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Chapter 18
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Movement Disorders
SalamZeineddine andNidhiS.Undevia
Keywords Sleep-related movement disorders · Restless legs syndrome · Periodic
limb movement disorder · Sleep-related leg cramps · Sleep-related bruxism ·
Sleep-related rhythmic movement disorder
Introduction
Sleep-related movement disorders are conditions that are characterized by simple,
usually stereotyped, movements that disturb sleep or its onset, such as RLS.The
Third Edition of the International Classication of Sleep Disorders (ICSD-3)
includes restless legs syndrome (RLS), periodic limb movement disorder (PLMD),
sleep-related leg cramps, sleep-related bruxism and sleep-related rhythmic movement disorder (RMD). Propriospinal myoclonus at sleep onset, sleep-related movement disorder due to a medical disorder, and sleep-related movement disorder due
to a medication or substance are also included under this heading [1] (Table18.1).
RLS is classied within this group of disorders due to its close association with
PLMD.Movement alone is not sufcient for the diagnosis of a sleep-related movement disorder as an associated sleep disturbance or an impairment of daytime functioning is required. Daytime impairment can affect any important area of functioning
S. Zeineddine
Department of Medicine, John D.Dingell VA Medical Center and Wayne State University
School of Medicine, Detroit, MI, USA
N. S. Undevia (
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Loyola Center
for Sleep Disorders, Loyola University Medical Center, Maywood, IL, USA
e-mail: nundevia@lumc.edu
M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine,
Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_18
*)
399© Springer Nature Switzerland AG 2022
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Table 18.1 Sleep-related movement disorders
Restless legs syndrome
Periodic limb movement disorder
Sleep-related leg cramps
Sleep-related bruxism
Sleep-related rhythmic movement disorder
Propriospinal myoclonus at sleep onset
Sleep-related movement disorder due to a medical disorder
Sleep-related movement disorder due to a medication or substance
S. Zeineddine and N. S. Undevia
such as mental, physical, social, behavioral, educational, or others. Each of these
topics will be discussed in this chapter.
Restless Legs Syndrome
RLS is a sensorimotor disorder characterized by a distressing urge to move the legs
and sometimes other parts of the body such as the arms. The British physician Sir
Thomas Willis rst described RLS in the seventeenth century by these very descriptive words “Wherefore to some, when being abed they betake themselves to sleep,
presently in the arms and legs, leapings and contractions of the tendons, and so great
a restlessness and tossings of their members ensue that the diseased are no more
able to sleep than if they were in a place of the greatest torture” [2]. The rst signicant clinical review was carried out by the Swedish neurologist Karl-Axel Ekbom
in the 1940s who also coined the term “restless legs” [3]. The severity of RLS can
vary from mild with only occasional symptoms to daily severe symptoms that can
have a profound effect on sleep and daytime functioning. The pathophysiology of
RLS is incompletely understood, but probably results from derangements in iron
and dopamine metabolism and has a genetic component [4–6].
Demographics
The prevalence of RLS varies from region to region; in Europe, South and North
America, and the Indian subcontinent, it is estimated to be 4–10% of the adult population, while in Japan, Korea, and China, for example, it is 0.6, 0.9, and 1.6%,
respectively [7–9]. In the United States, it is believed to affect more than ten million
adults. The 2005 National Sleep Foundation Poll reported RLS symptoms in 8% of
men and 11% of women [10]. Women and older adults appear to be at increased risk
[11]. The prevalence of RLS in women is roughly twice that reported in men [12].
A population survey study reported that the prevalence of symptoms of RLS was
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3% between the ages of 18 and 29years, 10% between the ages of 30 and 79years,
and 19% in persons older than 80years of age [13].
Diagnosis
RLS diagnosis is based on clinical grounds and no laboratory study reliably identies RLS.It does not require a polysomnogram (PSG) unless an additional sleep
disorder is thought to be present. The diagnosis of RLS in adults according to
ICSD-3 requires the following: (a) The patient reports an urge to move the legs,
usually accompanied or caused by uncomfortable and unpleasant sensation in the
legs. (b) The urge to move or the unpleasant sensations begin or worsen during
periods of rest or inactivity such as lying or sitting. (c) The urge to move or the
unpleasant sensations are partially or totally relieved by movement, such as walking
or stretching, at least as long as the activity continues. (d) The urge to move or the
unpleasant sensations are worse, or only occur, in the evening or night. (e) The condition is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. (f) The
symptoms cause concern, distress, sleep disturbance, or impairment in daytime
functionning [1] (Table18.2). Separate diagnostic criteria have been developed for
cognitively impaired adults and young children (age 2–12years) who have difculty in reporting these symptoms.
Associated Features
There are several supportive clinical features which, while not required, may assist
in diagnosis. These include a response to dopaminergic agents, the presence of periodic leg movements (PLMs) on diagnostic polysomnography (PSG), and a positive
family history for RLS.PLMs may occur in sleep (PLMS) and resting wakefulness
(PLMW). PLMS ≥5/hour is a highly sensitive marker for RLS, occurring in 80–90%
of patients, but has low specicity as it is also frequently associated with narcolepsy,
rapid eye movement behavioral disorder (RBD), and even healthy individuals, notably the elderly [14, 15]. PLMW may be noted during the wake time on standard
Table 18.2 Diagnostic criteria for restless legs syndrome (RLS)
Uncomfortable sensation in the legs associated with an urge to move
Symptoms are worse at rest
Symptoms are temporarily relieved by movement
Symptoms are worse or only occur at night
The condition is not better explained by another disorder
Symptoms cause concern, distress, sleep disturbance, or impairment in daytime functioning
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PSG recorded 1hour before the usual bedtime while the patient is upright in bed
with stretched-out legs (Suggested Immobilization Test– SIT). A rate greater than
40 PLMW/hour supports the diagnosis of RLS [1]. RLS is associated with PLMW
in ≈ 1/3 of patients [14]. The frequency of RLS among rst-degree relatives of
people with RLS is 3–5 times greater than in people without RLS [16]. There is a
negative impact of RLS symptoms on sleep including reports of disrupted sleep, an
inability to fall asleep, and insufcient hours of sleep [11]. Sleep disruption has also
been associated with negative effects on cognitive function in patients with RLS
[17]. Onset occurs at all ages from early childhood to late adult life with a mean age
of onset between the third and fth decade [18]. In children RLS may be misdiagnosed as “growing pains” or attention decit hyperactivity disorder (ADHD). Two
age-of-onset phenotypes for RLS have been described. Early-onset RLS usually
starts before the age of 45years with intermittent symptoms and progresses slowly.
Late-onset RLS is usually either stable at onset or rapidly progresses over 5years to
a stable pattern. Patients may describe the symptoms as creeping, crawling, pulling,
aching, prickling, or tingling. RLS can occur unilaterally or bilaterally in the lower
extremities. About half (48.7%) of patients with RLS complain of restlessness in the
arms as well. However, every patient who had arm restlessness also had leg restlessness. In most mild cases or RLS, symptoms are localized to the lower extremities,
and only with increased severity do they also affect the arms and other parts of the
body [19]. Peak intensity of RLS symptoms is on the falling phase of the core temperature cycle suggesting that RLS is related to the circadian rhythm [20].
S. Zeineddine and N. S. Undevia
Differential Diagnosis
The differential diagnosis of RLS includes neuropathic paresthesias, positional discomfort, akathisia, sleep starts (hypnic jerks), PLMD, sleep-related leg cramps,
habitual foot tapping, and pain from other conditions. RLS can be distinguished
from positional discomfort as the discomfort is resolved with change of body position without the need for continued movement and an urge to move the legs is not
present. Akathisia involves a generalized need to move the body and often in association with neuroleptic medication. Akathisia sufferers frequently report an inner
sense of restlessness rather than leg discomfort and lack the circadian pattern characteristic of RLS.Sleep starts produce brief body movements during the transition
from wake to sleep, and an urge to move is not present. PLMD is a disorder that is
only present during sleep without the essential diagnostic features of RLS.Sleeprelated leg cramps are painful sensations caused by sudden and intense involuntary
contractions of muscles and require stretching the legs to relieve symptoms rather
than movement alone. Patients also describe hardening of the leg muscles that is not
typical of RLS.Residual pain is also usually present with sleep-related leg cramps.
Pain may be worse at rest but does not include an urge to move the legs. The presence of pain does not exclude a diagnosis or RLS as some patients report their RLS
symptoms as pain; however, the additional characteristic features must also be
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present. Habitual foot tapping is easily differentiated from RLS but the absence of
nocturnal predominance of symptoms except when exacerbated by alcohol or medications taken in the evening.
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Primary Versus Secondary Factors
RLS can be classied as primary or secondary. The majority of cases of primary
RLS are hereditary (autosomal dominant) with possible loci on chromosomes 12,
14, and 9. Onset of symptoms before the age of 40years indicates an increased risk
of RLS occurrence in the family. Physical and neurologic examinations are normal
in the majority of primary RLS cases [21]. A number of secondary causes can contribute to RLS and can be expected to improve when the other disorders are treated.
Iron deciency has been associated with RLS.Pathologic studies suggest decreased
iron and ferritin in the substantia nigra of RLS patients [22]. Low serum ferritin
levels (< 45μg/l) correlate signicantly with increased RLS symptoms and with
decreased sleep efciency. A signicant correlation to serum iron levels has not
been found [23, 24]. Studies suggest disordered transport of iron from the periphery
to the central nervous system [25]. The most commonly reported neurologic cause
of secondary RLS is peripheral neuropathy [21]. Uremia associated with renal failure has also been identied as a cause of RLS.A 2008 study found that as many as
58.3% of dialysis patients have RLS [26]. Renal transplantation, unlike dialysis,
causes signicant or complete resolution of RLS symptoms [27]. Ekbom made the
rst observation that there is a high prevalence of RLS in pregnancy. In a study of
642 pregnant women, 26% were found to be affected by RLS during pregnancy.
RLS was strongly associated with the third trimester [12]. A recent study in a French
population of women in their third trimester of pregnancy found that 32% were
affected by RLS.RLS disappeared after delivery in 64.8% of the women [28]. In a
study of 184 narcolepsy with cataplexy patients, RLS was found to be signicantly
more prevalent compared to controls (14.7% vs. 3%). In this population, RLS
symptoms occurred more than 10years after narcolepsy onset and were less familial
and, in contrast to idiopathic RLS, not more prevalent in women [29]. Transient
RLS has been described in those undergoing spinal anesthesia [30]. Other secondary causes of RLS include myelopathy, Parkinson’s disease, and diabetes.
Medications may also precipitate RLS symptoms. Common medications which can
precipitate RLS include those with dopamine receptor-blocking properties (sedating antihistamines, antipsychotics, and antinausea drugs) and those with serotoninpromoting activity (most antidepressants with the exception of bupropion, with its
dopamine-promoting properties). There is limited or contradictory evidence for caffeine, tobacco, and alcohol as aggravating factors for RLS [31–33]. Multimorbidity
was shown to be a strong risk factor for RLS in two independent German cohort
studies indicating that the severity of underlying morbidity is a stronger risk factor
for RLS than any specic single disease. Furthermore, the association was stronger
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with incident than with preexisting RLS, suggesting that RLS developed subsequently to preexisting comorbid diseases [34].
S. Zeineddine and N. S. Undevia
Management
The rst step in managing RLS is performing a medication review. Medications that
can precipitate or worsen RLS should be discontinued if possible. Secondary causes
should undergo evaluation and treatment as this may resolve or improve symptoms.
Patients with iron deciency will benet from iron replacement therapy to target
ferritin levels ≥75μg/l [35]. Intravenous (IV) iron may be considered when oral
iron is not appropriate provided ferritin ≤100μg/l. IV iron, unlike oral iron whose
absorption in the gastrointestinal tract is highly variable, helps to achieve higher
levels of peripheral iron required to increase cerebral iron levels. Vitamin C may
enhance oral iron absorption. Non-pharmacologic treatments include improving
sleep hygiene, warm baths, leg massage, and acupuncture. Only one study assessed
the effect of a 12-week moderate-intensity aerobic and resistance exercise program
and found 39% improvement in symptoms with a ceiling effect after 6weeks [36].
Two studies, to date, have investigated the effectiveness of sequential compression
devices for the treatment of RLS [37, 38]. In a prospective, randomized, doubleblinded, sham-controlled trial, there was signicant improvement in RLS severity
and quality of life measures in those using the sequential compression device compared to the sham devices. Complete relief occurred in one-third of the therapeutic
group in this study [38]. There has been one case reporting the improvement in RLS
symptoms with a 4-week near-infrared light therapy [39]. A subsequent study by the
same group, with 34 volunteers, reported signicant improvement in RLS symptoms in the near-infrared light treatment group compared to the control group [40].
More research is necessary to investigate these and other potential non- pharmacologic
therapies.
Pharmacologic treatment of RLS consists of four classes of medications which
include dopaminergic agents, anticonvulsants, benzodiazepines, and opioids though
other agents have been used (Table18.3). An evidence-based review produced by a
task force commissioned by the Movement Disorder Society concluded that
levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin were
efcacious for the treatment of RLS, while rotigotine, bromocriptine, oxycodone,
carbamazepine, valproic acid, and clonidine were likely efcacious [41]. Levodopa/
benserazide or levodopa/carbidopa at dosages of 100/25 to 200/50mg is considered
efcacious for the treatment of RLS.The side-effect prole of levodopa is favorable; however treatment carries the highest incidence of augmentation among all
dopamine agonists; hence levodopa is used mainly to treat intermittent RLS [42].
The dopamine agonists ropinirole and pramipexole are FDA approved for the treatment of RLS.Ropinirole (0.25–4mg, mean 2mg) and pramipexole (0.75mg) are
efcacious for treating RLS in patients with moderate to severe symptoms. Several
studies have demonstrated the effectiveness of the rotigotine transdermal patch for
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Table 18.3 Treatment for RLS
Non-pharmacological treatments
Improved sleep hygiene
Exercise
Massage
Acupuncture
Sequential compression devices
Near-infrared light
Pharmacological treatments
Dopaminergic agents
Antiepileptics
Benzodiazepines
Opioids
Iron
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treatment of RLS including a randomized, double-blinded, placebo-controlled trial
including 505 participants with moderate to severe RLS [43–47]. Ergot-derived
dopamine agonists, including bromocriptine, pergolide, and cabergoline, require
special monitoring due to increased incidence of cardiac valvular brosis and other
brotic side effects. While efcacious, these agents are rarely used currently.
Augmentation is the main side effect of long-term dopaminergic treatment of RLS
and is characterized by an earlier onset of symptoms (≥ 4hours) or a shorter time
advance (2–4hours) along with other required features such as an overall increase
in severity of symptoms, a faster onset of symptoms at rest, and extension of the
symptoms to other body parts, notably the upper extremities. A paradoxical response
to dopaminergic agonists (worsening of symptoms with dosage increase and vice
versa) constitutes an alternative diagnostic criterion [48, 49]. Mild cases may be
followed with either a trial of judicious dose increase or dividing the dose and earlier dose administration, while in more severe cases, a complete change in treatment
is indicated [49]. Ferritin may play a role as a biomarker for patients likely to
develop augmentation [50], and treatment with oral/intravenous iron should be
strongly considered in combination with other measures if ferritin levels <50–75μg/l.
Side effects of dopaminergic agents include excessive daytime sleepiness, nausea,
vomiting, hallucinations, and insomnia. Dopaminergic therapy for RLS has also
been associated with impulse control behaviors such as compulsive gambling and
shopping. Antiepileptics used in the treatment of RLS include carbamazepine, gabapentin, pregabalin, and lamotrigine. Antiepileptics may be considered rst-line
therapy in those with concomitant neuropathy or painful leg symptoms. Gabapentin
has been reported to be as effective as ropinirole in improving the sensorimotor
symptoms in idiopathic RLS [51]. Pregabalin also has been demonstrated to improve
RLS symptoms in double-blinded, placebo-controlled trial [52, 53]. Of the benzodiazepines, clonazepam is the best documented for treatment of RLS.Side effects
of these agents include sleepiness and tolerance. Opioids are used in the treatment
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of RLS; however at sufcient analgesic doses, they cause a series of minor and
major adverse effects including sedation, fatigue, and constipation. Short-acting
agents including hydrocodone, oxycodone, and codeine may be used for intermittent or nightly symptoms. Tramadol has also been used. For more severe symptoms,
low dose of longer-acting opioids such as oxycodone and methadone is usually very
effective and safe in appropriate patients.
S. Zeineddine and N. S. Undevia
Periodic Limb Movement Disorder
Initially termed “nocturnal myoclonus” by the English neurologist Charles P
Symonds in 1953, the term periodic movements in sleep was suggested by Coleman
in 1980 [54, 55]. PLMD is characterized by periodic episodes of repetitive, highly
stereotyped, limb movements that occur during sleep (PLMS) and by clinical sleep
disturbance that cannot be accounted for by another primary sleep disorder. PLMS
typically involve the extension of the big toe, often in combination with partial exion of the ankle, the knee, and sometimes the hip. Similar movements can occur in
the upper limb. They can occur individually in association with arousals or awakenings from sleep. PLMS may occur unilaterally, alternate between legs, or occur
simultaneously in both legs. Signicant night-to-night variability may be present.
Demographics
In a study of randomly selected community-dwelling persons 65years and older,
the prevalence rate of PLMS was 45% [56]. Considerable clinical evidence suggests
that although PLMS are common, the diagnosis of PLMD is extremely rare in adults
and is best thought of as a diagnosis of elimination.
Diagnosis
The diagnosis of PLMD in adults according to the ICSD-3 requires the following:
(a) Polysomnography demonstrates repetitive, highly stereotyped, limb movements
that are 0.5–5seconds in duration, of amplitude greater than or equal to 25% of toe
dorsiexion during calibration, in a sequence of four or more movements, and separated by an interval of more than 5seconds and less than 90seconds. (b) The PLMS
index exceeds 5/hour in children and 15/hour in most adult cases. (c) There is clinical sleep disturbance or a complaint of daytime fatigue. (d) The PLMS are not better
explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder [1] (Table18.4).
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Table 18.4 Diagnostic criteria for periodic limb movement disorder (PLMD)
Polysomnography demonstrates repetitive, highly stereotyped, limb movements
The periodic limb movement index exceeds 15/hour in most adult cases
Clinical sleep disturbance or daytime fatigue
Limb movements during sleep are not better explained by another disorder
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Associated Features
Patients often report history of sleep onset or maintenance problems, unrefreshing
sleep, or excessive daytime hypersomnolence or fatigue. However, the presence of
insomnia or hypersomnia with PLMS is insufcient to diagnose PLMD, as in most
cases, the sleep disturbance is better explained by another underlying sleep disorder.
In that case, PLMS are solely noted as polysomnographic ndings. PLMS have been
associated with a number of sleep disorders including narcolepsy, RBD, and sleep
apnea as well as with a number of neurologic disorders. PSG is necessary to exclude
sleep-related breathing disorders as the cause of the PLMS.Bed partner observations
of leg movements may help in the clinical evaluation of PLMS.PLMD cannot be
diagnosed if sleep disruption of the bed partner is the only complaint. PLMS should
also be distinguished from other movements such as change in body position, stretching, or leg cramps. Movements are reported as an index of the number of leg movements per hour of sleep called the PLM index. PLMS may produce no change in the
EEG or associated arousal or may be associated with K complexes, K alpha complexes, alpha activity, or other evidence of arousal. In a study of 23 patients with
PLMs and/or RLS, 60% of PLMS were associated with microarousals, 4% were
associated with slow-wave activity, and 36% showed no electroencephalographic
changes. There was a prevalence of leg movements with microarousals in stage N1
and N2 sleep, while PLMS without microarousals were prevalent in slow- wave
sleep [57].
PLMS are usually absent during rapid eye movement (REM) sleep. Two types of
PLMS have been described. Type I has a peak frequency between midnight and
3a.m. followed by a decrease in late morning hours and is seen in those with RLS
and idiopathic PLMS. In Type II, leg movements are more evenly distributed
throughout the night and are associated with sleep-related breathing disorders,
RBD, and narcolepsy.
Differential Diagnosis
The differential diagnosis includes sleep starts, normal phasic REM activity, and
fragmentary myoclonus. Sleep starts are limited to the transition from wakefulness
to sleep and are shorter than PLMS.Normal phasic REM activity is usually associated with bursts of rapid eye movements and does not have the periodicity of
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S. Zeineddine and N. S. Undevia
PLMS.Fragmentary myoclonus activity is briefer and is primarily an EMG diagnosis with little or no visible movement.
Management
Similar to management of RLS, an investigation to identify secondary causes of
PLMD is recommended. Consideration should be given to discontinuing medications that may contribute to PLMD.The decision to treat PLMD should be based on
signs of EEG arousal, disturbed nocturnal sleep, or associated daytime mental or
functional impairment. Medication treatment is similar to that of RLS and includes
dopaminergic agents, anticonvulsants, benzodiazepines, and opioids. Given that
many patients may not be aware of PLMS, assessment of response to therapy is
dependent on improvement in sleep quality and daytime symptoms, including
fatigue. In some instances, PSG performed on treatment is required to assess
response to therapy.
Sleep-Related Leg Cramps
Sleep-related leg cramps are painful sensations caused by sudden and intense involuntary contractions of muscles or muscle groups, usually in the calf or small muscles of the foot and occurring during the sleep period. The lay term is “Charley
horse.” These episodes may last up to a few minutes, awaken the patient, and interrupt sleep.
Diagnosis
The diagnosis of sleep-related leg cramps according to ICSD-3 requires the following: (a) A painful sensation in the leg or foot is associated with sudden muscle hardness or tightness indicating a strong muscle contraction. (b) The painful muscle
contraction in the legs or feet occurs during the sleep period, although they may
arise from either wakefulness or sleep. (c) The pain is relieved by forceful stretching
of the affected muscles, releasing the contraction [1] (Table18.5).
Table 18.5 Diagnostic criteria for sleep-related leg cramps
Painful sensation in the leg or foot associated with strong muscle contraction
Painful muscle contraction occurs during the sleep period
Pain is relieved by forceful stretching of the affected muscles
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