Virtual Poster Presentation Assignment

REVIEW Neurology Series Editor, William J. Mullally, MD

Sleep Disorders

Milena K. Pavlova, MD, V�eronique Latreille, PhD

Department of Neurology, Brigham and Women’s Hospital, Boston, Mass.

Funding: Non

Conflict of In

Inc. and Lundbeck

dian Institutes of H

Authorship: B

writing of the man

Requests for

Department of N

1153 Centre Stree

E-mail address

0002-9343/© 2018 https://doi.org/10.

ABSTRACT

Sleep disorders are frequent and can have serious consequences on patients’ health and quality of life. While

some sleep disorders are more challenging to treat, most can be easily managed with adequate interventions. We

review the main diagnostic features of 6 major sleep disorders (insomnia, circadian rhythm disorders, sleep-dis-

ordered breathing, hypersomnia/narcolepsy, parasomnias, and restless legs syndrome/periodic limb movement

disorder) to aid medical practitioners in screening and treating sleep disorders as part of clinical practice.

� 2018 Elsevier Inc. All rights reserved. � The American Journal of Medicine (2019) 132:292−299

KEYWORDS: Insomnia; Neurological disease; Parasomnia; Sleep apnea; Sleep disorder

INTRODUCTION Sleep is a universal function of living species, comprising

one-third of human life. Poor or insufficient sleep has been

associated with a wide variety of dysfunction in most body

systems, including endocrine, 1 metabolic,

2 higher cortical

function, 3 and neurological disorders. Disorders of sleep

can manifest as complaints of either insufficient sleep,

excessive amount of perceived sleep, or abnormal move-

ments during sleep. This review article focuses on the most

commonly seen sleep disorders in neurological practice

(Table).

MAJOR SLEEP DISORDERS

Insomnia More than one-third of adults experience transient insomnia

at some point in their lives. In about 40% of cases, insomnia

can develop into a more chronic and persistent condition. 4

The diagnosis of insomnia is made when the patient reports

dissatisfaction with sleep (sleep-onset or sleep-maintenance

insomnia) as well as other daytime symptoms (eg, sleepiness,

e.

terest: MP has received research grants from Biomobie,

, Inc. VL is supported by a scholarship from the Cana-

ealth Research.

oth authors contributed to the literature search and the

uscript.

reprints should be addressed to Milena Pavlova, MD,

eurology, Brigham and Women’s Faulkner Hospital,

t, Boston, MA 02130.

: [email protected]

Elsevier Inc. All rights reserved.

1016/j.amjmed.2018.09.021

impaired attention, mood disturbances) for at least 3 nights

per week and last for more than 3 months. 4 Although several

insomnia subtypes have been delineated (eg, idiopathic, psy-

chophysiological, and paradoxical), diagnosis and treatment

is similar.

The precise pathophysiological mechanisms underlying

insomnia have not been identified yet, but some neurobio-

logical and psychological models have been proposed. Con-

tributing factors include behavioral, cognitive, emotional,

and genetic factors. 5 These are often conceptually classified

into predisposing, precipitating, and perpetuating factors. 6

Available treatments for insomnia include pharmacolog-

ical and nonpharmacological therapies. Treatment should

consider other comorbidities that lead to sleep disruption,

including other primary sleep disorders (eg, sleep apnea

and periodic limb movement in sleep). Initial counseling

and education about good sleep practices is usually helpful,

and often sufficient to reduce insomnia symptoms. Good

sleep habits include: keeping regular wake times (and

explaining that duration of wakefulness and circadian

rhythms both affect sleep onset); limiting time in bed to

sleep time; use of bed for sleep/intimacy only; avoid

afternoon caffeine and limit alcohol intake; and avoiding

daytime napping (otherwise these should be very brief,

< 30 minutes, and taken in the early afternoon at latest). In cases of persistent insomnia, cognitive behavioral therapy

may prove very helpful. Studies have shown that cognitive

behavioral therapy for insomnia may have equal or better

effect than pharmacological treatment, and that the effect is

longer lasting. 7−11

Other behavioral treatment methods

include sleep restriction and relaxation-based interventions.

K. Pavlova and Latreille Sleep Disorders 293

Pharmacological therapy may be appropriate when treat-

ment is anticipated to be short (eg, insomnia in the setting of

stress), or in addition to behavioral treatments. The choice of

agent should consider: 1) predominant type of complaints

−sleep initiation or sleep maintenance; 2) frequency of insomnia symptoms (nightly vs intermittent); 3) length of

treatment anticipated; 4) age and comorbidities of the patient.

CLINICAL SIGNIFICANCE

� Sleep disorders are common and may adversely affect health and well-being.

� While some sleep disorders are more challenging to treat, most can be easily managed with adequate interventions.

� Sleep disorders are often briefly addressed during standard medical training.

Sleep initiation insomnia may

respond well to short-acting

medications, and these can be

used as needed if the condition is

intermittent−in this case the choice of hypnotic should depend

on comorbidities. Nightly sleep

maintenance insomnia may

need nightly longer-acting medi-

cations, such as eszopiclone

or suvorexant. Patients with

comorbid anxiety or depressive

symptoms may benefit from anti-

depressant treatment, such as mir-

tazapine or trazodone. A history

of sleepwalking as a child should be considered a caution

when using zolpidem, as it may cause complex behaviors in

sleep. 12−14

Other factors such as the patient’s age and sex

should also be considered before starting pharmacological

treatment for insomnia. In 2013, the US Food and Drug

Administration (FDA) issued a warning, recommending that

a lower dose of hypnotics be used to prevent next-morning

impairment due to residual effect. Women appear to be more

susceptible to this risk (by FDA site, see Appendix, available

online).

Overall, medications most frequently used in the treat-

ment of insomnia include: 1) Benzodiazepines: they have

the advantages of being cheap and ubiquitous, however,

they are associated with various problems: excessive seda-

tion, high frequency of falls (due to nonselective gamma-

aminobutyric acid effects), hypotension, tendency to lose

efficacy after longer use, muscle relaxant effect, and signifi-

cant cognitive effects. 2) Other hypnotics include: zolpi-

dem, zolpidem CR, Intermezzo (Purdue Pharma, Stamford,

CT; zolpidem ultrashort acting, 1.75-3 mg), zaleplon, and

eszopiclone. The advantages of these hypnotics are that

some are very short acting (Intermezzo, zaleplon), and are

FDA-approved for chronic insomnia treatment (eszopi-

clone, zolpidem CR). However, frequent problems include

common side effects such as parasomnia, and over-seda-

tion, and some also have a potential to lose efficacy. 3)

Other options for insomnia treatment include: melatonin

agonists (ramelteon, tasimelteon), orexin antagonist (suvor-

exant), antidepressants (mirtazapine, trazodone, amitripty-

line), antihistamines, and other substances (eg, herbal).

Circadian Rhythm Sleep Disorders The timing of sleep and wakefulness is maintained on one

end by homeostatic factors, and on another by the

endogenous circadian system. 15

Normally, the sleep phase

of the circadian rhythm occurs about 2 hours after the onset

of melatonin secretion. It may occur later or earlier than

society-driven scheduled sleep time, resulting in a delayed

or advanced sleep−wake phase disorder. Circadian rhythm sleep−wake disorders are common.4 In

delayed sleep−wake phase disorder, sleep occurs systemati-

cally later than needed, whereas in

advanced sleep−wake phase disor- der, sleep occurs systematically ear-

lier than needed. Yet in both cases,

sleep length is normal and the patient

is refreshed when sleeping according

to his/her desired time. Delayed

sleep−wake phase disorder is thought to account for 10% of

patients with chronic insomnia and is

particularly common in adolescents

and young adults, occurring in 7%-

16%. 4 Advanced sleep−wake phase

disorder is estimated to occur in

1% of middle-aged adults and even

more commonly in older populations. Non-24-hour circadian

rhythm disorder is thought to occur in > 50% of blind indi- viduals, and up to 80% of this population complains of sleep

disturbances. Twenty percent of the workforce engages in

shift work and 10%-38% of this population is estimated to

suffer from shift work circadian rhythm disorder. 4

The diagnosis and treatment of circadian rhythm sleep

−wake disorders are sometimes difficult without an accu- rate assessment of the patient’s circadian phase. In research

conditions, plasma measurements of melatonin, and core

body temperature, are commonly used. 16

However, these

are labor-intensive, expensive, require special settings, and

are, therefore, impracticable for routine clinic use. More

feasible assessment parameters include salivary and urine

melatonin measures. 17−20

Despite their high prevalence,

circadian rhythm sleep−wake disorders are commonly mis- diagnosed as insomnia or, in some situations, hypersomnia.

A recent study of patients diagnosed with primary insomnia

demonstrated that 10%-22% had a bedtime out of phase

with their circadian sleep time, suggesting a circadian etiol-

ogy for their sleep problems. 21

This misdiagnosis may lead

to unsuccessful, expensive, and sometimes harmful conse-

quences.

Treatment of circadian rhythm sleep disorders are based

on timed bright or blue light (morning for delayed and after-

noon for advanced phase disorders) and melatonin (1 hour

prior to required bedtime in delayed phase disorder). 16

For

non-24-hour sleep−wake phase disorder, in blind individu- als, Tasimelteon has been recently found helpful. It is also

helpful to counsel patients that the accuracy of the timing of

any interventions for delayed sleep−wake phase disorder may be crucial to successful treatment. The effect of light,

for example, depends on the light spectrum/wavelength,

intensity, prior light exposure, and, most importantly, tim-

ing. 22

The same light intensity may delay the sleep phase of

Table Common Sleep Disorders in Neurology

Condition Defining Features Confirmatory Evaluations Treatment

Insomnia Difficulty with: � Sleep initiation or � Sleep maintenance

Results in: � Fatigue/malaise � Mood disturbance/irritability � Reduced productivity

Chronic: > 3 times/week and > 3 months

� Primary: clinical history � Ancillary: sleep log

� Hypnotics � Antidepressants � Melatonin agonists � Orexin antagonists

DSWPD � Sleep occurs systematically later tha needed

� Sleep length is normal and the patient is refreshed when sleeping according to his/ her desired time

� Sleep log � Actigraphy* � Melatonin*

� Melatonin 0.3-3 mg − evening (5 h before habitual bedtime)

� Combined with morning blue light

ASWPD � Sleep occurs systematically earlier than needed

� Sleep length is normal and the patient is refreshed when sleeping according to his/ her desired time

� Sleep log � Actigraphy* � Melatonin*

� Evening blue light

OSA � Snoring/apneas/gasping upon awakening � Other nonspecific symptoms - Morning headache - Attention deficits - Mood disturbance - Nocturia, night sweats - Aggravation of other disease

� Home sleep testing � Polysomnography In both cases, diagnosis requires:

� Apnea-Hypopnea Index > 5/h with symptoms or Index > 15/h regardless of symptoms

� Continuous or bilevel positive airway pressure

� Dental − oral appliances � Surgery − for select cases

Conservative measures − to use with another treatment or for few symptoms and Apnea-Hypo- pnea Index < 20 � Sleep position � Weight loss � Avoidance of “relaxants” close to bedtime

Narcolepsy Classic tetrad: � Sleepiness � Sleep paralysis � Hypnagogic hallucinations

Type 1: Cataplexy Type 2: Without cataplexy

Multiple sleep latency test � Sleep latency < 8 min � 2 Sleep-onset REM or � 1 SOREM and first REM on polysomnography < 15 min

Type 1: � Cerebrospinal fluid: low orexin

y

� HLA DQB1*0602

Sleepiness: � Modafinil � Armodafinil � Methylphenidate � Amphetamine salts � Sodium oxybate

Cataplexy: � Sodium oxybate � SSRI

REM behavior disorder � Abnormal behaviors, emerging from REM sleep

� Occur in the later parts of the night � Typical behaviors: talking, screaming, punching, kicking

� Associated with a vivid dream recall

� Clinical history � Polysomnography: REM without atonia

� Clonazepam � Other benzodiazepines � Melatonin � Treatment of associated disor- ders

� Safety measures NREM parasomnia � Large variety of behaviors (hallucinations,

eating, locomotion, aggression, sex, terrors)

� Frequent amnesia for the event � Behaviors may be from the same group (usually eating or talking), but variable in presentation (eg, saying different phrases)

� Clinical history � Counseling - Precipitating factors (eg, sleep deprivation, stress, fever, medications/ substances) � Benzodiazepines � Antidepressants

294 The American Journal of Medicine, Vol 132, No 3, March 2019

Table (Continued)

Condition Defining Features Confirmatory Evaluations Treatment

� Several different behaviors can co-occur � Distinction from seizures/postictal confu- sion is crucial

RLS/PLMS RLS: � Indescribable uncomfortable sensations that make the patient move limbs

� Difficulty with sleep initiation due to the above sensations and urge to move

� Often associated with PLMS � Fragmented sleep, discomfort � Daytime sleepiness

� Clinical history � Polysomnography may confirm PLMS

PLMS � PLMS > 15/h with symptoms

� Dopamine-agonists - Pramipexole starting at 0.125- 0.25 mg or

- Ropinirole 0.25-0.5 mg - The dose of dopamine agonists should be kept low

� Gabapentin enacarbil � Fe supplementation if indicated

(ferritin < 50), to be continued until > 100

� Opiates and benzodiazepines (more limited use)

ASWPD = advanced sleep−wake phase disorder; DSWPD = delayed sleep−wake phase disorder; NREM = non-rapid-eye movement; OSA = obstructive sleep apnea; PLMS = periodic limb movement of sleep; REM = rapid-eye movement; RLS = Restless legs syndrome; SSRI = selective serotonin reuptake inhibitor.

*Not covered by most insurances in the US. yNot commercially available in the US.

K. Pavlova and Latreille Sleep Disorders 295

the circadian cycle if administered prior to the core body

temperature minimum, or advance it if administered after

it. 16

For the same reasons, administration of exogenous mel-

atonin should also be timed by circadian phase.

Sleep-Disordered Breathing: Obstructive Sleep Apnea and Central Sleep Apnea Sleep apnea is a primary sleep disorder characterized by

pauses of breathing during sleep. There are 3 main types of

sleep apnea: obstructive sleep apnea, central sleep apnea,

and complex sleep apnea. An obstructive apnea is defined

as a cessation of airflow for at least 10 seconds, and results

from the collapse of the upper away during sleep. By con-

trast, during a central apnea, the interruption of airflow

occurs when there is a lack of effort to breathe−usually arising from the brain respiratory centers to the muscles

that control breathing. Some patients present with a combi-

nation of both obstructive and central apnea, which is

termed complex sleep apnea.

Sleep apnea can be diagnosed during polysomnography,

where the severity of sleep apnea is quantified by the num-

ber of respiratory events per hour of sleep. Along with clini-

cal symptoms, at least 5 events per hour (Apnea-Hypopnea

Index ≥ 5) are required for a diagnosis of sleep apnea.23

According to prevalent criteria, an Apnea-Hypopnea Index

between 5 and 14 will be considered mild sleep apnea,

between 15 and 29 moderate sleep apnea, and more than 30

events per hour is considered severe sleep apnea. Several

screening scales for sleep apnea have been developed to

identify at-risk patients. One of the most frequently used in

clinic is the STOP-BANG questionnaire, 24

which contains

4 yes-or-no questions that relate to clinical signs of sleep

apnea (S: snoring; T: tiredness during daytime; O: observed

apnea; P: high blood pressure), as well as 4 items related to

the well-known sleep apnea risk factors (B: body mass

index > 35; A: Age > 50 years; N: Neck circumference > 40 cm; G: male gender). A patient is at high risk of sleep apnea if 3 or more questions are positively answered.

24

In the general middle-aged population, moderate to

severe sleep apnea can be found in about 30%-50% of men

and 11%-23% of women. 25,26

Clinical symptoms include

most often loud snoring, choking/gasping, apneas witnessed

by the bed partner, excessive sleepiness and fatigue, and

morning headache. Sleep apnea has debilitating effects on

the patient and their family’s quality of life. When left

untreated, sleep apnea can also have major negative health

consequences; it increases the risk of hypertension, type

2 diabetes, and cardiovascular diseases. 27

In a large cohort

study, risk of stroke in men with moderate to severe

obstructive sleep apnea increased incrementally with each

unit of increased severity. 28

Sleep apnea is also a well-

known risk factor for cognitive deficits. 29 The negative con-

sequences of sleep apnea can be, at least partially, reversed

by consistent and accurate treatment.

Several treatment options are available. For mild cases

of obstructive sleep apnea, conservative therapies such as

weight loss and avoiding supine position (for positional

sleep apnea) can be helpful. The most widely used and cur-

rently first-line treatment for obstructive sleep apnea is pos-

itive airway pressure therapy. Continuous positive airway

pressure consists of a continuous flow of air into the nose,

while bilevel therapy provides a higher pressure on inspira-

tion and lower level on expiration. The latter is sometimes

more comfortable with higher pressures. Auto-titrating

machines have been very helpful to expedite treatment.

Adaptive servo-ventilation can also be used to treat com-

plex sleep apnea. Continuous positive airway pressure ther-

apy in obstructive sleep apnea individuals has been found

to reduce subjective daytime sleepiness, improve cognitive

Figure Example of a multiple

296 The American Journal of Medicine, Vol 132, No 3, March 2019

functioning, as well as mood and quality of life. 30−33

It also

can improve blood pressure and glucose control. 34

Oral

appliances such as mandibular advancement devices may

also help to improve mild to moderate cases of obstructive

sleep apnea that are not associated with any significant risk

factors, or for patients who are intolerant to positive airway

pressure therapy. Surgical treatment methods include, most

commonly, soft palate surgery, nasal surgery, and maxillo-

mandibular surgery. These may help sleep apnea severity,

although they generally do not cure sleep apnea.

sleep latency test in a patient with

narcolepsy. “W” delineates waking

stage, N1-3 the non-rapid eye move-

ment stages 1-3, respectively, and

the black solid bars indicate rapid

eye movement sleep. The green bars

delineate each nap opportunity.

Sleep is seen in all 5 nap opportuni-

ties, occurs within a few minutes of

the lights out, and rapid eye move-

ment sleep occurs in 3 of the 5 naps.

Hypersomnia: Narcolepsy and Idiopathic Hypersomnia When evaluating hypersomnia, the following issues should

be considered: Is there enough sleep opportunity? In adults,

typical sleep need is more than 7 hours, with adequate, con-

sistent timing. Are there factors that impair sleep quality

and, as a result, lead to insufficient/poor quality sleep?

These include medications and environmental factors, as

well as primary sleep disorders such as sleep apnea and

sleep-related movement disorders. Does it recur more than

3 times per week, for more than 3 months?

Disorders causing central hypersomnia are rare. They

include narcolepsy type 1 (with cataplexy), narcolepsy type

2 (no cataplexy), idiopathic hypersomnia (with long sleep

time or without long sleep time), and recurrent hypersom-

nia (such as Kleine-Levin syndrome). Narcolepsy is a disor-

der of rapid eye movement sleep regulation. 4

Classic

symptoms include sleepiness, sleep paralysis, and hypnago-

gic hallucinations. Cataplexy in narcolepsy type 1 consists

of a loss of muscle tone, provoked typically by positive

emotions, classically, laughing or telling a joke. Occasion-

ally, surprise or anger can be a trigger. Classically, in nar-

colepsy, any daytime naps are short (15-40 minutes) and

refreshing. There is a common genetic association

(DQB1*0602 haplotype), and patients with narcolepsy type

1 may also have lower orexin measured in cerebrospinal

fluid. 35,36

The diagnosis is made first clinically; however, an objec-

tive documentation using multiple sleep latency test is

needed to confirm the sleepiness. This test is typically per-

formed on the day after a polysomnography and consists of

5 nap opportunities. Most narcolepsy patients fall asleep

within minutes of being given the opportunity, and thus a

short sleep latency (average of < 8 minutes over the 5 naps), as well as rapid eye movement sleep during these

naps would be supportive of narcolepsy (see Figure). Cur-

rent criteria require that rapid eye movement sleep is either

seen in 2 or more naps or that rapid eye movement is seen

in one nap along with a rapid eye movement latency < 15 minutes on the preceding polysomnogram. Haplotype typ-

ing may be performed; however, it is difficult to interpret

and depends on genetics. Cerebrospinal fluid measurements

of hypocretin are performed in many European countries

but are not currently commercially available in the US.

Treatment of the sleepiness typically starts with modafi-

nil or armodafinil. If these are not tolerated or ineffective,

stimulants (methylphenidate or amphetamine/dextroam-

phetamine) can be used. Cautions should include monitor-

ing blood pressure and evaluating for arrhythmias, which

can be worsened by these medications. None of these have

been approved for use in pregnancy. Cataplexy responds to

antidepressants (typically selective serotonin reuptake

inhibitors [SSRI]) or sodium oxybate. Common comorbid-

ities of narcolepsy include rapid eye movement behavior

disorder, present in as much as 10% of narcolepsy

patients, 37

as well as periodic limb movement of sleep.

Both may be worsened by SSRI, including the ones used

for the cataplexy treatment.

Hypersomnia can sometimes be seen after head trauma,

in some reports affecting as much as half of the patients

with traumatic brain injury, 38 and a quarter of these patients

may have sleep-disordered breathing. Treatment of sleep-

disordered breathing may be helpful, and use of any sedat-

ing medications should be judicious.

In rare conditions, hypersomnia can be idiopathic. This

condition typically presents with long, nonrefreshing naps.

Two types exist: 1) with a long sleep time, and 2) without

long sleep time. The criteria for diagnosis include the clini-

cal presentation, as well as supportive evidence from the

multiple sleep latency test: a sleep latency < 8 minutes, no sleep-onset rapid eye movement. Treatment is often chal-

lenging, modafinil or armodafinil at higher doses can be

used, and sometimes other stimulants can be helpful. In

another rare condition, Kleine-Levin syndrome, hypersom-

nia is recurrent. Kleine-Levin syndrome typically presents

in adolescence or the early 20s, and consists of periods that

last for approximately 2 weeks, during which patients

K. Pavlova and Latreille Sleep Disorders 297

exhibit very long sleep (often 12-21 hours per day), and

during the waking periods individuals exhibit cognitive

abnormalities (eg, major apathy, confusion, slowness,

amnesia), dream-like behavior, hyperphagia, or hypersexu-

ality. Between episodes, individuals have a normal level of

functioning. Treatment with lithium may decrease the fre-

quency of episodes, while stimulants have a marginal effect

during the events. 39,40

Parasomnias: Non-Rapid Eye Movement Parasomnias and Rapid Eye Movement Behavior Disorder Parasomnias can be grouped by type of behavior seen, or

based on sleep stage from which they occur. The most com-

mon non-rapid eye movement parasomnias include som-

nambulism, confusional arousals, and night terrors. These

parasomnias are characterized by a wide variety of behav-

iors, but they mostly occur from slow-wave sleep, and as

such, they typically arise in the first half of the night. They

most commonly manifest with directed behaviors. They are

not stereotypic and may have a variable duration. Upon

awakening, the patient does not have any vivid dream

recall. If any dream mentation is recalled, it is very brief or

fragmented. The pathophysiology of non-rapid eye move-

ment parasomnias is not well understood, although the

hypothesis of dysregulated slow-wave sleep has been pro-

posed. 41

Treatment may involve benzodiazepines, or in

some cases, tricyclic antidepressants. Clinicians should be

aware that some medications may induce somnambulism;

according to a recent review, the strongest evidence for

medication-induced sleepwalking was found for zolpidem

and sodium oxybate. 42

Rapid eye movement parasomnias, particularly rapid

eye movement sleep behavior disorder, have been stud-

ied more extensively. Typically, the patient with rapid

eye movement behavior disorder will present with

abnormal behaviors during rapid eye movement sleep.

Dream enactment behaviors result from the loss of the

normal muscle atonia seen during this sleep stage. They

occur mostly in the latter part of the night and consist

of a wide variety of motor activity that appears to be

related to a dream. If the patient awakens during that

time, he/she would be frequently able to recall the

dream, which is consistent with the behavior exhibited,

and is often elaborate. The type of behavior that most

commonly brings the patient to medical attention is

often violent, such as screaming, punching, kicking, or

other such movements, however, nonviolent activity can

be seen as well.

Along with a history of recurrent dream-enactment

behaviors, the diagnosis is confirmed by nocturnal polysom-

nography, which shows typical muscle activations during

rapid eye movement sleep or in some cases may record the

abnormal events. This sleep disorder is frequently linked

with neurodegenerative conditions, particularly synucleino-

pathies. 43

Differential diagnosis includes other parasomnias,

conversion disorders, and seizures. Unlike seizures, rapid

eye movement behavior disorder events are directed, and are

not stereotypic. Identifying association with a dream is also

very helpful.

The most commonly used agent for treating rapid eye

movement behavior disorder is clonazepam, 44

which has to

be used with caution in patients with dementia and may

lead to excessive sedation. Due to the strong association

with neurodegenerative conditions, patients are likely to

have contraindications for benzodiazepine treatment.

Another option is melatonin−an inexpensive and safer option.

45−47 In one recent study, melatonin was found to be

equally effective as clonazepam for reducing the frequency

of dream-enactment episodes. 48

Restless Legs Syndrome and Periodic Limb Movements of Sleep Restless legs syndrome is characterized by an uncomfortable

sensation, leading to an urge to move the limbs that occurs

or worsens while at rest, with consistent evening predomi-

nance, associated with dysesthesia, and is partially relieved

by physical activity. Patients often describe the sensation as

“creeping, crawling tingling” or shock-like feelings, or sim-

ply indescribable discomfort. Over the course of the disease,

the sensations can spread to the arms or trunk. One of the

major characteristics of restless legs syndrome is its worsen-

ing in the evening and at night, which results in difficulty ini-

tiating sleep, as patients often get up and pace around the

room to relieve the discomfort. In turn, poor sleep often leads

to fatigue and daytime sleepiness.

Restless legs syndrome is one of the most common

sleep-related movement disorders, affecting about 15% of

adults. 49

Generally, it affects women more than men, and

prevalence is also higher with advancing age. 49

The cause

can be idiopathic or secondary. In its idiopathic form, there

is no known cause, but most patients will have a family his-

tory. Secondary restless legs syndrome most often has a

later-onset course, and is associated with various neurologi-

cal disorders (eg, multiple sclerosis, Parkinson disease),

iron deficiency (low ferritin level), or pregnancy.

The diagnosis is made by clinical history. Restless legs

syndrome and periodic limb movement of sleep frequently

co-occur; the latter is present in 80% to 90% of patients

diagnosed with restless legs syndrome. The presence of

periodic limb movement in sleep is also supportive for the

diagnosis of restless legs syndrome. Periodic limb move-

ment of sleep can be diagnosed by clinical history, but a

polysomnography may be useful to confirm the diagnosis,

particularly in patients with unexplained symptoms of

insomnia or hypersomnia.

Multiple studies highlight an important role of brain iron

levels in the pathology of restless legs syndrome and peri-

odic limb movement of sleep, but these are usually lower in

patients with restless legs syndrome. 50

Dysfunction of the

dopaminergic system has also been demonstrated as a

potential pathophysiological mechanism for restless legs

298 The American Journal of Medicine, Vol 132, No 3, March 2019

syndrome. Evaluation of serum ferritin level is recom-

mended. If ferritin is below 50 ug/L, replacement of iron

should be considered. Otherwise, pharmacological treat-

ment of restless legs syndrome may start with either dopa-

mine agonists or gabapentin or gabapentin enacarbil.

Levodopa, ropinirole, pramipexole, cabergoline, and pergo-

lide are all considered efficacious. The doses of dopamine

agonists should be kept as low as possible to decrease the

possibility of worsening symptoms over time (termed aug-

mentation). Other efficacious medications include pregaba-

lin, and rotigotine. In more advanced disease, when other

medications are no longer effective, or in the setting of

severe augmentation, opiates can be considered. Intrave-

nous ferric carboxymaltose and pneumatic compression

devices were reported likely efficacious in idiopathic rest-

less legs syndrome. Clonidine and bupropion seem to have

insufficient evidence for efficacy at this time. 51

A challenging long-term complication of restless legs

syndrome is the development of augmentation. This phe-

nomenon consists of earlier occurrence and worsening of

the symptoms. For example, a patient who presented with

typical symptom onset around bedtime (10-11 pm) reports

that symptoms now occur in the early evening or afternoon,

likely suffers from augmentation. To decrease the likeli-

hood for augmentation, initial treatment may consider

gabapentin or gabapentin enacarbil instead of any dopa-

mine agonists. 52

CONCLUSION Sleep is vital for all living species, and as it comprises

roughly one-third of our lives, when disrupted or perturbed,

it can have significant negative consequences on quality of

life and daytime function, and therefore, sleep disorders

should be promptly treated. Where appropriate, a subspe-

cialty referral should be considered.

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APPENDIX US Food and Drug Administration (FDA) recommenda-

tions regarding hypnotics:

� Immediate-release products: “FDA is requiring the manufacturers of certain immediate-release zolpidem

products (Ambien, Edluar, and Zolpimist) to lower

the recommended dose. FDA has informed manufac-

turers that: 1) The recommended initial dose for

women should be lowered from 10 mg to 5 mg,

immediately before bedtime; 2) The drug labeling

should recommend that health care professionals con-

sider prescribing a lower dose of 5 mg for men. In

many men, the 5-mg dose provides sufficient efficacy.

3) The drug labeling should include a statement that,

for both men and women, the 5-mg dose could be

increased to 10 mg if needed, but the higher dose is

more likely to impair next�morning driving and other activities that require full alertness.”

� Extended-release products: “FDA is also requiring the manufacturer of extended-release zolpidem (Ambien

CR) to lower the recommended dose. FDA has

informed the manufacturer that: 1) The recommended

initial dose for women should be lowered from 12.5

mg to 6.25 mg, immediately before bedtime; 2) The

drug labeling should recommend that health care pro-

fessionals consider prescribing a lower dose of 6.25

mg in men. In many men, the 6.25-mg dose provides

sufficient efficacy.