Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Movement disorders are classically thought to resolve during sleep. Sleep-related movement disorders, however, are a subset that are characterized by their presence in sleep. This article will discuss these sleep-related movement disorders based on the International Classification of Sleep Disorders-3rd Edition (ICSD-3). These include restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorder, benign sleep myoclonus of infancy, propriospinal myoclonus at sleep onset, sleep-related movement disorders due to medical disorders, and sleep-related movement disorders due to medication or other substance.
• Any patient suspected of having restless legs syndrome should be evaluated with serum ferritin as correction of iron-deficiency anemia may improve symptoms.
• When treating restless legs syndrome, consider a nondopaminergic medicine first, and if a dopaminergic agent is used, try the lowest effective dose or long-acting formulation.
• Periodic limb movements of sleep could be associated with increased cardiovascular risk due to transient elevations in blood pressure and heart rate.
• Myoclonic movements isolated in sleep in an otherwise developmentally normal infant typically do not need treatment.
• Sleep bruxism does not correlate with the presence or absence of pain symptoms.
Movement disorders of sleep have been described for centuries. Perhaps the oldest sleep-related movement disorder described is sleep bruxism, which has been recognized since the time of the Old Testament. The term “bruxism” originated from the Greek brygmos, which means gnashing of teeth, and the first scientific description of bruxism was reported in the early 1900s (12). Similarly, restless legs syndrome was first described by Sir Thomas Willis in 1685; centuries later, Karl-Axel-Ekbom first used the term “restless legs syndrome” in 1944. Because of the pioneering work of these two individuals, restless legs syndrome now shares the name Willis Ekbom Disease (48).
In modern times, many sleep-related movement disorders are studied and treated within the specialties of both sleep medicine and movement disorder neurology. The American Academy of Sleep Medicine published the third edition of the International Classification of Sleep Disorders (ICSD-3) in 2014, and it is now widely used in clinical practice to characterize sleep disorders (04). The ICSD-3 recognizes seven broad categories of sleep disorders, including the following:
This article will highlight the nine sleep-related movement disorders listed in the ICSD-3 category of sleep related movement disorders. These include restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorder, benign sleep myoclonus of infancy, propriospinal myoclonus at sleep onset, sleep-related movement disorders due to medical disorders, and sleep-related movement disorders due to medication or other substance. Of note, REM behavior disorder will not be addressed in this article as it is defined not as a movement disorder of sleep but rather a type of parasomnia that is associated with various movement disorders.
Although the most widely recognized movement disorders are those that occur when a person is awake, there are a subset of movement disorders that occur exclusively or worsen significantly in sleep. These sleep-related movement disorders are classically defined as stereotyped movements that occur during sleep or in the transition from wakefulness to sleep. Restless legs syndrome, the most common movement disorder overall, is the exception to this definition as the compensatory movements seen in restless legs syndrome are often nonstereotyped. Clinical manifestations for each disorder vary and will be discussed in more detail below.
Restless legs syndrome. Restless legs syndrome, also known as Willis Ekbom disease, is characterized by limb discomfort that occurs at times of rest and is at least partially relieved by movement (04). Although restless legs syndrome is common, it is often underrecognized. The International Restless Legs Syndrome Study Group (IRLSS) and the International Classification of Sleep Disorders (ICSD-3) have developed diagnostic criteria for restless legs syndrome. Each criterion was updated in 2014, and both are used in clinical practice and in the research setting.
According to the IRLSS definition of restless legs syndrome, all of the following essential diagnostic criteria must be met (02; 01):
(1) An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs.
The ICSD-3 criteria include:
(A) An urge to move the legs, usually accompanied by or thought to be caused by uncomfortable and unpleasant sensations in the legs. These symptoms must:
(1) Begin or worsen during periods of rest or inactivity, such as lying down or sitting;
(B) The above features are not solely accounted for as symptoms of another medical or a behavioral condition (eg, leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, or habitual foot tapping).
Though the legs are the most common site for restless legs syndrome, 21% to 57% of patients may experience similar symptoms in the arms (04). Patients may have difficulty describing the limb discomfort, and this can lead to delays in diagnosis. A painful subtype of restless legs syndrome has been well documented, and it may affect 47% to 61% of restless legs syndrome patients (23). Impairment of sleep, which can include both sleep onset and sleep maintenance, is often the primary reason patients seek medical attention, and this can occur in up to 90% of patients with restless legs syndrome (04). In patients with dementia, restless legs syndrome may manifest as agitation or "sundowning" (38).
Periodic limb movement disorder. Periodic leg movements during sleep are involuntary, repetitive, stereotyped movements that occur primarily in non-REM sleep. Periodic limb movements during sleep usually consist of a toe extension with foot dorsiflexion, but sometimes they can resemble the triple flexion reflex with toe extension combined with dorsiflexion as well as knee and hip flexion (09). The tibialis anterior muscle is most commonly involved followed by gastrocnemius, biceps femoris, and rectus femoris (13). Rarely, muscles of the upper limb can be involved. Periodic limb movements during sleep may be associated with arousals and activation of the autonomic nervous system. Periodic limb movements during sleep are considered part of a movement disorder once they begin to negatively impact a person’s life, either through sleep disturbance or impairment of daytime function. To meet criteria for periodic limb movement disorder, the periodic limb movements during sleep Index must reach more than five per hour in children and more than 15 per hour in adults. Of note, periodic limb movement disorder cannot be diagnosed if the periodic limb movements occur in the context of restless legs syndrome, narcolepsy, obstructive sleep apnea, and REM sleep behavior disorder, which they commonly do (04). The ICSD-3 proposes diagnostic criteria as follows:
Criteria A to D must be met:
(A) Polysomnography demonstrates periodic limb movements during sleep, as defined in the most recent version of the American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep and Associated Events.
(B) The frequency is more than five per hour in children or more than 15 per hour in adults.
(C) The periodic limb movements during sleep cause clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, behavioral, or other important areas of functioning.
(D) The periodic limb movements during sleep and the symptoms are not better explained by another current sleep disorder, medical or neurologic disorder, or mental disorder (eg, periodic limb movements during sleep occurring with apneas or hypopneas should not be scored).
Sleep-related leg cramps. Sleep-related leg cramps or nocturnal leg cramps are recurrent, irregular, painful contraction of the leg muscles, typically in the calf (03). The contractions can disrupt sleep, lead to secondary insomnia, and be unpredictable. Approximately 20% of patients with leg cramps will seek medical attention due to the severity and disruptive nature of the cramping. On average, episodes of cramping last nine minutes but can be followed by residual pain or recurrence of cramping over the hours after the acute episode. Cramping can cause movement of the legs, such as plantar flexion or dorsiflexion of the foot depending on the muscle involved. The ICSD-3 proposes diagnostic criteria as follows:
Criteria A to C must be met:
(A) A painful sensation in the leg or foot associated with sudden, involuntary muscle hardness or tightness, indicating a strong muscle contraction.
(B) The painful muscle contraction occurs during the time in bed, although contractions may arise from either wakefulness or sleep.
(C) The pain is relieved by forceful stretching of the affected muscle, thus, releasing the contraction.
These criteria, however, have not been widely accepted (37). A 2017 systematic review proposed seven criteria to help differentiate nocturnal leg cramps from other disorders in patients over 50 years of age: intense pain, maximum of 10 minutes duration, located in the calf or foot, relief of symptoms with no intervention, persisting pain afterwards, causing sleep disruption, and causing distress to patient (19).
Sleep-related bruxism. In 2013, an international consensus defined sleep bruxism as “repetitive jaw-muscle activity characterized by clenching or grinding of the teeth or bracing or thrusting of the mandible” (28). Sleep bruxism is limited to when the patient is asleep (08). Other clinical symptoms associated with sleep bruxism include hypersensitive or painful teeth, temporal headaches, tooth surface loss, teeth fractures, buccal lacerations, or masticatory muscle hypertrophy (08). Approximately one third of cases of sleep bruxism involve an associated noise that can disturb a patient’s bed partners (04). Although the ICSD-3 provides diagnostic criteria for sleep bruxism, there is no accepted measure to evaluate severity of sleep bruxism, such as number of muscle contractions over time, duration of events, intensity of events, etc. (33). However, severity of sleep bruxism does not correlate to severity or presence of associated symptoms, especially pain symptoms (04; 12). The ICSD-3 proposes diagnostic criteria as follows:
Criteria A and B must be met:
(A) The presence of regular or frequent tooth-grinding sounds occurring during sleep.
(1) Abnormal tooth wear consistent with above reports of tooth-grinding during sleep.
Sleep-related rhythmic movement disorder. Sleep-related rhythmic movements are common in developmentally normal children and are not classified as a disorder unless they are disruptive to a person either by impairing sleep or causing self-injury. Several clinical subtypes of this disorder exist. Body rocking is the most common subtype (09). This type of movement occurs when a child rocks back and forth while on his or her hands and knees. It typically involves movement of the entire body but can less commonly be isolated to the torso. Head-banging is another form that occurs in the prone position with the head and at times the torso lifted from bed and struck back down on the pillow. Head-rolling tends to occur in the supine position with the head rocking side-to-side. Other forms of the disorder include body rolling, leg banging, or leg rolling. Though these rhythmic movements can occur at any time during sleep, they are most commonly observed at the onset of sleep.
The ICSD-3 provides the following criteria, all of which should be met:
(A) The patient exhibits repetitive, stereotyped, and rhythmic motor behaviors involving large muscle groups.
(1) Interference with normal sleep.
(D) The rhythmic movements are not better explained by another movement disorder or epilepsy.
Benign sleep myoclonus of infancy. Benign sleep myoclonus of infancy describes movements that begin in the first week of life and occur in quiet sleep or in the transition from sleep to wakefulness. These rapid jerking movements most commonly involve the upper extremities, though they can occur in any location, including, rarely, the face. Movements are synchronous but may be asymmetric. In addition, the movements may vary in duration and rhythmicity.
According to the ICSD-3, diagnostic criteria A to E must be met:
(A) Observation of repetitive myoclonic jerks that involve the limbs, trunk, or whole body.
Propriospinal myoclonus at sleep onset. Propriospinal myoclonus is a subtype of spinal myoclonus (04). Propriospinal myoclonus is clinically described as sudden jerks of axial muscles followed by spread of movement up and down. Movements are typically flexor in nature but can rarely cause extension. Propriospinal myoclonus primarily involves the trunk and abdomen first followed by the neck, knees, and hips. Though the movements tend to occur at the transition from wakefulness to sleep and resolve at the onset of sleep, they can recur overnight during periods of wakefulness. These myoclonic jerks may occur in clusters or, alternatively, can have a more quasi-periodic frequency. The ICSD-3 diagnostic criteria are as follows:
Criteria A to E must be met:
(A) The patient complains of sudden jerks, mainly of the abdomen, trunk, and neck.
Sleep-related movement disorder due to medical disorder. Abnormal movements in sleep can be linked with multiple medical or neurologic syndromes and may mimic other sleep-related movement disorders. For example, cycling of legs, kicking, or body rocking can be due to sleep-related hypermotor epilepsy rather than a primary sleep-related movement disorder (09). Therefore, a person’s comorbid medical and neurologic conditions should be extensively reviewed when sleep-related movement disorders do not meet criteria for another specific movement disorder. The ICSD-3 diagnostic criteria are as follows:
Criteria A to C must be met:
(A) The patient manifests sleep-related movements that disturb sleep or its onset.
Sleep-related movement disorder due to medication or substance. When a movement does not meet the criteria for an alternative sleep-related movement disorder, a person’s list of medications and substance use history should be reviewed. It can be somewhat challenging to attribute a sleep-related movement disorder to a particular substance as most substances or medications tend to either exacerbate an underlying sleep disorder or cause movements that occur throughout the day rather than predominantly at night (04). The ICSD-3 diagnostic criteria are as follows:
Criteria A to C must be met:
(A) The patient manifests sleep related movements that disturb sleep or its onset.
Restless legs syndrome. Restless legs can be classified based on age at time of onset, and this classification may help to predict course of disease. Early-onset restless legs syndrome (defined as onset earlier than 45 years of age) typically progresses more slowly than late-onset restless legs syndrome, which can have a rapidly progressive course. One third of patients with early-onset restless legs syndrome can experience stable symptoms or even remission over time (04). Restless legs syndrome tends to be a chronic disease, and studies assessing quality-of-life measures have demonstrated that individuals with restless legs syndrome have lower quality of life as compared to the general population. The impact on quality of life is often multifactorial and related to impaired sleep, relationship strain, effect on mood, decreased work productivity, and economic burden (22). Response to treatment is variable and depends on severity of symptoms; restless legs syndrome may diminish in 15% of patients and remit in only 8% (02).
Periodic limb movement disorder. The typical course of periodic limb movement disorder has not been well described though there are reports suggesting that some cases of pediatric-onset periodic limb movement disorder may progress to restless legs syndrome over time. Perhaps the most important prognostic consideration to highlight is that periodic limb movement disorder has been linked with higher risk for hypertension and cardiovascular disease. Periodic limb movements during sleep are associated with time-linked sympathetic bursts manifesting as increased heart rate and blood pressure (up to 20mmHg). In particular populations, this increased cardiovascular risk is directly related to a higher mortality rate. Studies have shown that in patients with both end-stage renal disease and periodic limb movements during sleep, 2-year cardiovascular mortality rate is 90% compared to 50% in patients end-stage renal disease but without periodic limb movements during sleep; similarly, over a 10-year period, the risk of stroke in patients with end-stage renal disease and periodic limb movements during sleep was twice that of patients without periodic limb movements during sleep. Similar data have been shown in patients with congestive heart failure and concurrent periodic limb movements during sleep with one study demonstrating a hazard ratio of 2.4 (13). In addition to cardiovascular risk, there are also higher rates of comorbid mood disorders, anxiety, attention deficit, and oppositional behavior in periodic limb movement disorder (04). In a study of older men without dementia, a higher rate of periodic limb movements during sleep was associated with a higher risk of cognitive decline over three to four years, with a particular decline in executive function (26).
Sleep-related leg cramps. The natural history of nocturnal leg cramps is not well understood (04). It is known that patients can have periods wherein they have symptoms followed by periods without leg cramps (29). Nocturnal leg cramps can affect quality of sleep and, therefore, a patient’s quality of life. Due to the unpredictable nature of nocturnal leg cramps, the impact of cramps on quality of life can vary as the patient’s symptoms wax and wane. However, there is no documented social or psychological dysfunction associated with nocturnal leg cramps (04).
Sleep-related bruxism. Sleep-related bruxism can remain asymptomatic for some patients throughout their lifetime (04). Sleep bruxism alone is, therefore, not an indication for treatment (08). With elimination of causes or risks factors for sleep bruxism (such as medication or stress), symptoms can resolve completely. Multiple studies have demonstrated that up to 80% of patients with sleep bruxism will self-report poorer sleep quality and more excessive daytime sleepiness than patients without bruxism (32; 11). Poor sleep quality may be related to the cumulative duration of sleep bruxism when assessed by overnight EMG and not the frequency or event type (32). Polysomnography can show lower sleep efficiency and increased sleep fragmentation in patients with sleep bruxism compared to those without although these findings were not found to be associated with subjective (self-reported) sleep quality. Furthermore, a self-reported oral health impact profile in a study of a Brazilian population find that sleep bruxism negatively impacts quality of life (11).
Sleep-related rhythmic movement disorder. Sleep-related rhythmic movement disorders tend to resolve by the second or third year of life but can persist beyond five years in 5% of children. Sustained symptoms are more likely to occur in a child with developmental or intellectual delay (18). It is unusual for these movements to continue into adulthood. Though the movements and accompanying noise created may be distressing or disruptive to other members of a person’s household, it is rare for an individual to cause self-harm.
Benign sleep myoclonus of infancy. Benign sleep myoclonus tends to resolve after two months, and 95% of cases will resolve by six months of age. Infants who experience benign sleep myoclonus are expected to develop normally.
Propriospinal myoclonus at sleep onset. The natural history of propriospinal myoclonus at sleep onset is poorly understood. In general, propriospinal myoclonus is felt to be a chronic condition that is difficult to treat.
Sleep-related movement disorder due to medical disorder. Prognosis is based on optimization of the underlying medical or neurologic disorder.
Sleep-related movement disorder due to medication or substance. Prognosis of this disorder is based on a clinician’s ability to identify the offending agent and discontinue said agent.
Mrs. M was a 40-year-old woman with a history of depression who presented to a neurologist for abnormal leg movements. She reported that for the past year, she had developed discomfort in her legs that seemed to arise primarily at night when she was lying in bed. She described the discomfort as a “crawling” sensation that occurred in both legs equally. She had noted that if she moved her legs in bed, the sensation improved but recurred when she stopped moving. She often got out of bed and walked around to try to find relief, and this as disruptive both for her own sleep and also for her husband who shared the same bed. Her husband, who accompanied her to the visit, reported that even when she did fall asleep, she tended to have jerking movements in her legs. She was generally fatigued during the day and overall felt that her mood had been worsening as a result of her poor sleep. Otherwise, during the day, she denied having any other abnormal movements, sensory loss, or pain.
Past medical history: Depression
Medications: Fluoxetine 20mg
Family history: Her mother described similar symptoms. Father had coronary artery disease.
Examination: A complete neurologic examination was normal. There was no evidence of sensory loss to light touch, pinprick, vibration, or proprioception. Pulses in the lower extremity were intact. There was no pedal edema appreciated.
Impression: The patient described a classic example of restless legs syndrome, and the jerking movements her husband observed during sleep were periodic limb movements during sleep, a common associated feature of restless legs syndrome. Her gender and family history placed her at higher risk for development of restless legs syndrome, and her use of a selective serotonin reuptake inhibitor was thought to unmask or exacerbate the disorder. In this particular patient, further diagnostic testing was unnecessary.
A multifaceted approach to management could include transitioning to an alternative antidepressant, such as bupropion, which does not worsen restless legs syndrome symptoms, along with screening for iron deficiency with serum ferritin. Oral iron supplementation should be provided if ferritin level is lower than 75 and this alone may help to improve restless legs syndrome symptoms. If further therapy is required, a long-acting, nondopaminergic medication, such as gabapentin enacarbil, could be initiated to avoid long-term risk of augmentation.
Restless legs syndrome. Though the exact cause of primary restless leg syndrome has not been defined, evidence suggests an interplay between brain iron deficiency, dopamine regulation, and genetics. Support for the relationship between brain iron deficiency and development of restless legs syndrome comes from CSF and multiple imaging studies showing decreased iron in the substantia nigra in patients with restless legs syndrome. Despite normal serum ferritin levels, CSF ferritin may be low in these patients. In addition, clinical studies have demonstrated alleviation of symptoms following intravenous iron administration (45). A retrospective observation study suggests that restless legs syndrome symptoms have seasonal variability, with worse symptoms in summer months, possibly related to changes in microvascular regulation, sweating, and serum iron levels during times of increased temperatures (27). Multiple randomized control trials have confirmed the beneficial role of dopaminergic agents in the treatment of restless legs syndrome, and this, in turn, has lent support to the association between the dopamine system and restless legs syndrome, though the exact mechanism remains unknown. A review of the neurochemical features of restless legs syndrome has identified a possible role for other neurotransmitters to be involved in the pathophysiology of the condition, in particular, glutamate, gamma-hydroxybutyric acid, and adenosine (42). Systems involving these neurotransmitters may be a result of iron deficiency and would explain the benefit of gabapentinoid agents. Additionally, vitamin D deficiency and elevated phosphorous levels have been shown to be associated with restless legs syndrome (30). Both vitamin D and phosphorous are involved in dopamine function, suggesting that they may be involved in the pathophysiology of restless legs syndrome. The high rate of familial restless legs syndrome, particularly in early onset cases, has led to exploration of a genetic cause for the disease. Although a causative gene has not been identified, genome-wide association studies have linked four reproducible single nucleotide polymorphisms (SNPs) with restless legs syndrome: BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD. These genes are being explored in various subtypes of restless legs syndrome. For example, a pilot study implicates a variant in the TOX3 gene in the painful restless leg syndrome subtype (23). There are now 19 risk loci identified that are associated with increased risk of restless legs syndrome with MEIS1 showing the strongest association (41).
Periodic limb movement disorder. Some of the same mechanisms that have been proposed in the pathophysiology of restless legs syndrome have been applied to periodic limb movement disorder. These include dopamine dysregulation, impaired iron storage, and genetic factors. Genome-wide association studies have identified single nucleotide polymorphisms that are shared between periodic limb movements during sleep and restless legs syndrome, including BTBD9, MEIS1, and MAP2K5 (09).
Sleep-related leg cramps. The underlying etiology of nocturnal leg cramps is unknown (03). There is a theory that shortening of muscle length in older adults who are less active may cause nocturnal leg cramps (19). It is believed that the majority of cases are idiopathic (04). Studies evaluating EMG during leg cramps have shown that there is hyperactivity of the peripheral nerves, causing high frequency, repetitive firing of motor unit action potentials at a rate higher than involuntary contractions (37).
Sleep-related bruxism. Initial theories regarding the etiology of sleep bruxism focused on structural changes in the mouth, such as dental occlusion (08). Studies have since refuted this hypothesis, and sleep bruxism is now believed to be due to activation of the central nervous system during sleep (08). Studies have suggested that sleep bruxism is an extreme form of normal muscle contraction in sleep (08) and is characterized by rhythmic masticatory muscle activity (04; 11). Sleep bruxism has been found to be most common during periods of microarousals of sleep. Microarousals are 3- to 10-second-long periods of increased heart rate and muscle activity identified in healthy subjects. These can occur eight to 15 times per hour, during which episodes of sleep bruxism have been found to cluster. Patients with sleep bruxism have been found to have more microarousals during sleep than healthy subjects (08). Recent studies have supported this by showing that sleep bruxism severity can be predicted by symptomatic motor features of the jaw and changes in polysomnography, particularly decreased N2 sleep and increased N3 sleep. (39). There is debate regarding the function of sleep bruxism in sleep. One proposed function of sleep bruxism is to maintain airway patency during sleep, which may explain the increase in sleep bruxism in patients with obstructive sleep apnea (08). Another theory suggests that sleep bruxism may stimulate saliva flow, which may explain the observation that increased muscle activity during arousals is associated with increased swallowing activity.
Sleep-related rhythmic movement disorder. The pathophysiology of sleep-related rhythmic movement disorders is not precisely understood. Some postulate that rhythmic movement disorder aids in the development of motor control by stimulating the vestibular system (04). Others suggest that the movements themselves are soothing and may be used as a coping measure in the context of environmental stress or lack of environmental stimulation (18).
Benign sleep myoclonus of infancy. The biological basis of benign sleep myoclonus of infancy is unknown though some question whether it is representative of immature myelination leading to impaired motor inhibition (04).
Propriospinal myoclonus at sleep onset. Propriospinal myoclonus is thought to have three subtypes: idiopathic, secondary, and functional. Whether or not propriospinal myoclonus at sleep onset is a separate subtype remains to be determined. Though a small proportion of propriospinal myoclonus is attributable to a structural lesion in the thoracic cord where propriospinal myoclonus typically originates, the subtype at sleep onset is typically felt to be idiopathic (06).
Sleep-related movement disorder due to medical disorder. The biological basis for this disorder is dependent on the underlying medical or neurologic disorder identified.
Sleep-related movement disorder due to medication or substance. The biological basis for this disorder is dependent on the medication or substance thought to be causing the movement disorder.
Restless legs syndrome. In European populations, the prevalence of restless legs syndrome is estimated at 5% to 10% (04). The incidence is lower in Asian populations; (approximately 1.6% to 2.0%); however, the reason for this is unclear (15). Women over the age of 35 are twice as likely as males to develop restless legs syndrome (15). Pregnancy also increases the prevalence in women to approximately 21% as discussed below. Though the disease can occur at any age, the prevalence increases with age. Restless legs syndrome can be separated into early-onset (before 45 years of age) and late-onset (after 45 years of age). The peak age of early-onset is typically between 20 and 40 years. Pediatric forms of restless legs syndrome are recognized as well, with a prior European study demonstrating a prevalence of 1.9% in 8- to 11-year-olds and 2% in 12- to 17-year-olds.
Periodic limb movement disorder. Due to the overlap between periodic limb movements during sleep and restless legs syndrome, the prevalence of periodic limb movement disorder is not well known. The prevalence is thought to increase with age with rates of periodic limb movements during sleep greater than 15 per hour estimated as 7.6% in 18- to 65-year-olds. There appears to be a higher rate of periodic limb movements during sleep in Caucasians as is seen in restless legs syndrome, but unlike restless legs syndrome, there is no difference in frequency between genders (04).
Sleep-related leg cramps. Fifty percent to 60% of adults and 7% of children will experience nocturnal leg cramps in their lifetime (03). Leg cramps are more common in women (04). The prevalence increases with age, where 33% of the population over 50 years of age and 50% over the age of 80 years experience nocturnal leg cramps (04; 19). Furthermore, 20% of patients who report nocturnal leg cramps may get cramping during the day when at rest (19). A large-scale epidemiologic study found that 30% of adults with nocturnal leg cramps experience these at least five times per month and 6% at least 15 times per month (16). Epidemiologic studies have shown that worse perceived overall health is highly predictive of nocturnal leg cramps more than any specific disease or disorder.
Sleep-related bruxism. Eighty-five percent to 90% of the population has experienced bruxism in their lifetime. The overall prevalence varies greatly between studies but is generally accepted at around 8% to 13% of the general population (08). Sleep bruxism is less common than awake bruxism. Prevalence can vary with age as children have been found to have the highest prevalence of sleep bruxism (14% to 18%) and elderly patients the lowest prevalence (approximately 3%) (08). Primary sleep bruxism is not due to any pre-existing medical condition whereas secondary sleep bruxism is the product of an underlying psychiatric or medical condition or the use of medication or toxins that directly cause the sleep bruxism (08). Risk factors include smoking, caffeine or heavy alcohol intake, certain medications or illicit drug use, obstructive sleep apnea, gastrointestinal reflux, and, commonly, stress or anxiety. Patients are twice as likely to report increased stress if they have sleep bruxism than those who do not (11).
Sleep-related rhythmic movement disorder. Rhythmic movement disorder is common in infants, and prevalence decreases with age. Per studies using parental report, an estimated 66% of infants at age nine months demonstrate rocking, head-banging, or head-turning as compared to 45% of 18-month-olds and just 6% of five-year-olds (18). There is no known gender difference in children; in adolescent cases, males seem to be more affected (04). Sleep-related rhythmic movement disorders that persist beyond childhood are associated with developmental disabilities or intellectual disorders. Perinatal risk factors such as prematurity, surgical delivery for intrauterine hypoxia, and neonatal jaundice requiring phototherapy are present in one third of patients with persistent sleep-related rhythmic movement disorder (36).
Benign sleep myoclonus of infancy. The prevalence of benign sleep myoclonus is unknown; however, there are an estimated 3.7 cases per 10,000 live births (04). There are no defined risk factors for development of this disorder though it is thought to be more common in males (20).
Propriospinal myoclonus at sleep onset. Propriospinal myoclonus at sleep onset is a rare disorder, and precise epidemiologic data are absent from medical literature.
Sleep-related movement disorder due to medical disorder. The prevalence of sleep-related movement disorders due to a medical disorder is difficult to estimate due to significant overlap with other disorders.
Sleep-related movement disorder due to medication or substance. The overall prevalence of sleep-related movement disorders due to a medication or substance is unknown.
Restless legs syndrome. Secondary restless legs syndrome has been linked with iron deficiency anemia, pregnancy, chronic renal failure, and prolonged immobility. In individuals with known risk for development of restless legs syndrome, particularly those with a family history, avoidance of these states may help to mitigate this risk. Maintaining a normal serum iron level may help to decrease the severity of symptoms. Several medications are also thought to precipitate or worsen restless legs syndrome. These include antihistamines, dopamine antagonists, and most antidepressants, namely selective serotonin reuptake inhibitors and tricyclics. For this reason, bupropion should be used in patients who are known to be at risk for restless legs syndrome (04).
Periodic limb movement disorder. Similar to what is seen in restless leg syndrome, several medications are thought to unmask periodic limb movements during sleep, including selective serotonin reuptake inhibitors, tricyclic antidepressants, lithium, and dopamine antagonists (04).
Sleep-related leg cramps. Although sleep-related leg cramps are associated with multiple medical conditions and medications, data have not proven that treating or eliminating these risk factors decreases or resolves leg cramps in these patients.
Sleep-related bruxism. Because many patients with sleep bruxism are asymptomatic, it is difficult to identify universal methods for prevention of the disorder. Some groups suggest that improving sleep hygiene and reducing stress can eliminate or reduce sleep bruxism (24). However, well designed studies on the efficacy of techniques to prevent sleep bruxism are lacking.
Sleep-related rhythmic movement disorder. There are no known preventative measures for sleep-related movement disorder.
Benign sleep myoclonus of infancy. There are no known preventative measures for benign sleep myoclonus of infancy.
Propriospinal myoclonus at sleep onset. There are no known preventative measures for propriospinal myoclonus at sleep onset.
Sleep-related movement disorder due to medical disorder. Optimization or avoidance of the particular medical or neurologic disorder helps to prevent development of abnormal movements.
Sleep-related movement disorder due to medication or substance. This movement disorder can be prevented by avoidance of the culprit medication or substance.
Restless legs syndrome. The differential diagnosis for restless legs syndrome is broad and includes many common complaints. These include leg cramps, positional discomfort, arthralgias or arthritis, myalgias, leg edema, peripheral neuropathy, radiculopathy, and habitual foot-tapping. The discomfort is not isolated to the joint as would be expected in arthritis. In addition, the examination is typically normal in the setting of restless legs syndrome without evidence of sensory loss, reflex asymmetry, or weakness as may be revealed in a neuromuscular disorder. Other less common mimics could include neuroleptic-induced akathisia, myelopathy, symptomatic venous insufficiency, peripheral artery disease, eczema, orthopedic problems, painful legs and moving toes, and anxiety-induced restlessness. The key feature distinguishing restless legs syndrome from these syndromes is the preponderance of movements at rest (04).
Periodic limb movement disorder. Periodic limb movement disorder should be distinguished from sleep starts (otherwise known as hypnic jerks), which are physiologic and occur at the transition from wakefulness to sleep. Sleep starts are typically briefer in duration (20 to 100 milliseconds) and do not have a periodic pattern (04).
Sleep-related leg cramps. Differentiating nocturnal leg cramps from other disorders relies on the description of the cramps as this disorder can often be confused with other sleep-related movement disorders, such as restless legs syndrome and periodic limb movement disorder (19). Claudication is differentiated by dull, aching pain that worsens with activity and is alleviated by rest (03). Hypnic jerks (as described above) are fast, brief jerks at onset of sleep that can wake patients. Myositis is a dull constant pain that produces weakness and has associated high creatine kinase levels. Periodic leg movements of sleep are painless, and the patient is often unaware of them. Peripheral neuropathy can be described as burning, numbness, sharp, shock-like pain and can be identified on EMG. Finally, restless legs syndrome is an uncomfortable feeling that causes an urge to move the legs for relief and has no associated visible muscle cramping. Dystonia can be differentiated on EMG by the presence of ongoing agonist-antagonist contraction (04).
Sleep-related bruxism. The differential diagnoses for sleep-related bruxism include temporomandibular joint disorder, myofascial pain, seizures, and sleep myoclonus. Clinical presentation has significant overlap for many of these disorders as subjective pain is the primary complaint (12). Some experiments have suggested that repetitive muscle contraction alone is not sufficient to cause pain and temporomandibular joint disorder symptoms, suggesting that additional risk factors predispose certain patients with sleep bruxism to jaw muscle and face pain. Other mimics of sleep bruxism include faciomandibular myoclonus, REM sleep behavior disorder, abnormal swallowing, gastroesophageal reflux disease, night terrors, confusional arousals, dyskinetic jaw movements persisting in sleep (dystonia, tremor, chorea, palatal myoclonus, dyskinesias), and, rarely, sleep-related epilepsy (04). Polysomnographic monitoring and dental examination can ultimately be used to differentiate these disorders if necessary, prior to treating a patient.
Sleep-related rhythmic movement disorder. Due to the more complex nature of movements in rhythmic movement disorder, REM sleep behavior disorder could be considered in the differential diagnosis, and videopolysomnography can be a helpful tool to differentiate the two (04). The movements associated with REM sleep behavior disorder appear more purposeful and occur exclusively in REM sleep. Other entities that may mimic rhythmic movement disorder include sleep-related bruxism, thumb-sucking, and hypnogogic foot tremor. Stereotypies, which are often noted in children with autism spectrum disorder, occur primarily with wakefulness. Rhythmic movement disorder can be distinguished from nocturnal epilepsy via absence of ictal changes on EEG.
Benign sleep myoclonus of infancy. The primary differential diagnoses to consider in an infant with myoclonic movements are myoclonic seizures; distinguishing these two entities is important as it helps to avoid unnecessary diagnostic testing and treatment (04). The major features that differentiate benign sleep myoclonus of infancy from myoclonic seizures are the presence of movements only in sleep and the ability to abort the movements when an infant is aroused. In addition, infants with benign sleep myoclonus of infancy tend to be developmentally normal, whereas those with perinatal injury, such as ischemia, infection, or a metabolic disorder, have a higher risk for development of a seizure disorder. Infantile spasms, which clinically present as sudden head flexion with arm extension, tend to present later than benign sleep myoclonus of infancy, usually after one month of age (04). Other mimics of benign sleep myoclonus of infancy include “sleep starts,” which tend to occur as nonrepetitive movements at the transition from wakefulness to sleep, and “phasic-REM muscle activity,” which is characterized by movements of the eyes and smaller muscles. Jitteriness, drug withdrawal, hyperekplexia, and myoclonic encephalopathies may have a similar appearance to benign sleep myoclonus of infancy but occur during wakefulness.
Propriospinal myoclonus at sleep onset. Secondary causes of propriospinal myoclonus should be considered first on the differential (04). Suspicion for a secondary cause is raised when the history of propriospinal myoclonus accompanies abnormal findings on neurologic examination, such as spasticity, abnormal gait, or a sensory level. Exaggerated sleep starts can resemble propriospinal myoclonus at sleep onset. When evaluated with EMG, propriospinal myoclonus lasts longer and is a slower movement as compared to exaggerated sleep starts. In addition, the propriospinal propagation of muscle contraction is a unique feature to propriospinal myoclonus (10).
Sleep-related movement disorder due to medical disorder. All other sleep-related movement disorders should be considered in the differential before attributing the abnormal movement to an underlying medical or neurologic disease.
Sleep-related movement disorder due to medication or substance. Sleep-related movements caused by medications or substances can often mimic other movement disorders of sleep, and the differential is often broad.
Restless legs syndrome. The risk of restless leg syndrome increases with certain underlying comorbidities. Most common is iron deficiency anemia and Parkinson disease on dopaminergic treatment, although it can also be associated with migraine and renal failure requiring hemodialysis (15). In addition, studies have shown that having multiple comorbidities is a strong risk factor for restless leg compared to the presence of any one condition. There is also a question of restless legs syndrome being associated with cardiovascular disease, and a study from the Canadian Longitudinal Study on Aging found an association between restless leg syndrome and objective atherosclerosis measured by carotid intima-media thickness (51). Evidence also suggests that restless legs syndrome is more common and severe in patients with multiple sclerosis as well (44). There also seems to be evidence of a bidirectional relationship between irritable bowel syndrome and restless legs syndrome (17).
Periodic limb movement disorder. Periodic limb movement disorder is a diagnosis of exclusion, as certain syndromes are linked with higher rates of periodic limb movements in sleep, including restless legs syndrome, narcolepsy, multiple system atrophy, dopa-responsive dystonia, sleep-related eating disorder, spinal cord injury, end-stage renal disease, congestive heart failure, Parkinson disease, sickle cell disease, posttraumatic stress disorder, Asperger syndrome, Williams syndrome, and multiple sclerosis (04). Children with Down syndrome have also been shown to have an increased risk of periodic limb movements, which suggests that this should be screened for along with sleep disordered breathing in these children (40).
Sleep-related leg cramps. Nocturnal leg cramps have been associated with metabolic disorders (parathyroid dysfunction, hyper- or hypocalcemia), nerve damage, medication usage (most commonly intravenous iron infusion, naproxen, diuretics, and estrogen-based medication such as raloxifene), chronic medical conditions (chronic liver disease, Parkinson disease, motor neuron disease, lumbar spinal stenosis, dialysis--although not chronic kidney disease), respiratory disease, depression, and venous insufficiency. These comorbidities should, therefore, be evaluated in the differential diagnosis of nocturnal leg cramps (03).
Sleep-related bruxism. The relationship between headache and sleep bruxism has also been poorly studied and is likely confounded by the intimate relationship between sleep bruxism, temporomandibular joint disorder, and headaches. Morning headaches in particular have been found to be associated with sleep bruxism (47). Other comorbid sleep disorders associated with sleep arousal can also be seen with sleep bruxism, including sleep walking, night terrors, and sleep talking (08).
Restless legs syndrome. Though restless leg syndrome is typically a clinical diagnosis, polysomnography may be used to confirm the diagnosis (04). Objective findings on polysomnography in restless legs syndrome include prolonged sleep latency and higher arousal index. Whereas periodic limb movements of sleep gradually decrease throughout the night in periodic limb movement disorders, they tend to follow a circadian pattern in restless legs syndrome, reaching their maximum in the first half of the night. The frequency of periodic limb movements during sleep is five or more per hour in the majority of patients. Periodic limb movements of wakefulness are greater than 40 per hour in restless legs syndrome. Ruling out restless legs syndrome mimics, such as neuropathy or radiculopathy, may require that clinicians obtain dedicated imaging or neurophysiologic studies, such as EMG. As previously mentioned, ferritin levels should be checked in all patients with symptoms of restless legs syndrome. It should also be noted that an individual can certainly have more than one attributable cause for leg discomfort, which may include restless legs syndrome. In particular populations, such as individuals with chronic kidney disease, concurrent restless legs syndrome and neuropathy may be noted. Patients with Parkinson disease are at risk for development of multiple forms of sleep disorders, and distinguishing these etiologies helps to guide management. Though the compensatory movements associated with restless legs syndrome may at times share the complex appearance of those seen in REM sleep behavior disorder, the latter occur exclusively during REM sleep.
Periodic limb movement disorder. Polysomnography allows for quantification of periodic limb movements during sleep and determination of the PLMS Index, which equates to the number of periodic limb movements during sleep per hour of sleep (04). The PLMS Index is more than 5 per hour in children and more than 15 per hour in adults with periodic limb movement disorder. A tibialis anterior EMG will demonstrate repeated muscle contraction lasting 0.5 to 10 seconds. EEG shows no ictal activity. Actigraphy is not recommended for periodic limb movements in the most recent consensus statement by the American Academy of Sleep Medicine (43).
Sleep-related leg cramps. The mainstay of diagnosis for nocturnal leg cramps is a complete patient history. This should include a full review of medications and underlying medical conditions. Physical examination often does not reveal any cramping but should include checking pulses, evaluating pedal edema, pinprick, and motor evaluation of the lower extremities (03). EMG, venous studies such as ultrasound or angiography, and laboratory tests for calcium, parathyroid hormone, and liver function are only indicated if the history suggests an underlying condition that could be confirmed through these tests.
Sleep-related bruxism. A thorough history and clinical examination of teeth can help to diagnose sleep bruxism (08). The Brux scale, which asks patients to report how often they grind or clench their teeth both when awake and asleep, has been developed to identify sleep bruxism when evaluating a patient. Self-report, however, may be inaccurate as up to 80% of patients with sleep bruxism are not aware of the bruxism, and patients with jaw pain often over-report sleep bruxism (08; 12). Reported noise during sleep on history is highly suggestive of sleep bruxism, and it has been shown that this reported finding alone has 78% sensitivity and 94% specificity when validated by polysomnography (25). EMG of the masseter or temporalis muscle in sleep may aid in diagnosis. This can show repetitive phasic activity or tonic clenching activity (08). However, EMG cannot differentiate sleep bruxism from other muscle activity, such as talking, swallowing, or lip-biting. Intra-oral devices that can identify force applied during clenching or grinding, muscle activity recordings, and polysomnography may all be helpful in the workup of sleep bruxism. Polysomnography is generally considered the gold standard for diagnosis but can be expensive and, therefore, is typically limited to the research setting.
Sleep-related rhythmic movement disorder. Often, rhythmic movement disorder is brought to medical attention by parental report. Because of variability night to night, a polysomnogram may underestimate frequency of rhythmic movement disorder on a single night. A home study may, therefore, be preferable (18).
Benign sleep myoclonus of infancy. In order to rule out an epileptic cause for myoclonus in the infant, an EEG is often obtained. Both the ictal and interictal EEG should be normal in benign sleep myoclonus of infancy.
Propriospinal myoclonus at sleep onset. To rule out a structural cause for propriospinal myoclonus, contrasted MRI imaging of the cervical and thoracic spine should be pursued, though these will typically be unrevealing. Polymyography is used to aid in the diagnosis of propriospinal myoclonus and shows propagation of electrical impulses from cervical or thoracic innervated muscles to rostral and caudal muscles on EMG. Concurrent EEG recording should confirm the absence of a cortical impulse prior to muscle activity (06).
Sleep-related movement disorder due to medical disorder. Diagnosis of a movement disorder related to a medical disorder may require laboratory screening for organ dysfunction.
Sleep-related movement disorder due to medication or substance. In order to determine whether a movement disorder is related to a particular medication or toxic substance, serum drug level or urine toxicology screen may be obtained in some cases.
Restless legs syndrome. Treatment for restless legs syndrome can be divided into pharmacologic and nonpharmacologic therapy. There are four oral medications currently approved by the Food and Drug Administration for treatment of moderate to severe restless legs syndrome. These include three dopamine agonists (ropinirole, pramipexole, rotigotine) and one alpha-2delta receptor ligand (gabapentin enacarbil) (07). Of these, pramipexole and ropinirole carry a high level of evidence for their use as first-line agents and are considered standard of care. Gabapentin enacarbil is also supported with high level of evidence. For those patients who require trial of a second-line agent, there is a low level of evidence for use of gabapentin, carbamazepine, clonidine, and opioids. Botox is being explored for use in restless legs syndrome with some evidence for improved restless legs syndrome symptoms, pain score, and quality of life (31). Iron supplementation may be an effective treatment in individuals who are found to have iron deficiency anemia with serum ferritin levels lower than 75 ug/L.
There are also multiple nonpharmacologic therapies that are being explored for treatment of restless legs syndrome. These include exercise training, electrical stimulation, vibratory stimulation, enhanced external counter pulsation, pneumatic compression devices, light therapy, repetitive transcranial magnetic stimulation, acupuncture, and yoga. Exercise has been shown to be an effective therapy in both the general restless legs syndrome population and, more specifically, in patients with restless legs syndrome secondary to chronic kidney disease. In this particular population, studies have shown that aerobic exercise can improve restless legs syndrome symptoms based on the International Restless Legs Syndrome Rating Scale by up to 42% (50).
Periodic limb movement disorder. According to the 2012 American Academy of Sleep Medicine Clinical Practice Guideline, there is “insufficient evidence” to support use of a particular medication when periodic limb movement disorder occurs in isolation. That being said, studies exploring the use of medications in treatment of restless legs syndrome demonstrated concurrent decrease in periodic limb movements; these agents include carbidopa-levodopa-entacapone, pramipexole, ropinirole, rotigotine, gabapentin, and pregabalin (07). When rotigotine is compared to placebo, it has been shown to decrease the periodic limb movement index by up to 32.1/hour (49). Though benzodiazepines may improve perceived sleep quality, they are not felt to decrease the Periodic Limb Movements During Sleep Index and are, therefore, not recommended for long-term therapy. Alternative agents that have been considered include melatonin, valproate, and selegiline, each of which have previously demonstrated effect on nighttime frequency of periodic limb movements during sleep (07).
Sleep-related leg cramps. There is currently no recommended treatment for nocturnal leg cramps that is both safe and effective (03). Historically, quinine was a recommended treatment for nocturnal leg cramps, and in a 2015 Cochrane review it was found to reduce cramps in older adults by 28% (37). There is some concern that these results are due to a strong placebo effect. Unfortunately, quinine is no longer recommended as treatment for nocturnal leg cramps (see outcomes section below). Magnesium has also been studied in randomized control trials and was found to have no benefit overall for idiopathic cramps but may have modest benefit in pregnant patients (37). Other small studies have revealed some evidence for short-term benefit of calcium channel blockers, gabapentin, vitamin B complex, the vasodilator naftidrofuryl, and the anticholinergic orphenadrine citrate, although evidence is limited for these medications (37). There is limited or contradictory evidence for massage, passive stretching, trigger-point injections, and exercise before bedtime to prevent or treat nocturnal leg cramps (03; 37). However, these methods are safe, and patients may anecdotally find benefit from them. Avenues of research that may show promise include botulinum toxin of the gastrocnemius muscle (34).
Sleep-related bruxism. There is much debate about the efficacy of treatments for sleep bruxism. Treatment should only be implemented when there are consequences to withholding treatment (08). There are few high-quality studies on effective treatment for sleep bruxism. Oral appliances, in particular splints, can be applied when the aim is prevention of teeth damage (08; 11). Use of splints in patients with obstructive sleep apnea should be done with caution, as evidence has shown that splinting could worsen obstructive sleep apnea by possibly reducing the reflexes that maintain airway patency (08). Behavioral interventions, including biofeedback, relaxation, and improvement in sleep hygiene have all been described but had limited effect or concern for worsening daytime sleepiness (08). An updated review of the literature in 2018 identified cranial electrotherapy stimulation as a potentially effective biofeedback modality (21). Cranial electrotherapy stimulation appears to reduce sleep bruxism-related EMG activity in the short term; however, long-term data are lacking for this modality. There is lack of evidence to support the efficacy of other commonly used treatments, such as hypnotherapy, habit-reversal therapy, massed practice therapy, and relaxation techniques (33).
Multiple medications have been tried and may show some efficacy, including benzodiazepines, dopaminergic medication, clonidine, anticonvulsants, and antidepressants. However, a Cochrane review revealed that the data are conflicting, therefore, medication is not recommended at this time for management of sleep bruxism (08). Botulinum toxin has been shown effective in reducing sleep bruxism to the same extent as occlusal splinting (08). A randomized placebo-controlled trial found subjective improvement in bruxism symptoms in a slightly larger sample size than previous trials, suggesting that this is a treatment worth evaluating in large multicenter trials (33).
Sleep-related rhythmic movement disorder. Pharmacologic therapies are not typically effective in treatment of sleep-related rhythmic movement disorder. The goal may shift rather to reducing injury with measures including installation of bedrails, use of padding, or distancing the bed from walls or other furniture (18).
Benign sleep myoclonus of infancy. Though infants with benign sleep myoclonus are often given antiepileptics due to initial concern for seizure, treatment of these movements is not warranted.
Propriospinal myoclonus at sleep onset. Response to treatment is marginal in propriospinal myoclonus, with a remission rate of 11% reported in secondary propriospinal myoclonus and 24% in idiopathic cases (46). Medications that are effective in treatment of other forms of myoclonus are also felt to be effective in treatment of propriospinal myoclonus, including clonazepam, levetiracetam, and, perhaps, valproic acid.
Sleep-related movement disorder due to medical disorder. Treatment of sleep-related movement disorders that are felt to be related to a medical comorbidity are managed through optimization of that medical disease.
Sleep-related movement disorder due to medication or substance. Treatment of sleep-related movement disorders that are felt to be related to a particular medication or substance are best treated with discontinuation of that agent.
There are limited long-term data on the treatment outcomes for sleep-related movement disorders. However, for restless legs syndrome and nocturnal leg cramps, long-term complications of treatments have been identified and will be reviewed below.
Restless legs syndrome. Many patients will experience improvement or resolution of their restless legs syndrome with pharmacologic therapy. However, augmentation is a long-term complication of treatment. Augmentation describes the phenomenon of overall worsening restless legs syndrome symptoms, which can include one or more of the following features: earlier onset of restless legs syndrome symptoms in the day, decreased time to symptom onset after rest, spread of symptoms to other previously uninvolved body parts, shorter duration of medication effect, and increased intensity of discomfort (14). A paradoxical effect of medication may occur in which increasing dosage of medication leads to worsening of symptoms whereas decreasing medication dose leads to symptom relief. Augmentation can occur with use of any dopaminergic agent; however, studies suggest that the risk is highest with the use of levodopa followed by short-acting dopamine agonists (ie, pramipexole, ropinirole) then longer-acting agonists (rotigotine, cabergoline) (14). The yearly incidence rate of augmentation with dopaminergic agents is approximately 8%, and overall prevalence increases with duration of treatment (05). Risk factors for augmentation include lower ferritin levels, more frequent and more severe restless legs syndrome pretreatment, greater discomfort pretreatment, asthma, older age, longer treatment duration, development of dopaminergic agent tolerance, positive family history of restless legs syndrome, fewer outpatient clinic appointments, and lack of neuropathy (05). A combined task force, including the International Restless Legs Syndrome Study Group, the European Restless Legs Syndrome Study Group, and the Restless Legs Syndrome Foundation suggests that clinicians should consider the following measures to prevent or lessen augmentation:
(1) Choose an agent with no risk for augmentation, such as an alpha-2delta receptor ligand for initial therapy
Once augmentation occurs, the treatment is to eliminate the short acting dopaminergic agent in favor of a long acting dopamine agonist (rotigotine), an alpha2 ligand, or in severe cases a long acting opiate (05).
Sleep-related leg cramps. Although quinine has previously been shown to reduce nocturnal leg cramps, it is no longer recommended as treatment due to long-term complications. Quinine has been found to interact with many medications and can cause life-threatening side effects of hypersensitivity and thrombocytopenia, and at toxic doses, it can cause cardiac arrhythmias (03; 37). The United States Food and Drug Administration in 2010 issued a statement that the modest benefit of quinine does not outweigh the risks (03).
Of the movement disorders of sleep, restless legs syndrome is most important to consider in the pregnant population due to its high prevalence and unique management strategy. Roughly one in five pregnant women in Western populations report symptoms of restless legs syndrome, and overall, the rate of restless legs syndrome in pregnancy is two to three times that seen in the general population (04; 35). Increased parity also increases the risk of restless legs syndrome in pregnancy (42). The pathophysiology behind these higher rates in pregnancy is not well understood, although the interplay between changes in hormone levels and change in iron levels are likely contributory (42). However, the presence of restless legs syndrome increases the risk for prolonged labor, cesarian section, preeclampsia, and mood disorders, all of which are likely due to the change in sleep quality associated with restless legs (15). Symptoms tend to peak in the third trimester and typically resolve by one month after delivery. Most patients have resolution of their symptoms at or just before delivery. A past history of restless legs syndrome when not pregnant, prior restless legs syndrome with pregnancy, or a hemoglobin less than 11 g/dL are each independent predictors for the development of restless legs syndrome in pregnancy (35). Symptoms can be severe in up to 54% of pregnant patients.
A consensus statement regarding the diagnosis and treatment of restless legs syndrome in pregnancy from the IRLSS was published in 2014. This highlights the fact that the diagnosis of restless legs syndrome in pregnant women is no different than the general population though there are multiple pregnancy-related symptoms that may mimic restless legs syndrome in this population. These include leg cramps, positional discomfort, venous stasis, leg edema, compression and stretch neuropathies, sore leg muscles, ligament sprain or tendon strain, positional ischemia leading to numbness, dermatitis, or bruising. These guidelines also highlight the importance of nonpharmacologic therapies as first-line treatment of restless legs syndrome in pregnancy, including moderate intensity exercise, yoga, massage, and pneumatic compression devices. In addition, care should be taken to eliminate or decrease aggravating factors, such as iron deficiency, immobility, and serotonergic medications. Oral iron may be safely administered in pregnant patients with restless legs syndrome who have a serum iron lower than 75 ug/L. Intravenous iron may be used in the third trimester if oral therapy is ineffective or if serum iron is lower than 35 ug/L. If medication is required, a nighttime dose of extended-release levodopa or low-dose clonazepam may be considered. There is insufficient safety evidence for use of gabapentin enacarbil, gabapentin, or pregabalin, and use of opioids comes with the risk for neonatal withdrawal syndrome (35).
Similarly, sleep-related leg cramps are more common in pregnant women. However, it is unclear if this is due to venous insufficiency in pregnancy or pregnancy itself. Treatments with magnesium, sodium tablets, and multivitamins have all been evaluated in pregnant women and may safely provide some benefit to patients (03).
Stephanie Bissonnette MPH DO
Dr. Bissonnette of Boston University Medical Center has no relevant financial relationships to disclose.See Profile
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Italfarmaco and Pfizer.See Profile
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