive, an open educational dialog concerning sleep patterns and requirements often provides the patient with the reassurance
Fig. 1. Actigraphic study of paradoxical insomnia This is an actigraphic study of a patient who
reports many nights of no sleep. The height of the bars indicates movement, which is highly correlated with wake/sleep. The actigraph indicates a clearly identifiable consolidated period of
sleep, with sleep onset occurring at 11 pm and sleep offset occurring at 6 am to 8 am with
rare nighttime awakenings. This supported the clinical diagnosis of sleep state misperception
(paradoxical) insomnia.
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needed to begin subjective improvement. Identifying and addressing potential dysfunctional attitudes and maladaptive coping strategies concerning
sleep may also be of benefit. The actigraphic study results coupled with
the history of no true excessive daytime sleepiness can be used to try to convince the patient that adequate sleep is being obtained.
Case 4: Disorder of Arousal
A 20-year-old college student is accompanied by his concerned and
frightened parents to the sleep clinic because of a recent episode of dangerous activity arising from sleep five nights previously. He had fallen asleep at
1:30 am and awakened at 3 am to discover that he had shattered a window
next to his bed and was lying in the glass shards on his bed, bleeding profusely from his wrist, knees, and nose. These injuries required sutures
(Fig. 2). He had been sleep-deprived before this episode. Recreational drugs
or alcohol were not involved.
His history of complex behaviors arising from sleep dates back to childhood. Once when staying at a cabin, he ran out into the street believing he
was being chased. On another occasion, he had walked up to the railing of
a boat and needed to be guided back to his bunk. Roommates have noted
that slight noises may trigger an episode. His review of systems and past
medical history were unremarkable.
Questions
What Is the Differential Diagnosis?
Many conditions can present with complex behaviors arising from the
sleep period. These include disorders of arousal (confusional arousals, sleepwalking, or sleep terrors), REM sleep behavior disorder, nocturnal seizures,
and psychogenic dissociative disorders [22].
Fig. 2. Disorder of arousal injury. This is a photograph of the injury sustained by this patient
when he thrust his hand through a window during a sleepwalking episode.
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Disorders of arousal are the most impressive and most frequent of the
parasomnias. These share common features: they tend to arise from slowwave sleep (stages 3 and 4 of NREM sleep), therefore usually occurring in
the first third of the sleep cycle (and rarely during naps), and they are common in childhood, usually decreasing in frequency with increasing age.
There is often a family history of disorders of arousal; however, this association has recently been questioned. Although they most frequently occur
during stages 3 and 4 of NREM sleep (slow-wave sleep), disorders of
arousal may occur during any stage of NREM sleep and may occur late
in the sleep period [23]. Disorders of arousal occur on a broad spectrum
ranging from confusional arousals, to somnambulism (sleepwalking), to
sleep terrors. Some take the form of ‘‘specialized’’ behaviors, such as
sleep-related eating and sleep-related sexual activity, without conscious
awareness [24,25].
Persistence of these behaviors beyond childhood or their development in
adulthood is often taken as an indication of significant psychopathology
[26,27]. Numerous studies have dispelled this myth, indicating that significant psychopathology is usually not present in adults with disorders of
arousal [28–30].
Although usually benign, these behaviors may be violent, resulting in
considerable injury to the victim or others or damage to the environment,
occasionally with forensic implications [31].
What Studies Should Be Done?
Given the high prevalence of these disorders in normal individuals, formal sleep center evaluation should be confined to those cases in which the
behaviors are potentially injurious or violent, extremely bothersome to other
household members, result in symptoms of EDS, or have unusual clinical
characteristics. In general, if the behaviors are bothersome enough to warrant treatment, then formal sleep studies are indicated to establish a specific
diagnosis. Formal sleep studies should include a full EEG seizure montage,
with interpretation by an appropriately trained and experienced sleep medicine clinician.
Should This Be Treated? If So, How?
Treating disorders of arousal is often not necessary. Reassurance of their
typically benign nature, lack of psychological significance, and the tendency
to diminish over time is often sufficient. Tricyclic antidepressants and benzodiazepines may be effective and should be administered if the behaviors
are dangerous to person or property or extremely disruptive to family members. Paroxetine and trazodone have been reported effective in isolated cases
of disorders of arousal. Nonpharmacologic treatment such as psychotherapy, progressive relaxation, or hypnosis is recommended for long-term management. Anticipatory awakening has been reported to be effective in
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treating sleepwalking in children. The avoidance of precipitants such as
drugs, alcohol, and sleep deprivation is also important [23].
Case 5: REM Sleep Behavior Disorder
A 54-year-old man was seen in the sleep clinic at the urging of his wife.
For the past 1.5 years he has experienced progressively worsening dreamenacting behaviors. He reported vivid dreams, which he acts out, resulting
in thrashing, punching, and kicking injurious to his wife. The content of
the dreams usually involved some type of defensive behavior where he feels
that his farm is being invaded by animals or by other human beings. His
only medication was lisinopril for mild hypertension. A detailed neurologic
evaluation was completely normal. Specifically, there was no evidence of extrapyramidal dysfunction.
Questions
What Is the Differential Diagnosis?
Numerous conditions may result in complex or potentially violent/injurious behaviors arising from the sleep period. These include disorders of
arousal (confusional arousals, sleepwalking, or sleep terrors), REM sleep
behavior disorder (RBD), nocturnal seizures, sleep apnea, psychogenic dissociative disorders, or malingering. This patient’s history of injurious
dream-enacting behavior is highly suggestive of RBD.
RBD is a fascinating experiment in nature predicted by animal experiments in 1965.
The typical complaint of a patient with RBD is violent dream-enacting
behaviors that are potentially injurious to the individual or bed partner.
There are acute and chronic forms of RBD. Acute RBD is almost always
induced by medications (tricyclic antidepressants, monoamine oxidase inhibitors, SSRIs, or venlafaxine) or associated with their withdrawal (alcohol, barbiturate, or meprobamate).
RBD most frequently presents with the complaint of dramatic, violent,
potentially injurious motor activity during sleep. These behaviors include
talking, yelling, swearing, grabbing, punching, kicking, jumping, or running
out of the bed. Injuries are not uncommon and include ecchymoses, lacerations, or fractures involving the individual or bed partner. The violence of
the sleep-related behavior is often discordant with the waking personality.
The reported motor activity usually correlates with remembered dream mentation, leading to the complaint of ‘‘acting out my dreams.’’ Less frequently,
the primary complaint is one of sleep interruption. The duration of behaviors is brief, and upon awakening from an episode there is usually rapid return of alertness and orientation. Some patients adopt extraordinary
measures to prevent injury during sleep: they may tether themselves to the
bed with a rope or belt, sleep in sleeping bags, or sleep on a mattress on
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the floor in a room without furniture. The older (above age 50) and male
predominance (80% to 90%) in RBD is overwhelming, although women
and virtually all age groups are represented.
Systematic study of patients with neurologic syndromes indicates that
RBD and REM sleep without atonia may be far more prevalent than previously suspected. The chronic form of RBD is idiopathic in less than half
of occurrences. The remainder are associated with various neurologic disorders, most notably the synucleinopathies (Parkinson’s disease, multiple
system atrophy, including olivopontocerebellar degeneration and the ShyDrager syndrome, and dementia with Lewy body disease). RBD may
precede the appearance of other symptoms of these disorders by a decade
or more [32].
What Studies Should Be Done?
Formal PSG evaluation with a full seizure montage is indicated. This patient’s PSG revealed no sleep apnea and no electrical or clinical seizure activity. Prominent tonic and phasic EMG activity was present in both arms
and legs during REM sleep, associated with frequent twitching movements
and vocalization (Fig. 3). This observation of REM sleep without atonia
coupled with the clinical history of dream-enacting behavior confirms the diagnosis of RBD.
Fig. 3. Polysomnogram of REM sleep without atonia in an REM sleep behavior disorder. Normally during REM sleep there is atonia of all somatic muscles except the diaphragm. This PSG
sample shows prominent tonic and phasic EMG activity of the arms and legs during REM sleep
(REM sleep without atonia) in a patient with REM sleep behavior disorder. LOC/ROC, left,
right outer canthus; A1, A2, left, right ear; C3, left central EEG; O2, right occipital EEG;
chin, submental EMG; arms, left, right extensor digitorum EMG; legs, left, right anterior tibialis EMG; ECG, electrocardiogram.
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How Should This Be Treated?
The acute form of RBD is self-limited following discontinuation of the
offending medication or completion of withdrawal. About 90% of patients
with chronic RBD respond well to clonazepam administered one-half hour
before sleep time. The dose ranges from 0.5 to 2.0 mg, and there has been
little, if any, tendency to develop tolerance, dependence, abuse, or adverse
sleep effects despite years of continuous administration and efficacy. Melatonin has also been reportedly effective [32]. Due to the large percentage of
patients with RBD who eventually demonstrate extrapyramidal diseases,
annual neurologic evaluation is recommended.
Case 6: Restless Legs Syndrome
A 52-year-old married man was referred to the sleep clinic with the complaint of restless sleep. His complaint began 3 years earlier coincident with
his beginning hemodialysis for chronic renal failure. He had difficulty initiating and maintaining sleep. He often got up at night and paced about. Although he denied excessive daytime sleepiness, there was a history of falling
asleep driving and during conversations. He also frequently fell asleep while
pacing in the middle of the night. On one such occasion, he abruptly was
overcome with sleep while standing, fell down to the ground in an awkward
position, and fractured several metatarsal bones in his foot. On another, he
fell asleep sitting on the edge of his bed; he fell forward, hitting his face on
the nightstand and breaking four front teeth. On examination, he was ostensibly severely hypersomnolent, having difficulty maintaining enough alertness to participate in the clinical interview.
There was no clinical history to suggest either sleep apnea or narcolepsy.
A review of his family medical history revealed that his father and brother
both had restless legs syndrome. Initially, the patient received empiric treatment for insomnia, including prescriptions for clonazepam, triazolam, zolpidem, and sertraline. These attempts at treatment for presumptive insomnia
were all without any benefit. He had undergone a formal sleep study elsewhere, but no diagnosis or management strategy was offered, as only 11
minutes of sleep occurred during the study.
His sleep was so disrupted that it severely interfered with his wife’s sleepd
to the extent that she became chronically sleep-deprived, once falling asleep
while driving, crashed her car and sustaining severe injuries that resulted in
a spinal cord transection with permanent paraplegia.
Questions
What Is the Differential Diagnosis?
Few causes of insomnia result in such severe hypersomnia. Two possibilities come to mind: obstructive sleep apnea and severe restless legs syndrome
with periodic extremity movements during sleep. Either or both of these are
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highly likely in this patient, as these conditions are extremely prevalent in
patients with chronic renal failure on dialysis [33].
What Studies Should Be Done?
Formal sleep studies are clearly indicated in view of the dire consequences
of the patient’s sleepiness. A 3-week actigraphic study revealed no identifiable sleep periods.
The first PSG was difficult to interpret because of the patient’s nearly
complete inability to initiate or maintain sleep due to periodic movements
involving the entire body (Fig. 4). The total sleep time was 285 minutes
with a sleep efficiency of 48%. During periods of apparent wakefulness he
was obviously confused and disoriented. While sitting on the edge of the
bed, he frequently fell asleep, falling backward into bed, hitting the side
rails. In retrospect, the lack of apparent sleep on the actigraphic study
was due to the prominent periodic extremity movements, which were severe
enough to involve the entire body. A second PSG study the next night was
nearly identical. During the day, following these studies, he was profoundly
hypersomnolent, virtually unable to maintain wakefulness even during stimulation. Because he could not care for himself in this state, he was admitted
to the hospital for observation and further study.
Before a third PSG the next night, he was given oxycodone and pramipexole, with marked improvement in sleep continuity. He was discharged
Fig. 4. Polysomngram of severe periodic leg movement in patient with restless legs syndrome.
This is a polysomnographic sample of prominent periodic movements of sleep demonstrating
severe sleep fragmentation associated with periodic movements involving the entire body.
LOC/ROC, left, right outer canthus; A1, A2, left, right ear; C3, left central EEG; O2, right occipital EEG; chin, submental EMG; arms, left, right extensor digitorum EMG; legs, left, right
anterior tibialis EMG; ECG, electrocardiogram.
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from the hospital on oxycodone and pramipexole with nearly complete resolution of the insomnia and EDS.
What Is the Diagnosis?
This represents an extreme case of restless legs syndrome (RLS). RLS is
a neurologic sensory/movement disorder that presents as severe insomnia.
RLS is characterized primarily by a vague and difficult-to-describe unpleasant sensation involving the lower extremities. This discomfort appears primarily during periods of inactivity, particularly during the transition from
wake to sleep. Patients often have difficulty describing the unpleasant sensations; they rarely use conventional terms of discomfort, such as ‘‘numbness,
tingling, or pain,’’ but rather bizarre terms such as ‘‘pulling, searing, drawing, crawling, or boring,’’ suggesting that the sensations are unlike any
experienced by unaffected individuals. These distressing sensations are
typically relieved only by movement or stimulation of the legs. Many coping
techniques have been found by patients: walking or stomping the feet; rubbing, squeezing, or stroking the legs; taking hot showers or baths; or applying ointment, hot packs, or wraps to the legs. Although these maneuvers are
effective while they are being performed, the discomfort usually returns as
soon as the individual becomes inactive or returns to bed. The symptoms
may also involve the trunk or upper extremities, but usually to a lesser degree than the legs. Those more severely affected may find it extremely difficult to sit for prolonged periods of time, such as during long performances,
car trips, or plane rides. The motor restlessness often appears to follow a circadian pattern, peaking between midnight and 4 am [34].
RLS is common, affecting between 5% and 15% of the general population. It may begin in childhood, but tends to be more prevalent with increasing age. It affects men and women. Its association with menstruation,
pregnancy, and menopause may explain the female predominance. The
prevalence appears to increase with age, but retrospective analysis indicates
that symptom onset may begin before the age of 20 in 43% [35,36].
Most cases of RLS are idiopathic or familial. A positive family history
may be obtained in up to 50% of cases. Hormonal influences are suggested
by the history of exacerbation during menstruation, pregnancy, or menopause. Up to 27% of pregnant women may experience RLS. Although
RLS has been associated with a wide variety of other medical and neurologic conditions, such as iron deficiency anemia and various peripheral neuropathies, such cases appear to be uncommon. RLS associated with iron
deficiency has been reported following multiple blood donations [37]. RLS
affects 20% to 40% of patients with chronic renal failure on dialysis, and
may be extraordinarily bothersome, to the extent of interfering with dialysis
treatments [38,39]. The RLS symptoms disappear following successful renal
transplantation [40]. Extensive and expensive medical and neurologic evaluations are not warranted unless there are historic or physical examination
suggestions of other medical disorders. Hemoglobin, serum iron, iron
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saturation, and ferritin determinations should be obtained to look for mild
degrees of anemia [41,42]. Low ferritin levels may be associated with either
the development or exacerbation of RLS. Although once felt to be psychiatric in nature, there is no evidence that RLS is related to any psychological
or psychiatric problems.
Evidence is accumulating that some cases of RLS are related to iron metabolism abnormalities within the CNS: some patients have low CSF ferritin
levels despite normal serum ferritin levels [43], and MRI-determined brain
iron concentrations in the subtantia nigra and putamen are reduced [44].
RLS is often confused with periodic limb movements of sleep (PLMS).
RLS is a clinical symptom often resulting in severe insomnia, whereas
PLMS is a polysomnographic observation, which may or may not have clinical significance. The reason for the confusion that most patients (80%) with
RLS have the polysomnographic finding of PLMS; however, the converse is
not true [34].
RLS is one of the most important causes of insomnia because of its prevalence and its response to treatment. Most cases of RLS respond gratifyingly to medical treatment, and there are four main classes of medications
that are effective [45]:
Anti-Parkinson medications, such as L-Dopa/carbidopa, bromocriptine,
pergolide, pramipexole, ropinirole, cabergoline, or selegiline
Benzodiazepines, such as diazepam, clonazepam, temazepam, or triazolam
Opiates, such as codeine, oxycodone, methadone, tramadol, or propoxyphene
Anticonvulsants, such as carbamazepine, gabapentin, or lamotrigine
Intravenous iron
Specific treatment for iron-deficiency anemia is indicated if present.
How Should This Be Managed?
In view of the objective improvement in the patient’s sleep while receiving
oxycodone and pramipexole, these medications were continued, with nearly
immediate and complete resolution of his insomnia and profound sleepiness.
Case 7: Delayed Sleep-Phase Syndrome
A 29-year-old woman was referred to the sleep clinic to evaluate the complaint of an inability to fall asleep at a conventional time and severe difficulty awakening in the morning. She recalled that even as a child she
often could not fall asleep until 1 am to 5 am and would be unable to
awaken at a ‘‘reasonable’’ time in the morning. She recently lost her job
as a teaching assistant as a result of her inability to awaken early enough
to get to work on time, despite using multiple alarm clocks and arranging
to receive numerous telephone calls in the morning to attempt to awaken
her. She was currently working an evening shift between 4 pm and 10 pm
without difficulty. With this work schedule, she went to sleep between 2
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am and 4 am and slept without interruption until noon or 2 pm. She has
a history of depression and bipolar affective disorder, under adequate control at the time of examination.
Questions
What Is the Diagnosis?
The most likely diagnosis is delayed sleep-phase syndrome (DSPS). This
is the most common of the circadian rhythm disorders seen in sleep medicine
clinics, typically presenting as either sleep-onset insomnia or excessive daytime sleepiness (especially in the morning). The patients with DSPS will often state that if they are allowed to sleep at their preferred time, there are no
wake-sleep complaints. It is the timing, not the quality or quantity of sleep,
that is problematic. Onset is often during adolescence, but some patients report onset in childhood. A history of DSPS in family members has been
noted clinically. The differential diagnosis includes irregular sleep wake pattern and psychiatric disorders associated with disturbed sleep, such as major
depression, mania, dysthymia, obsessive-compulsive disorder, and schizophrenia, as well as obstructive sleep apnea syndrome, narcolepsy (particularly during its development in adolescents), and the periodic limb
movement disorder with or without the restless legs syndrome [46].
What Studies Should Be Done?
An actigraphic study performed when the patient is allowed to sleep without time constraints usually confirms the diagnosis (Fig. 5). Actigraphic
documentation may be valuable in convincing employers or school officials
of the organic nature of this condition, so the patient’s schedule may be altered to accommodate the biological clock.
How Should This Be Treated?
The administration of melatonin 5 to 7 hours before desired sleep onset
and bright light exposure upon awakening have been shown to be effective
in advancing sleep onset [47,48]. If melatonin is to be effective in advancing
the sleep phase in DSPS, a dose range of 0.3 to 3.0 appears to be adequate.
Case 8: Nocturnal Seizures
A 39-year-old man with mild developmental delay was brought by his
parents to the sleep clinic for evaluation of a 10-year history of unusual behaviors during his sleep, typically occurring approximately once monthly,
but occasionally on subsequent nights. Within 15 to 20 minutes of going
to bed, he begins moaning. His parents find him wandering about his bedroom confused and agitated, with frothy sputum around his mouth. He then
develops stereotypic movements of scratching and reaching for things that
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Fig. 5. Actigraphic study of delayed sleep phase syndrome. This is an actigraphic study of a patient with a severe delayed sleep phase syndrome showing late sleep onsets, typically between
3 am and 6 am, with resultant delayed sleep offsets, typically between noon and 3 pm.
are not there. Often he falls during these episodes, and his parents worry
about his falling down the stairs leading from his bedroom. Following these
episodes, he gradually becomes fully awake after 30 minutes. Because of the
potential for injury, his parents had been unwilling to leave him alone at
home. They were unable to travel to the family cabin.
There was no history of seizures. He was gainfully employed as a janitor.
He underwent a sleep study elsewhere and was found to have mild obstructive sleep apnea. He was placed on nasal CPAP with no improvement in
these spells.
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285
Questions
What Is the Differential Diagnosis?
Numerous conditions can result in complex behaviors arising during the
sleep period. These include disorders of arousal (confusional arousals, sleepwalking, sleep terrors), REM sleep behavior disorder, obstructive sleep apnea, nocturnal seizures, psychogenic dissociative disorders, or malingering
[22].
What Studies Should Be Done?
Because it may be impossible on clinical grounds to differentiate among
the various parasomnias, formal sleep studies with a full EEG seizure montage are mandatory, with interpretation by an appropriately trained and experienced sleep medicine clinician.
This patient’s formal PSG with full seizure montage was unremarkable.
No abnormal behaviors occurred during the study. No EEG abnormalities
were present, and normal atonia was present during REM sleep.
What Is the Diagnosis?
Because sleep and epilepsy are closely related, it stands to reason that
sleep disorders may mimic, cause, or even be triggered by epileptic phenomena, and vice versa. It is known that, in some individuals, sleep potentiates
seizures, as does sleep deprivation [49,50]. In most cases, epilepsy is highly
state-dependent: non–rapid-eye-movement (NREM) sleep promotes seizures, whereas rapid-eye-movement (REM) sleep is an antiepileptic state
[51,52]. This reflects the dramatic reorganization of the entire central nervous system as it moves across the three states of being: wakefulness,
NREM sleep, and REM sleep.
Nocturnal frontal lobe epilepsy (NFLE) may be particularly difficult to
diagnose. NFLE, sometimes autosomal dominant, presents a broad spectrum of behaviors, including frequent isolated paroxysmal arousals, episodic
nocturnal wanderings, and nocturnal paroxysmal dystonia [53–56]. Temporal lobe seizures may also result in hyperkinetic behaviors [57]. The disorders
of arousal may difficult to differentiate from nocturnal seizures, and vice
versa [58,59].
In this case, the formal sleep study did not identify a specific diagnosis.
Given the recurrent, stereotyped, and inappropriate nature of his sleeprelated behaviors, nocturnal seizures were felt to be a likely possibility.
How Should This Be Managed?
Because of the high likelihood that these spells represented nocturnal seizures, the patient was placed on carbamazepine 200 mg at HS with immediate and sustained complete cessation of these spells. His parents can now
leave him home alone so they can enjoy their cabin. Patients with exclusively
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nocturnal seizures may only require antiepileptic medication immediately
before bedtime.
Case 9: Sleep-Related Eating Disorder
A 30-year-old happily married woman with inconsequential sleepwalking
during childhood and early adolescence presents with a 3-year history of episodes of eating arising from the sleep period, associated with partial amnesia. During these events, she ate peanut butter, cheese, crackers, chips, pasta,
chocolate, and ice cream, but virtually never vegetables or fruit. (In contrast,
during the day she had always eaten in a healthful manner and had maintained a trim figure). At first she had sporadic sleep-related eating episodes
(one to three times weekly), but eventually she was eating once or twice
nightly. She attributed a 12-pound weight gain over the past year to her nocturnal eating. She denied feelings of hunger preceding the eating episodes.
There was no history suggestive of restless legs syndrome. She did not snore
and denied excessive daytime sleepiness. She kept a high level of functioning
with a busy life. Her family history was negative for sleep or eating disorders. Her past medical history was normal. There was no history of a diurnal
eating disorder.
She slept in the same bed as her husband who reported no other sleep
problem. She was a still and quiet sleeper apart from the one to two nightly
eating episodes.
Questions
What Is the Differential Diagnosis?
This most likely represents a case of sleep-related eating disorder
(SRED). This condition is seen most frequently in women and is usually
not associated with an underlying primary eating disorder or with major
psychiatric conditions. It may best be thought of as a specialized form of
sleepwalking. The eating episodes are associated with varying degrees of
awareness. SRED may also be the manifestation of another sleep disorder,
such as sleep apnea or restless legs syndrome [24]. Zolpidem has been implicated in triggering SRED [60].
What Studies Should Be Done?
In view of the association between SRED and other sleep disorders, formal PSG studies are recommended to rule out sleep apnea or restless legs
syndrome with or without periodic extremity movements of sleep. This patient declined PSG study.
What Is the Treatment?
SRED may respond to a combination of a dopaminergic agent and an
opiate or a topiramate [61]. This patient responded well to topiramate.
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287
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