Sleep-related movement disorders primarily manifest during sleep or shortly before a person falls asleep. The International Classification of Sleep Disorders, Third Edition (ICSD-3) details six such disorders affecting adults, all of which will be discussed in this article, with an emphasis on restless legs syndrome (RLS).
RESTLESS LEGS SYNDROME
RLS, also known as Willis-Ekbom disease, is a common sensorimotor disorder that predominantly, but not exclusively, affects the legs. RLS may result in severe sleep disruption and impairs quality of life to a similar extent as other chronic diseases, although treatment improves quality of life. RLS is diagnosed clinically via diagnostic criteria available from the International RLS Study Group, the ICSD-3, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The three classifications vary slightly, but all contain five core criteria, encapsulated with the mnemonic URGED:
- Urge to move the legs, often accompanied by leg discomfort
- Rest worsens the urge to move
- Getting up and moving improves the urge
- Evening or night worsens symptoms
- Disorders that mimic RLS have been excluded
In particular, sleep-related leg cramps and positional discomfort (ie, needing to shift to a more comfortable position) can bear surface resemblance to RLS; common mimics are listed in Table 4-1.
Several supportive criteria, which are useful in cases with equivocal symptom description, include periodic limb movements of sleep (PLMS), first-degree relatives with RLS, and symptom improvement with a dopaminergic medication. PLMS are repetitive limb movements that occur predominantly within the first several hours of sleep. Periodic limb movements may also occur during wakefulness prior to sleep onset or during wakefulness after sleep onset. PLMS cluster as at least four movements, which are separated by 5 to 90 seconds (Table 4-2). Classically, they are described as a Babinski (triple flexion type) movement, but involved muscles and their activation sequences are variable between and within individuals. PLMS most commonly affect the legs and are quantified during sleep studies using tibialis anterior surface EMG. PLMS are neither fully sensitive nor specific for an RLS diagnosis, and a sleep study is not required for an RLS diagnosis. PLMS are seen on sleep studies in 80% of patients with RLS and in more than one-fourth of the middle-aged European population.
RLS has substantial regional variation in prevalence, which is highest in European populations (5% to 12%), intermediate in Asian countries (1% to 8%), and lowest in African countries, in which the fewest studies have been performed (less than 1%). RLS is more common in women than in men, an effect driven by parity. Nulliparous women have a similar rate of RLS to men, but the prevalence of RLS in women increases with the number of prior pregnancies.
Three conditions most strongly associated with RLS are pregnancy, iron deficiency, and end-stage renal disease. RLS symptoms very commonly appear during pregnancy, increase in prevalence and severity with each passing trimester, and resolve with delivery in most affected women. RLS is present in 25% to 35% of patients with iron deficiency anemia. RLS symptoms are also very common in patients with end-stage renal disease, in whom dialysis does not relieve symptoms but successful renal transplant does.
RLS appears overrepresented in several neurologic disorders, including stroke, multiple sclerosis, and migraine. In all but the latter, structural lesions related to the primary disease may cause RLS symptoms to manifest. However, an alternative hypothesis for the association with stroke may be that RLS increases the risk for vascular events, including stroke.
Epidemiologic studies have also shown an association between RLS and mood disorders (eg, depression, anxiety, panic disorder), which is independent of antidepressant use. This relationship might reflect a common pathophysiologic substrate, or RLS might worsen mood through sleep disruption. Treatment of RLS is beneficial for mood symptoms, albeit sometimes modestly. Antidepressants also cause or worsen RLS in 9% of patients. This effect is most pronounced with mirtazapine (28%), less so with duloxetine (5%), and is least pronounced with citalopram (2%).
An association between RLS and cardiovascular disease was first reported in 2001, with an adjusted odds ratio of 2.5 for heart problems in patients with RLS. Subsequently, the majority (approximately 75%) of cross-sectional studies have confirmed associations between RLS or PLMS and cardiovascular disease or hypertension. Prospective studies on this association have been mixed, suggesting quite different possible relationships, which include: (1) an increased risk of stroke or heart disease in those with RLS at baseline; (2) no increased risk of cardiovascular disease in those with RLS; and (3) an increased risk of incident RLS in those with cardiovascular disease risk factors at baseline. Mechanistically, several pathways exist by which RLS could increase cardiovascular risk. PLMS present in the majority of patients with RLS and are accompanied by transient increases in heart rate and blood pressure; these sympathetic surges are similar to those seen in obstructive sleep apnea and may represent a cardiovascular risk factor. Alternatively, the sleep disruption or mood dysregulation seen in RLS may contribute to cardiovascular risk. RLS treatment with rotigotine results in a greater decrease in nocturnal blood pressure elevations than placebo, but it is presently unknown whether treatment of RLS or limb movements modifies long-term vascular risk.
RLS is also comorbid to numerous other diseases, leading to several distinct hypotheses. First, the majority (89%) of disorders linked to RLS have an inflammatory or immune basis, suggesting that RLS could be mediated by inflammation. Second, RLS might be triggered by multimorbidity even in the presence of a relatively low genetic predisposition.
Pathophysiology and Genetics
RLS is strongly heritable, with approximately one-half of patients having at least one affected first-degree relative. Genome-wide association studies have to date identified single-nucleotide polymorphisms that confer risk for RLS within the genes BTBD9, MEIS1, PTPRD, MAP2K5, SKOR1, and TOX3. Animal models of RLS based upon BTBD9 have provided face validity for the importance of this variant, and ongoing reverse-genetic approaches building on genome-wide association findings have begun to identify relationships between these genes and iron and dopamine metabolism, both implicated in RLS pathophysiology.
A hypodopaminergic pathology has long been suspected in the pathophysiology of RLS based on the clinical observation that dopaminergic medications improve RLS. However, dopamine deficiency has not been consistently demonstrated. More recently, a hyperdopaminergic state, superimposed upon the circadian changes in dopamine availability, has been postulated in the pathophysiology of RLS.
The role of central nervous system iron deficiency in RLS is better established, although, at present, it is not clear if brain iron deficiency explains all or only some cases of RLS. Iron and dopamine are intertwined in the central nervous system; for example, iron is a necessary cofactor for dopamine production via tyrosine hydroxylase, and animals raised in the setting of iron deficiency have abnormally functioning dopamine transporters. Thus, a prevailing hypothesis is that, at least in some patients, central iron deficiency results in a state of dopaminergic dysfunction that manifests as RLS.
A review of the patient’s medication list is the first management step in RLS. Antipsychotics and other medications causing dopamine antagonism, such as metoclopramide, may be an occult cause of RLS. For patients with depression and RLS, changes in depression treatment may be helpful. Bupropion is often suggested as a first-line treatment for depression in patients with RLS based on its dopaminergic activity. A randomized controlled trial of bupropion for RLS did not demonstrate sustained superiority over placebo, but did provide evidence that bupropion does not worsen RLS.
Nonpharmacologic treatment of RLS may be helpful as monotherapy or adjunctive treatment. Lower body resistance and aerobic exercise decrease RLS severity. A vibratory counterstimulation device cleared by the US Food and Drug Administration (FDA) has demonstrated benefit in almost one-half of patients with RLS (compared to 17% of those receiving sham treatment), although challenges of insurance coverage have limited adoption in practice. Furthermore, the recent American Academy of Neurology (AAN) practice guideline for RLS notes weak evidence against use of vibratory counterstimulus devices for RLS symptoms but weak evidence for their use to improve sleep in patients with RLS (Supplemental Digital Content 4-1, links.lww.com/CONT/A220).
Because of the common co-occurrence of RLS and iron deficiency, clinical guidelines recommend checking an iron panel (ferritin, percent of transferrin saturation, total iron binding capacity, and iron) in all patients with RLS. Several placebo-controlled trials of iron for the treatment of RLS have been performed with mixed results, which may reflect study heterogeneity (eg, oral versus IV iron, different iron preparations, baseline iron status). In meta-analysis, evidence is not sufficient to conclude that iron therapy is effective for treatment of RLS. However, based on clinical practice experience, guidelines recommend replacing iron in patients with RLS with ferritin levels lower than 50 ng/mL to 75 ng/mL, generally beginning with oral iron and proceeding to IV iron (particularly ferric carboxymaltose) if needed.
The FDA has approved four medications and cleared one device for the treatment of RLS (Table 4-3), although several other medications are also supported by randomized controlled trials. In cases where symptoms are severe enough to warrant prescription pharmacotherapy, dopamine agonists and α2δ calcium channel ligands are generally considered first-line treatments. Doses of dopamine agonists used for RLS treatment are much lower than typical doses in patients with Parkinson disease and are timed to be taken approximately 2 hours before typical symptom onset. The starting dose of ropinirole is 0.25 mg/d, then is titrated as follows: 0.25 mg for 2days, then 0.5 mg for 5 days, then may increase by 0.5 mg increments every week until an effective or maximum dose is achieved, whichever comes first. Doses above 4 mg/d should be avoided in patients with RLS whenever possible. The pramipexole starting dose is 0.125 mg/d, and it may be increased by 0.125 mg increments every 4 to 7 days until symptom control or maximum dose is reached. The maximum recommended RLS dose of pramipexole is 0.75 mg/d (although this is an expert consensus recommendation that differs from the FDA labeling of 0.5 mg/d). Rotigotine is the only dopamine agonist that is dosed via daily transdermal patch, which is initiated at 1 mg/d, and may be escalated to 2 mg/d or 3 mg/d in increments of 1 mg/d every week.
Common side effects of dopamine agonists include nausea and headache. Impulse control disorders have been reported in patients with RLS on dopamine agonists, so prescribers should educate patients about this side effect and regularly ask patients about this. Augmentation, which is a treatment-induced worsening of RLS over time that follows an initial response to medication, is characterized by the geographic spread of RLS symptoms to the upper body or arms and earlier temporal onset of symptoms. Augmentation is a particularly problematic side effect seen with dopamine agonists. Augmentation may be identified using several key questions about timing and location of symptoms (Table 4-4). Although augmentation is frequent and problematic, optimal management is unknown. The International RLS Study Group has offered a variety of strategies for augmentation treatment, including removal of exacerbating factors (eg, sleep deprivation, medications); split dosing of medication if augmentation is mild; or changing from a dopamine agonist to an α2δ calcium channel ligand, a longer-acting dopamine agonist, or an opiate. A 10-day drug-free period has also been advocated, but may be challenging. Patients experiencing augmentation should have iron levels rechecked with oral or IV iron repletion if ferritin values are at or below the 50ng/mL to 75 ng/mL range (Case 4-1).
The α2δ calcium channel ligands (gabapentin, pregabalin, and gabapentin enacarbil) are now considered first-line RLS treatment, in part because of growing recognition that dopaminergic augmentation is relatively common and can greatly distress patients. Of these three medications, only gabapentin enacarbil is approved for RLS treatment. Gabapentin enacarbil is a gabapentin prodrug with different dosing than gabapentin, taken as a single dinner-time dose of 600 mg. Clinical trials have demonstrated efficacy for RLS with gabapentin (usual effective dose of 900 mg/d to 2400 mg/d, divided into 2or 3 daily or nightly doses) and pregabalin (usual effective dose of 150 mg/d to 450 mg/d given nightly 2 hours before bedtime or ahead of habitual symptom onset; if a total dosage of more than 300 mg is needed, this should be divided into 2 separate doses). Common side effects of α2δ calcium channel ligands include somnolence, dizziness, and peripheral edema. In light of the comorbidity of RLS and mood disorders, the potential for worsening of depression or even suicidality with this family of medications should be kept in mind. Recently, a large prospective pregnancy registry study has also suggested that pregabalin may have teratogenic risk in women of childbearing potential. A large trial randomly assigned patients with RLS to pregabalin (300 mg/d) or pramipexole (0.25 mg/d or 0.5 mg/d) and demonstrated that both pregabalin and pramipexole were effective in reducing RLS symptoms, but with a higher rate of augmentation with pramipexole.
For patients refractory to other medications, opioids may be useful in select cases. Opioids have proven efficacy for RLS compared to placebo, and clinical series suggest that serious opioid side effects may be relatively rare in this population. However, the decision to use opioid medications must be made in the broader context of opioid risks and benefits. Recently released Centers for Disease Control and Prevention (CDC) guidelines for the use of opioids to treat chronic pain, while not specifically addressing RLS, may offer some guidance.
A 72-year-old man presented for a second opinion regarding restless legs syndrome (RLS). His symptoms met the diagnostic criteria and had begun decades earlier. After gradual worsening of symptoms, their severity eventually reached the point that he had opted to start treatment 2 years ago. Initially, his symptoms had responded well to pramipexole 0.5 mg taken 2 hours before symptom onset at bedtime. Over the 2 months prior to presentation for a second opinion, his symptoms had become markedly worse, had spread to his arms, had begun as early as 2:00 pm, and had become much more intense. His primary care doctor added gabapentin 300 mg before bedtime, which he could not titrate further because it resulted in a worsened mood.
When he presented for the second opinion, his laboratory values demonstrated a ferritin level of 10 ng/mL, a transferrin percent saturation of 8%, total iron binding capacity of 500 mcg/dL, and iron of 35 mcg/dL. Initiation of oral iron therapy was advised, with a plan to change to IV iron if oral iron was not tolerated or was insufficient and with a consideration of changing from pramipexole to rotigotine. He reported gradual improvement in symptoms with oral iron therapy. His primary care doctor began an evaluation of iron deficiency.
Comment. In this case, augmentation is diagnosed based on the earlier onset of symptoms, the spread of symptoms to previously unaffected body parts, and the greater severity of symptoms, which occurred in the setting of a dopaminergic treatment that was initially beneficial. Treatment strategies for augmentation considered in this case include screening for and treating iron deficiency and changing to a longer-acting form of a dopamine agonist. If gabapentin had been well tolerated, increasing the dose and weaning pramipexole would have been another reasonable treatment strategy, as would have consideration of opioid therapy.
PERIODIC LIMB MOVEMENT DISORDER
PLMS are a frequent finding in adults undergoing polysomnography and are characterized by a periodically recurring series of at last four consecutive limb movements lasting between 0.5 seconds and 10.0 seconds, with an intervening period between limb movements lasting between 5 seconds and 90 seconds (Figure 4-1). PLMS are present in most patients with RLS, but are not specific for an RLS diagnosis, and the presence of PLMS does not imply RLS. PLMS also frequently occur in patients with narcolepsy, Parkinson disease, idiopathic REM sleep behavior disorder, and diabetes mellitus, among others, and increase with age. Distinct from the mere presence of PLMS on a sleep study, the syndrome of periodic limb movement disorder has been proposed to encompass both the presence of PLMS and a symptom of either insomnia or excessive daytime sleepiness, with the implication that treatment of the limb movements will result in improvement in insomnia or daytime sleepiness symptoms. While occasional patients endorse symptom improvement with treatment of PLMS, the diagnosis of periodic limb movement disorder should be used judiciously, because it appears that, in most cases, the presence of PLMS is unrelated to insomnia or sleepiness, and treatment of PLMS has no clear symptomatic benefit. Whether treatment of PLMS will impact vascular health remains an unanswered question, thus the majority of observed PLMS remain untreated.
SLEEP-RELATED LEG CRAMPS
Sleep-related leg cramps are perhaps the most ubiquitous sleep-related movement disorder, present occasionally in at least one-third of adults older than age 60 and in one-half of adults older than age 80. Nocturnal leg cramps may arise from sleep or wakefulness and are distinguished from RLS by the presence of a painful cramp (ie, a charley horse) or sustained involuntary muscle contraction. When frequent leg cramps are also prominent during wakefulness, especially when cramps are more diffuse and affect other muscles beyond the calves or feet, the possibility of an underlying comorbid neuromuscular disorder should be considered. When sleep-related leg cramps are present in isolation, workup is rarely necessary. However, when daytime cramps occur, a thorough neuromuscular examination and investigations such as serum creatine kinase and nerve conduction studies and EMG should be considered when appropriate to exclude neuromuscular disorders that are frequently associated with prominent cramping, including cramp-fasciculation syndrome, peripheral neuropathy, motor neuron disease, myotonic dystrophy, and inflammatory myositis.
Despite their commonality and associated sleep disruption, optimal treatment for leg cramps is not defined. A recent Cochrane Review found that quinine treatment of 200 mg/d to 500 mg/d reduces the number of cramps as well as the number of days in which cramps occur (low-quality evidence) and reduces cramp intensity (moderate-quality evidence), with a low incidence of serious adverse events with use up to 60 days. However, the FDA has recommended that prescription quinine not be used for leg cramps because of the risk of cardiac arrhythmias and hematologic events. Tonic water, which contains a smaller amount of quinine (40 mg/L to 80 mg/L; approximately 20 mg in an 8-ounce glass) has historically been recommended, but its efficacy and safety for this purpose has not been well studied. Medications that may contribute to cramps (long-acting β-agonists, potassium-sparing diuretics, and thiazide diuretics) should be removed when possible. Interventions that have shown at least some reported benefit for leg cramps include leg stretches, diltiazem, and magnesium, although magnesium has been reported to be helpful specifically in women who are pregnant. Of these measures, stretching of the calves and hamstrings is the least invasive and therefore may be a reasonable first-line option. Other proposed treatments for sleep-related leg cramps lacking a firm evidence basis include gabapentin, sodium channel blocking antiepileptic drugs (ie, carbamazepine, oxcarbazepine, lamotrigine), B vitamins, verapamil, and carisoprodol.
Bruxism is the repetitive clenching or grinding of teeth. It may be present during sleep or wakefulness, but these two manifestations are generally considered two distinct entities with partial clinical overlap. Sleep-related bruxism may come to clinical attention when the noise disturbs bed partners, when rhythmic masticatory muscle activity is seen during polysomnography, or because of possibly associated symptoms such as morning jaw muscle pain, fatigue, temporal headache, or dental wear. Bruxism may frequently coexist with obstructive sleep apnea. When daytime bruxism is also present, the possibility of comorbid associated anxiety disorders should also be sought.
Treatment of bruxism is typically accomplished via a dental appliance used during sleep. However, in cases where bruxism results in morning facial pain or fatigue, a mouth guard alone may not be sufficient. Pharmacologic options for bruxism that is refractory to dental appliances alone may include clonazepam, botulinum toxin, or clonidine, but available data are limited.
SLEEP-RELATED RHYTHMIC MOVEMENT DISORDER
Rhythmic, stereotyped, nonepileptic, large-amplitude body movements may occur shortly before sleep onset and persist into sleep in some cases. The behaviors tend to repeat at a frequency between 0.5 Hz and 2 Hz. Common manifestations include body rocking, head banging, and head rolling. If these behaviors are disruptive to sleep, result in daytime dysfunction, or are potentially injurious, they are characterized as sleep-related rhythmic movement disorder. Such rhythmic movements are ubiquitous in infants (present in up to 60% of infants at 9 months of age) but decrease with age (5% at 5 years of age), sometimes persisting into adulthood. Although these behaviors typically have been characterized as a method of self-soothing, children tend to be amnestic for the movements, and adults generally do not report a volitional component. Successful treatment with clonazepam has been reported. Head banging behaviors may be violent and frequent, especially in some children and adults with psychomotor maldevelopment, and, in such cases, recommendation for protective head gear worn at bedtime should be considered to prevent injury.
PHYSIOLOGIC (HYPNIC) MYOCLONUS
Sleep-wake transition (hypnic) myoclonus may be focal or axial, and while physiologic, occasionally becomes prominent enough for patients to seek clinical attention. Diagnosis is usually clear on clinical history, with reports of focal or multifocal/axial body jerks that occur at the sleep-wake transition, generally within the first hour of sleep, leading to arousal and sleep fragmentation. Addressing and correcting aggravating influences such as excessive caffeine use, physical or emotional stress, or comorbid anxiety or mental health disorders is usually effective, but a brief course of clonazepam (0.25 mg to 0.5 mg) at bedtime can be considered to help minimize arousals in severe cases.
Propriospinal myoclonus is a rare sleep-wake transition movement disorder that also may occur during wakefulness. Typical movements include axial “sit-up” or “jack knife” type movements that may variably extend to the limbs, especially the legs. Diagnosis requires video-EEG polysomnography or waking movement disorder laboratory studies employing axial and thoracic EMG electrodes to demonstrate initiation of the myoclonic jerks segmentally over the axial muscles prior to the characteristic spread to other segments. Treatment is frequently difficult, with clonazepam or topiramate most often recommended. Recent evidence suggests that propriospinal myoclonus may often be overdiagnosed or misdiagnosed, and that functional movement disorders may emulate these movements quite closely.
The sleep-related movement disorders are common, with age- and region-specific variations in prevalence, and may contribute to impaired quality of life, disrupted sleep, and pain or discomfort. RLS is associated with a variety of neurologic and psychiatric disorders, and growing evidence supports a relationship between RLS and vascular disease. While treatment options for RLS are plentiful and well supported by clinical trials, treatment options for the remaining sleep-related movement disorders are more limited and based on lower-level evidence.
- Diagnosis of restless legs syndrome requires five criteria: the urge to move the legs, worsening of symptoms with rest, worsening of symptoms in the evening or night, improvement of symptoms with movement, and symptoms that are not better explained by another condition.
- Supportive criteria for a diagnosis of restless legs syndrome are periodic limb movements, a positive family history, and response to dopaminergic therapy.
- Periodic limb movements of sleep are seen in 80% of patients with restless legs syndrome on a single sleep study, but are also common in people without restless legs syndrome.
- The prevalence of restless legs syndrome is highest in European populations (5% to 12%), followed by Asian populations (1% to 8%). Scant data from African countries suggest a prevalence of less than 1%.
- Iron deficiency, end-stage renal disease, and pregnancy are strongly associated with restless legs syndrome. Resolution of these conditions (ie, with iron replacement therapy, renal transplant, or delivery) often improves restless legs syndrome.
- Neurologic disorders associated with restless legs syndrome include stroke, multiple sclerosis, and migraine. Psychiatric disorders associated with restless legs syndrome include depression and anxiety.
- Cross-sectional studies suggest an association between restless legs syndrome and cardiovascular disease. Restless legs syndrome might cause cardiovascular disease through increases in sympathetic activity associated with periodic limb movements of sleep (as manifested by increases in heart rate and blood pressure). Other work suggests that multimorbidity itself might increase the risk of restless legs syndrome.
- Six loci associated with the genetic risk for restless legs syndrome have been identified through genome-wide association studies. The mechanistic relationship between these genes and restless legs syndrome is under investigation, but work to date implicates genetic alterations of dopamine and iron function.
- Despite initial improvement in symptoms with dopaminergic treatment, the pathophysiology of restless legs syndrome is now suspected to reflect dopamine dysfunction rather than a hypodopaminergic state.
- Central nervous system iron deficiency is part of the restless legs syndrome pathophysiology in at least some patients, and it interacts with dopamine to exacerbate the dopamine dysfunction.
- Treatment of restless legs syndrome should include the discontinuation, if possible, of medications that exacerbate restless legs syndrome: antidepressants, antipsychotics, and metoclopramide.
- A serum iron panel should be checked in all patients diagnosed with restless legs syndrome or augmentation.
- First-line treatments of restless legs syndrome include α2δ calcium channel ligands and dopamine agonists.
- Medication should be dosed 2 hours before typical onset of symptoms, not after symptoms have begun.
- The term periodic limb movement disorder should be reserved for patients who have periodic limb movements of sleep that cause sleep disruption or daytime dysfunction.
- Sleep-related leg cramps are present at least occasionally in most older adults. Quinine is no longer recommended because of serious adverse events. Alternative treatment is not well tested, but might include leg stretches at bedtime and diltiazem.
- Sleep-related bruxism may be treated with a mouth guard to prevent dental wear. Pharmacologic therapy, if necessary, may be attempted with botulinum toxin, clonidine, or benzodiazepines.
- Sleep-related rhythmic movements are ubiquitous in infants but decrease in prevalence through childhood and adulthood. Treatment with benzodiazepines is proposed for cases in which treatment is needed (eg, injury or disruption), but is not yet substantiated by clinical trial evidence.
- Hypnic myoclonus is a generally benign phenomenon seen within the first hour of sleep and is typically treated by minimizing triggers such as caffeine and stress.
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