Restless Legs Syndrome and Sleep-Related Movement Disorders

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Review Article

Address correspondence to Dr Lynn Marie Trotti, Restless Legs Syndrome 12 Executive Park Dr NE, Atlanta, GA 30329, [email protected]. and Sleep-Related Relationship Disclosure: Dr Trotti serves on the editorial board of the Journal Movement Disorders of Clinical Sleep Medicine and has received personal compensation as a speaker Lynn Marie Trotti, MD, MSc for the American Academy of Neurology, Associated Professional Sleep Societies, Movement Disorder Society, ABSTRACT New Jersey Sleep Society, Purpose of Review: This article provides an update on six sleep-related movement New York University, Ohio disorders: restless legs syndrome (RLS), periodic limb movement disorder, sleep- State University, and Southern Sleep Society. Dr Trotti has related leg cramps, bruxism, rhythmic movement disorder, and propriospinal received research/grant myoclonus, with an emphasis on RLS. support from the National Recent Findings: RLS is a common sensorimotor disorder that impairs quality of life. Institute of Neurological Disorders and Stroke and the RLS is frequently comorbid to neurologic, psychiatric, vascular, and inflammatory National Institutes of Health diseases. Accumulating evidence implicates the pathophysiology of RLS as a state of (K23 NS083748). dopamine dysfunction and iron deficiency that occurs on a background of genetic Unlabeled Use of susceptibility conferred by 6 gene polymorphisms. Multiple treatments approved by Products/Investigational Use Disclosure: the US Food and Drug Administration (FDA) are available. Dopamine agonists and Dr Trotti discusses the !2% calcium channel ligands are considered first-line treatments, but these treatments unlabeled/investigational have very different side effect profiles that should be taken into consideration. use of benzodiazepines, botulinum toxin, clonazepam, Summary: Sleep-related movement disorders are frequently encountered in clinical and clonidine for the practice. For some disorders, particularly RLS and periodic limb movement disorder, treatment of bruxism; of our understanding of biology, epidemiology, and treatment is advanced. For others, clonazepam for the treatment of hypnic myoclonus and much work is needed to determine optimal treatment strategies. rhythmic movement disorder; of carbamazepine, carisoprodol, diltiazem, Continuum (Minneap Minn) 2017;23(4):1005–1016. gabapentin, lamotrigine, magnesium, oxcarbazepine, quinine, and verapamil for the treatment of leg cramps; INTRODUCTION treatment improves quality of life.3 of clonazepam and topiramate for the treatment of Sleep-related movement disorders pri- RLS is diagnosed clinically via diagnos- propriospinal myoclonus; and marily manifest during sleep or shortly tic criteria available from the Interna- of gabapentin, iron (including 4 1 ferric carboxymaltose), before a person falls asleep. The Interna- tional RLS Study Group, the ICSD-3, opioids, and pregabalin for tional Classification of Sleep Disorders, and the Diagnostic and Statistical the treatment of restless Manual of Mental Disorders, Fifth legs syndrome. Third Edition (ICSD-3)detailssixsuch * 2017 American Academy 1 5 disorders affecting adults, all of which will Edition (DSM-5). The three classifica- of Neurology. be discussed in this article, with an empha- tions vary slightly, but all contain five sisonrestlesslegssyndrome(RLS). core criteria, encapsulated with the mnemonic URGED6: RESTLESS LEGS SYNDROME & Urge to move the legs, often RLS, also known as Willis-Ekbom dis- accompanied by leg discomfort ease, is a common sensorimotor dis- & Rest worsens the urge to move order that predominantly, but not & Getting up and moving improves exclusively, affects the legs. RLS may the urge Supplemental digital content: result in severe sleep disruption and & Evening or night worsens symptoms Direct URL citations appear in impairs quality of life to a similar extent & Disorders that mimic RLS have the printed text and are included 2 in the HTML, PDF, and app as other chronic diseases, although been excluded versions of this article.

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KEY POINTS h Diagnosis of restless legs In particular, sleep-related leg sleep study is not required for an RLS syndrome requires five cramps and positional discomfort (ie, diagnosis. PLMS are seen on sleep 10 criteria: the urge to needing to shift to a more comfortable studies in 80% of patients with RLS move the legs, position) can bear surface resem- andinmorethanone-fourthofthe 11 worsening of symptoms blance to RLS; common mimics are middle-aged European population. with rest, worsening of listed in Table 4-1. symptoms in the Several supportive criteria, which are Epidemiology evening or night, useful in cases with equivocal symptom RLS has substantial regional variation in improvement of description, include periodic limb move- prevalence, which is highest in Europe- symptoms with ments of sleep (PLMS), first-degree an populations (5% to 12%), intermedi- movement, and relatives with RLS, and symptom im- ate in Asian countries (1% to 8%), and symptoms that are not provement with a dopaminergic med- lowest in African countries, in which the better explained by 4 another condition. ication. PLMS are repetitive limb fewest studies have been performed movements that occur predominantly (less than 1%).12 RLSismorecommon h Supportive criteria for a within the first several hours of sleep. inwomenthaninmen,aneffectdriven diagnosis of restless legs Periodic limb movements may also by parity. Nulliparous women have a syndrome are periodic limb movements, occur during wakefulness prior to sleep similarrateofRLStomen,butthe a positive family history, onset or during wakefulness after sleep prevalence of RLS in women increases 13 and response to onset. PLMS cluster as at least four with the number of prior pregnancies. dopaminergic therapy. movements, which are separated by 5 Three conditions most strongly asso- 7 h Periodic limb movements to 90 seconds (Table 4-2). Classically, ciated with RLS are pregnancy, iron of sleep are seen in 80% they are described as a Babinski (triple deficiency, and end-stage renal disease. of patients with restless flexion type) movement, but involved RLS symptoms very commonly appear legs syndrome on a muscles and their activation sequences during pregnancy, increase in preva- single sleep study, but arevariablebetweenandwithinindi- lence and severity with each passing are also common in viduals.8,9 PLMS most commonly affect trimester, and resolve with delivery in people without restless the legs and are quantified during sleep most affected women.14 RLS is present legs syndrome. studies using tibialis anterior surface in 25% to 35% of patients with iron 15 h Theprevalenceofrestless EMG. PLMS are neither fully sensitive deficiency anemia. RLS symptoms are legs syndrome is highest nor specific for an RLS diagnosis, and a also very common in patients with end- in European populations stage renal disease, in whom dialysis (5% to 12%), followed does not relieve symptoms but success- Common Mimics by Asian populations TABLE 4-1 ful renal transplant does.16 (1% to 8%). Scant data of Restless Legs Syndromea RLS appears overrepresented in sev- from African countries eral neurologic disorders, including suggest a prevalence of b stroke,multiplesclerosis,andmi- less than 1%. Akathisia graine.17,18 In all but the latter, struc- h b Iron deficiency, end-stage Arthralgia tural lesions related to the primary renal disease, and b Habitual foot tapping disease may cause RLS symptoms to pregnancy are strongly b manifest. However, an alternative hy- associated with restless Myalgia pothesis for the association with stroke legs syndrome. b Peripheral venous Resolution of these may be that RLS increases the risk for insufficiency, leg edema 19 conditions (ie, with iron vascular events, including stroke. b Positional discomfort replacement therapy, Epidemiologic studies have also renal transplant, or b Sleep-related leg cramps shown an association between RLS delivery) often improves a Data from Allen RP, et al, Sleep Med.4 and mood disorders (eg, depression, restless legs syndrome. sleep-journal.com/article/S1389- anxiety, panic disorder), which is inde- 9457(14)00190-7/abstract. pendent of antidepressant use.6 This relationship might reflect a common

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS a h TABLE 4-2 Scoring Criteria for Periodic Limb Movements of Sleep Neurologic disorders associated with restless b Duration of movement between 0.5 seconds and 10 seconds legs syndrome include stroke, multiple b 2 Amplitude of movement at least 8 V above resting EMG amplitude sclerosis, and migraine. b At least four consecutive movements Psychiatric disorders associated with restless b Minimum time of 5 seconds between onset of consecutive movements legs syndrome include b Maximum time of 90 seconds between onset of consecutive movements depression and anxiety. b Movement does not occur within 0.5 seconds of a respiratory event h Cross-sectional studies suggest an association EMG = electromyography. a Data from Iber C, et al, American Academy of Sleep Medicine.7 between restless legs syndrome and cardiovascular disease. pathophysiologic substrate, or RLS similar to those seen in obstructive Restless legs syndrome might cause might worsen mood through sleep sleep apnea and may represent a 6 cardiovascular disease disruption. Treatment of RLS is benefi- cardiovascular risk factor. Alternatively, through increases in cial for mood symptoms, albeit some- the sleep disruption or mood dys- sympathetic activity 3,20,21 times modestly. Antidepressants regulation seen in RLS may contribute associated with periodic 26 also cause or worsen RLS in 9% of to cardiovascular risk. RLS treatment limb movements of 22 patients. This effect is most pro- with rotigotine results in a greater sleep (as manifested by nounced with mirtazapine (28%), less decrease in nocturnal blood pressure increases in heart rate so with duloxetine (5%), and is least elevations than placebo,27 but it is and blood pressure). pronounced with citalopram (2%). presently unknown whether treatment Other work suggests An association between RLS and car- of RLS or limb movements modifies that multimorbidity diovascular disease was first reported long-term vascular risk. itself might increase in 2001, with an adjusted odds ratio of RLS is also comorbid to numerous the risk of restless legs syndrome. 2.5 for heart problems in patients with other diseases, leading to several dis- RLS.23 Subsequently, the majority (ap- tinct hypotheses. First, the majority h Six loci associated with proximately 75%) of cross-sectional (89%) of disorders linked to RLS have the genetic risk for studies have confirmed associations an inflammatory or immune basis, restless legs syndrome have been identified between RLS or PLMS and cardiovascu- suggesting that RLS could be mediated 24 28 through genome-wide lar disease or hypertension. Prospec- by inflammation. Second, RLS might association studies. The tive studies on this association have be triggered by multimorbidity even in mechanistic relationship been mixed, suggesting quite different the presence of a relatively low genetic between these genes 15 possible relationships, which include: predisposition. and restless legs (1) an increased risk of stroke or heart syndrome is under disease in those with RLS at baseline; Pathophysiology and Genetics investigation, but work (2) no increased risk of cardiovascular RLS is strongly heritable, with approxi- to date implicates disease in those with RLS; and (3) an mately one-half of patients having at genetic alterations increased risk of incident RLS in those least one affected first-degree relative. of dopamine and with cardiovascular disease risk factors Genome-wide association studies have iron function. at baseline.24 Mechanistically, several to date identified single-nucleotide poly- pathways exist by which RLS could morphisms that confer risk for RLS increase cardiovascular risk. PLMS pres- within the genes BTBD9, MEIS1, PTPRD, Y ent in the majority of patients with RLS MAP2K5, SKOR1,andTOX3.29 31 Animal and are accompanied by transient in- models of RLS based upon BTBD9 have creases in heart rate and blood pres- provided face validity for the impor- sure25; these sympathetic surges are tance of this variant,32 and ongoing

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KEY POINTS h Despite initial reverse-genetic approaches building on rity over placebo, but did provide improvement in genome-wide association findings have evidence that bupropion does not 37 symptoms with beguntoidentifyrelationshipsbetween worsen RLS. dopaminergic treatment, these genes and iron and dopamine Nonpharmacologic treatment of RLS the pathophysiology of metabolism, both implicated in RLS may be helpful as monotherapy or restless legs syndrome is pathophysiology.33 adjunctive treatment. Lower body re- now suspected to reflect A hypodopaminergic pathology has sistance and aerobic exercise decrease dopamine dysfunction long been suspected in the pathophysi- RLS severity.38 A vibratory counter- rather than a ology of RLS based on the clinical stimulation device cleared by the US hypodopaminergic state. observation that dopaminergic medica- Food and Drug Administration (FDA) h Central nervous system tions improve RLS.34 However, dopamine has demonstrated benefit in almost iron deficiency is deficiency has not been consistently one-half of patients with RLS (com- part of the restless demonstrated. More recently, a hyper- pared to 17% of those receiving sham legs syndrome dopaminergic state, superimposed upon treatment39), although challenges of pathophysiology in at the circadian changes in dopamine avail- insurance coverage have limited adop- least some patients, ability, has been postulated in the path- tion in practice. Furthermore, the and it interacts with 35 dopamine to ophysiology of RLS. recent American Academy of Neurol- exacerbate the The role of central nervous system ogy (AAN) practice guideline for RLS dopamine dysfunction. iron deficiency in RLS is better estab- notes weak evidence against use of lished, although, at present, it is not vibratory counterstimulus devices for h Treatment of restless legs syndrome should clear if brain iron deficiency explains all RLS symptoms but weak evidence for include the or only some cases of RLS. Iron and their use to improve sleep in patients discontinuation, if dopamine are intertwined in the central with RLS (Supplemental Digital Con- possible, of medications nervous system; for example, iron is a tent 4-1, links.lww.com/CONT/A220). that exacerbate restless necessary cofactor for dopamine pro- Because of the common co- legs syndrome: duction via tyrosine hydroxylase, and occurrence of RLS and iron deficiency, antidepressants, animals raised in the setting of iron clinical guidelines recommend checking antipsychotics, and deficiency have abnormally functioning an iron panel (ferritin, percent of trans- metoclopramide. dopamine transporters.36 Thus, a pre- ferrin saturation, total iron binding h A serum iron panel vailing hypothesis is that, at least in capacity, and iron) in all patients with should be checked in all some patients, central iron deficiency RLS.40,41 Several placebo-controlled tri- patients diagnosed with results in a state of dopaminergic dys- als of iron for the treatment of RLS have restless legs syndrome function that manifests as RLS. been performed with mixed results, or augmentation. which may reflect study heterogeneity Treatment (eg, oral versus IV iron, different iron A review of the patient’s medication preparations, baseline iron status). In list is the first management step in meta-analysis, evidence is not sufficient RLS. Antipsychotics and other medica- to conclude that iron therapy is effective tions causing dopamine antagonism, for treatment of RLS.42 However, based such as metoclopramide, may be an on clinical practice experience, guide- occult cause of RLS. For patients with lines recommend replacing iron in depression and RLS, changes in de- patients with RLS with ferritin levels pression treatment may be helpful. lower than 50 ng/mL to 75 ng/mL,41 Bupropion is often suggested as a generally beginning with oral iron and first-line treatment for depression in proceeding to IV iron (particularly ferric patients with RLS based on its dopa- carboxymaltose) if needed. minergic activity. A randomized con- The FDA has approved four medi- trolled trial of bupropion for RLS did cations and cleared one device for not demonstrate sustained superio- the treatment of RLS (Table 4-3),

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 43 KEY POINTS from the FDA labeling of 0.5 mg/d). h TABLE 4-3 Interventions First-line treatments of Approved or Rotigotine is the only dopamine agonist restless legs syndrome Cleared by the that is dosed via daily transdermal patch, include !2% calcium US Food and Drug which is initiated at 1 mg/d, and may be channel ligands and Administration for Treatment escalated to 2 mg/d or 3 mg/d in dopamine agonists. of Restless Legs Syndrome increments of 1 mg/d every week. h Medication should be Common side effects of dopamine dosed 2 hours before b !2% Calcium Channel Ligands agonists include nausea and headache. typical onset of Gabapentin enacarbil Impulse control disorders have been symptoms, not after b Device reported in patients with RLS on dopa- symptoms have begun. mine agonists, so prescribers should Vibratory counterstimulus educate patients about this side effect device and regularly ask patients about this.40 b Dopamine Agonists Augmentation, which is a treatment- Pramipexole induced worsening of RLS over time that follows an initial response to med- Ropinirole ication, is characterized by the geo- Rotigotine graphic spread of RLS symptoms to the upper body or arms and earlier temporal onset of symptoms. Augmentation is although several other medications a particularly problematic side effect are also supported by randomized seen with dopamine agonists. Augmen- controlled trials. In cases where symp- tation may be identified using several toms are severe enough to warrant key questions about timing and location prescription pharmacotherapy, dopa- of symptoms (Table 4-4). Although mine agonists and !2% calcium channel augmentation is frequent and problem- ligands are generally considered first- atic, optimal management is unknown. line treatments. Doses of dopamine The International RLS Study Group has agonists used for RLS treatment are offered a variety of strategies for aug- much lower than typical doses in pa- mentation treatment, including removal tients with Parkinson disease and are of exacerbating factors (eg, sleep depri- timed to be taken approximately 2 hours vation, medications); split dosing of before typical symptom onset. The medication if augmentation is mild; or starting dose of ropinirole is 0.25 mg/d, changing from a dopamine agonist to an then is titrated as follows: 0.25 mg for !2% calcium channel ligand, a longer- 2days,then0.5mgfor5days,thenmay acting dopamine agonist, or an opiate.43 increaseby0.5mgincrementsevery A 10-day drug-free period has also been week until an effective or maximum advocated, but may be challenging.43 dose is achieved, whichever comes first. Patients experiencing augmentation Dosesabove4mg/dshouldbeavoided should have iron levels rechecked with in patients with RLS whenever possi- oral or IV iron repletion if ferritin ble.43 The pramipexole starting dose is values are at or below the 50 ng/mL 0.125 mg/d, and it may be increased by to 75 ng/mL range (Case 4-1). 0.125 mg increments every 4 to 7 days The !2% calcium channel ligands until symptom control or maximum (gabapentin, pregabalin, and gabapentin dose is reached. The maximum recom- enacarbil) are now considered first-line mendedRLSdoseofpramipexoleis RLS treatment, in part because of 0.75 mg/d (although this is an expert growing recognition that dopaminergic consensus recommendation that differs augmentation is relatively common and

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TABLE 4-4 Clinical Screening Questions for Augmentation in Patients With Restless Legs Syndromea

b Do symptoms currently begin earlier in the day than they did before the medication was started? b Are higher doses or an earlier timing of the medication needed to control restless legs syndrome compared to a previously effective dose or timing? b Have symptoms become more intense since starting the medication? b Have symptoms spread to previously unaffected body parts (such as the arms) since starting the medication? a Data from Garcia-Borreguero D, et al, Sleep Med.43 sleep-journal.com/article/S1389- 9457(16)00056-3/abstract.

can greatly distress patients. Of these prodrug with different dosing than three medications, only gabapentin gabapentin, taken as a single dinner- enacarbil is approved for RLS treatment. time dose of 600 mg. Clinical trials have Gabapentin enacarbil is a gabapentin demonstrated efficacy for RLS with

Case 4-1 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.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS gabapentin (usual effective dose of series of at last four consecutive limb h The term periodic limb 900 mg/d to 2400 mg/d, divided into movements lasting between 0.5 seconds movement disorder 2or3dailyornightlydoses)andpre- and 10.0 seconds, with an intervening should be reserved for gabalin (usual effective dose of 150 mg/d period between limb movements last- patients who have to 450 mg/d given nightly 2 hours before ing between 5 seconds and 90 seconds periodic limb bedtime or ahead of habitual symptom (Figure 4-1). PLMS are present in most movements of sleep onset; if a total dosage of more than patients with RLS, but are not specific that cause sleep 300 mg is needed, this should be divided for an RLS diagnosis, and the presence disruption or into 2 separate doses).41 Common side of PLMS does not imply RLS. PLMS also daytime dysfunction. effects of !2% calcium channel ligands frequently occur in patients with narco- h Sleep-related leg cramps include somnolence, dizziness, and pe- lepsy, Parkinson disease, idiopathic REM are present at least ripheral edema. In light of the comor- sleep behavior disorder, and diabetes occasionally in most older bidity of RLS and mood disorders, the mellitus, among others, and increase adults. Quinine potential for worsening of depression with age.11 Distinct from the mere is no longer or even suicidality with this family of presence of PLMS on a sleep study, the recommended because of serious adverse medications should be kept in mind. syndrome of periodic limb movement events. Alternative Recently, a large prospective pregnancy disorder has been proposed to encom- treatment is not well registry study has also suggested that passboththepresenceofPLMSanda tested, but might pregabalin may have teratogenic risk in symptom of either insomnia or exces- include leg stretches at 44 women of childbearing potential. A sive daytime sleepiness, with the impli- bedtime and diltiazem. large trial randomly assigned patients cation that treatment of the limb with RLS to pregabalin (300 mg/d) or movements will result in improvement pramipexole (0.25 mg/d or 0.5 mg/d) in insomnia or daytime sleepiness symp- and demonstrated that both pregabalin toms.1 While occasional patients en- and pramipexole were effective in re- dorse symptom improvement with ducing RLS symptoms, but with a treatment of PLMS, the diagnosis of higher rate of augmentation with periodic limb movement disorder pramipexole.45 should be used judiciously, because it For patients refractory to other med- appears that, in most cases, the pres- ications, opioids may be useful in select ence of PLMS is unrelated to insomnia cases. Opioids have proven efficacy for or sleepiness, and treatment of PLMS RLS compared to placebo,46 and clinical has no clear symptomatic benefit. series suggest that serious opioid side Whether treatment of PLMS will impact effects may be relatively rare in this vascular health remains an unanswered population.47 However, the decision to question, thus the majority of observed use opioid medications must be made PLMS remain untreated. in the broader context of opioid risks and benefits. Recently released Centers SLEEP-RELATED LEG CRAMPS for Disease Control and Prevention Sleep-related leg cramps are perhaps (CDC) guidelines for the use of opioids the most ubiquitous sleep-related move- to treat chronic pain, while not specif- ment disorder, present occasionally in ically addressing RLS, may offer some at least one-third of adults older than guidance.48 age 60 and in one-half of adults older than age 80.1 Nocturnal leg cramps PERIODIC LIMB MOVEMENT may arise from sleep or wakefulness DISORDER and are distinguished from RLS by the PLMS are a frequent finding in adults presence of a painful cramp (ie, a undergoing polysomnography and are charley horse) or sustained involuntary characterized by a periodically recurring muscle contraction. When frequent leg

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FIGURE 4-1 Periodic limb movements of sleep in a 54-year-old woman. Four consecutive 30-second epochs are shown, with periodic leg movements occurring approximately every 20 seconds and culminating in an arousal from sleep (arrow).

Courtesy of Erik K. St. Louis, MD, MS, FAAN, FAASM.

cramps are also prominent during disease, myotonic dystrophy, and in- wakefulness, especially when cramps flammatory myositis. are more diffuse and affect other Despite their commonality and as- muscles beyond the calves or feet, the sociated sleep disruption, optimal possibility of an underlying comorbid treatment for leg cramps is not de- neuromuscular disorder should be fined. A recent Cochrane Review found considered. When sleep-related leg that quinine treatment of 200 mg/d to cramps are present in isolation, work- 500 mg/d reduces the number of up is rarely necessary. However, when cramps as well as the number of days daytime cramps occur, a thorough in which cramps occur (low-quality neuromuscular examination and inves- evidence) and reduces cramp intensity tigations such as serum creatine kinase (moderate-quality evidence), with a and nerve conduction studies and low incidence of serious adverse EMG should be considered when ap- events with use up to 60 days.49 propriate to exclude neuromuscular However, the FDA has recommended disorders that are frequently associated that prescription quinine not be used with prominent cramping, includ- for leg cramps because of the risk of ing cramp-fasciculation syndrome, pe- cardiac arrhythmias and hematologic ripheral neuropathy, motor neuron events. Tonic water, which contains a

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS smaller amount of quinine (40 mg/L to where bruxism results in morning facial h Sleep-related bruxism 80 mg/L; approximately 20 mg in an pain or fatigue, a mouth guard alone may be treated 8-ounce glass) has historically been may not be sufficient. Pharmacologic with a mouth guard to recommended, but its efficacy and options for bruxism that is refractory to prevent dental wear. safety for this purpose has not been dental appliances alone may include Pharmacologic therapy, well studied. Medications that may clonazepam, botulinum toxin, or cloni- if necessary, may be contribute to cramps (long-acting $- dine, but available data are limited.52 attempted with agonists, potassium-sparing diuretics, botulinum toxin, and thiazide diuretics50) should be SLEEP-RELATED RHYTHMIC clonidine, or removed when possible. Interventions MOVEMENT DISORDER benzodiazepines. that have shown at least some reported Rhythmic, stereotyped, nonepileptic, h Sleep-related rhythmic benefit for leg cramps include leg large-amplitude body movements may movements are stretches, diltiazem, and magnesium, occur shortly before sleep onset and ubiquitous in infants but although magnesium has been reported persist into sleep in some cases. The decrease in prevalence to be helpful specifically in women behaviors tend to repeat at a frequency through childhood and adulthood. Treatment who are pregnant. Of these measures, between 0.5 Hz and 2 Hz. Common with benzodiazepines is stretching of the calves and hamstrings manifestations include body rocking, proposed for cases in is the least invasive and therefore may head banging, and head rolling. If these which treatment is 51 be a reasonable first-line option. Other behaviors are disruptive to sleep, result needed (eg, injury or proposed treatments for sleep-related in daytime dysfunction, or are poten- disruption), but is not leg cramps lacking a firm evidence tially injurious, they are characterized yet substantiated by basis include gabapentin, sodium as sleep-related rhythmic movement clinical trial evidence. channel blocking antiepileptic drugs disorder.47 Such rhythmic movements (ie, carbamazepine, oxcarbazepine, are ubiquitous in infants (present in up lamotrigine), B vitamins, verapamil, to 60% of infants at 9 months of age) and carisoprodol.50 but decrease with age (5% at 5 years of age), sometimes persisting into adult- SLEEP-RELATED BRUXISM hood. Although these behaviors typi- Bruxism is the repetitive clenching or cally have been characterized as a grinding of teeth. It may be present method of self-soothing, children tend during sleep or wakefulness, but these to be amnestic for the movements, two manifestations are generally consid- and adults generally do not report ered two distinct entities with partial a volitional component.1 Successful clinical overlap.1 Sleep-related bruxism treatment with clonazepam has been may come to clinical attention when the reported. Head banging behaviors may noise disturbs bed partners, when be violent and frequent, especially in rhythmic masticatory muscle activity is some children and adults with psycho- seen during polysomnography, or be- motor maldevelopment, and, in such cause of possibly associated symptoms cases, recommendation for protective such as morning jaw muscle pain, head gear worn at bedtime should be fatigue, temporal headache, or dental considered to prevent injury. wear. Bruxism may frequently coexist with obstructive sleep apnea. When PHYSIOLOGIC (HYPNIC) daytime bruxism is also present, the MYOCLONUS possibility of comorbid associated anxi- Sleep-wake transition (hypnic) myoc- ety disorders should also be sought. lonus may be focal or axial, and while Treatment of bruxism is typically physiologic, occasionally becomes prom- accomplished via a dental appliance inent enough for patients to seek used during sleep. However, in cases clinical attention. Diagnosis is usually

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KEY POINT h Hypnic myoclonus is a clear on clinical history, with reports of disease. While treatment options for generally benign focal or multifocal/axial body jerks that RLS are plentiful and well supported phenomenon seen occur at the sleep-wake transition, gen- by clinical trials, treatment options for within the first hour erally within the first hour of sleep, the remaining sleep-related movement of sleep and is typically leading to arousal and sleep fragmen- disorders are more limited and based treated by minimizing tation. Addressing and correcting ag- on lower-level evidence. triggers such as caffeine gravating influences such as excessive and stress. caffeine use, physical or emotional REFERENCES stress, or comorbid anxiety or mental 1. American Academy of Sleep Medicine. International classification of sleep disorders. health disorders is usually effective, but 3rd ed. Darien, IL: American Academy of a brief course of clonazepam (0.25 mg Sleep Medicine, 2014. to 0.5 mg) at bedtime can be con- 2. Allen RP, Walters AS, Montplaisir J, et al. sidered to help minimize arousals in Restless legs syndrome prevalence and impact: severe cases. REST general population study. Arch Intern Med 2005;165(11):1286Y1292. doi:10.1001/ archinte.165.11.1286. PROPRIOSPINAL MYOCLONUS 3. Hornyak M, Scholz H, Kohnen R, et al. Propriospinal myoclonus is a rare sleep- What treatment works best for restless legs wake transition movement disorder that syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep also may occur during wakefulness. Med Rev 2014;18(2):153Y164. doi:10.1016/ Typical movements include axial “sit- j.smrv.2013.03.004. up” or “jack knife” type movements 4. Allen RP, Picchietti DL, Garcia-Borreguero D, that may variably extend to the limbs, et al. Restless legs syndrome/Willis-Ekbom especially the legs. Diagnosis requires disease diagnostic criteria: updated International Restless Legs Syndrome Study video-EEG polysomnography or waking Group (IRLSSG) consensus criteriaYhistory, movement disorder laboratory studies rationale, description, and significance. employing axial and thoracic EMG Sleep Med 2014;15(8):860Y873. doi:10.1016/ electrodes to demonstrate initiation of j.sleep.2014.03.025. the myoclonic jerks segmentally over 5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders the axial muscles prior to the character- 5th Edition (DSM-5). Washington, DC: istic spread to other segments. Treat- American Psychiatric Association, 2013. ment is frequently difficult, with 6. Becker PM, Sharon D. Mood disorders in clonazepam or topiramate most often restless legs syndrome (Willis-Ekbom disease). J Clin Psychiatry 2014;75(7): recommended. Recent evidence sug- e679Ye694. doi:10.4088/JCP.13r08692. gests that propriospinal myoclonus 7. Iber C, Ancoli-Israel S, Chesson A, et al. may often be overdiagnosed or mis- The AASM manual for the scoring of sleep diagnosed, and that functional move- and associated events. Westchester, IL: ment disorders may emulate these American Academy of Sleep Medicine, 2007. movements quite closely. 8. de Weerd AW, Rijsman RM, Brinkley A. Activity patterns of leg muscles in periodic limb movement disorder. J Neurol Neurosurg CONCLUSION Psychiatry 2004;75(2):317Y319. doi:10.1136/ The sleep-related movement disorders jnnp.2003.010652. are common, with age- and region- 9. Provini F, Vetrugno R, Meletti S, et al. Motor pattern of periodic limb movements specific variations in prevalence, and during sleep. Neurology 2001;57(2):300Y304. may contribute to impaired quality of doi:10.1212/WNL.57.2.300. life, disrupted sleep, and pain or dis- 10. Montplaisir J, Boucher S, Poirier G, et al. Clinical, comfort. RLS is associated with a variety polysomnographic, and genetic characteristics of neurologic and psychiatric disorders, of restless legs syndrome: a study of 133 patients diagnosed with new standard and growing evidence supports a rela- criteria. Mov Disord 1997;12(1):61Y65. tionship between RLS and vascular doi:10.1002/mds.870120111.

1014 ContinuumJournal.com August 2017

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 11. Haba-Rubio J, Marti-Soler H, Marques-Vidal P, 22. Rottach KG, Schaner BM, Kirch MH, et al. et al. Prevalence and determinants of periodic Restless legs syndrome as side effect of limb movements in the general population. second generation antidepressants. Ann Neurol 2016;79(3):464Y474. doi:10.1002/ J Psychiatr Res 2008;43(1):70Y75. ana.24593. doi:10.1016/j.jpsychires.2008.02.006. 12. Koo BB. Restless leg syndrome across the 23. Ulfberg J, Nystro¨ m B, Carter N, Edling C. globe: epidemiology of the restless legs Prevalence of restless legs syndrome among syndrome/Willis-Ekbom disease. Sleep Med men aged 18 to 64 years: an association Clin 2015;10(3):189Y205, xi. doi:10.1016/ with somatic disease and neuropsychiatric j.jsmc.2015.05.004. symptoms. Mov Disord 2001;16(6): 1159Y1163. doi:10.1002/mds.1209. 13. Pantaleo NP, Hening WA, Allen RP, Earley CJ. Pregnancy accounts for most of the 24. Ferini-Strambi L, Walters AS, Sica D. The gender difference in prevalence of familial relationship among restless legs syndrome RLS. Sleep Med 2010;11(3):310Y313. (Willis-Ekbom Disease), hypertension, doi:10.1016/j.sleep.2009.04.005. cardiovascular disease, and cerebrovascular disease. J Neurol 2014;261(6):1051Y1068. 14. Picchietti DL, Hensley JG, Bainbridge JL, doi:10.1007/s00415-013-7065-1. et al. Consensus clinical practice guidelines for the diagnosis and treatment of restless 25. Pennestri MH, Montplaisir J, Colombo R, legs syndrome/Willis-Ekbom disease during et al. Nocturnal blood pressure changes in pregnancy and lactation. Sleep Med Rev patients with restless legs syndrome. 2015;22:64Y77. doi:10.1016/ Neurology 2007;68(15):1213Y1218. j.smrv.2014.10.009. doi:10.1212/01.wnl.0000259036.89411.52. 15. Trenkwalder C, Allen R, HPgl B, et al. Restless 26. Innes KE, Selfe TK, Agarwal P. Restless legs legs syndrome associated with major syndrome and conditions associated with diseases: a systematic review and new metabolic dysregulation, sympathoadrenal concept. Neurology 2016;86(14):1336Y1343. dysfunction, and cardiovascular disease risk: doi:10.1212/WNL.0000000000002542. a systematic review. Sleep Med Rev 2012; 16(4):309Y339. doi:10.1016/j.smrv.2011.04.001. 16. Kahvecioglu S, Yildiz D, Buyukkoyuncu N, et al. Effect of renal transplantation 27. Bauer A, Cassel W, Benes H, et al. in restless legs syndrome. Exp Clin Rotigotine’s effect on PLM-associated blood Transplant 2016;14(1):45Y49. doi:10.6002/ pressure elevations in restless legs syndrome: ect.2014.0163. an RCT. Neurology 2016;86(19):1785Y1793. 17. Schu¨ rks M, Winter A, Berger K, et al. doi:10.1212/WNL.0000000000002649. Migraine and restless legs syndrome: a 28. Weinstock LB, Walters AS, Paueksakon P. systematic review. Cephalalgia 2014;34(10): Restless legs syndromeYtheoretical roles of 777Y794. doi:10.1177/0333102414537725. inflammatory and immune mechanisms. Y 18. Chen PK, Fuh JL, Wang SJ. Bidirectional Sleep Med Rev 2012;16(4):341 354. triggering association between migraine doi:10.1016/j.smrv.2011.09.003. and restless legs syndrome: a diary study. 29. Stefansson H, Rye DB, Hicks A, et al. A Y Cephalalgia 2016;36(5):431 436. genetic risk factor for periodic limb doi:10.1177/0333102415596444. movements in sleep. N Engl J Med 2007; Y 19. Ferri R, Cosentino FI, Moussouttas M, et al. 357(7):639 647. doi:10.1056/NEJMc072518. Silent cerebral small vessel disease in restless 30. Winkelmann J, Schormair B, Lichtner P, et al. Y legs syndrome. Sleep 2016;39(7):1371 1377. Genome-wide association study of restless doi:10.5665/sleep.5966. legs syndrome identifies common variants in three genomic regions. Nat Genet 20. Montagna P, Hornyak M, Ulfberg J, et al. Y Randomized trial of pramipexole for 2007;39(8):1000 1006. doi:10.1038/ng2099. patients with restless legs syndrome (RLS) 31. Winkelmann J, Czamara D, Schormair B, and RLS-related impairment of mood. Sleep et al. Genome-wide association study Med 2011;12(1):34Y40. doi:10.1016/ identifies novel restless legs syndrome j.sleep.2010.08.005. susceptibility loci on 2p14 and 16q12.1. PLoS Genet 2011;7(7):e1002171. 21. Benes H, Mattern W, Peglau I, et al. doi:10.1371/journal.pgen.1002171. Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS 32. Freeman A, Pranski E, Miller RD, et al. Sleep patients: a multicentre, randomized, fragmentation and motor restlessness in a placebo-controlled study. J Neurol Drosophila model of Restless Legs 2011;258(6):1046Y1054. doi:10.1007/ Syndrome. Curr Biol 2012;22(12):1142Y1148. s00415-010-5879-7. doi:10.1016/j.cub.2012.04.027.

Continuum (Minneap Minn) 2017;23(4):1005–1016 ContinuumJournal.com 1015

33. Rye DB. The molecular genetics of restless syndrome/Willis-Ekbom disease, legs syndrome. Sleep Med Clin 2015;10(3): prevention and treatment of dopaminergic 227Y233, xii. doi:10.1016/j.jsmc.2015.05.015. augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. 34. Scholz H, Trenkwalder C, Kohnen R, et al. Sleep Med 2016;21:1Y11. doi:10.1016/ Dopamine agonists for restless legs j.sleep.2016.01.017. syndrome. Cochrane Database Syst Rev 2011;(3):CD006009. doi:10.1002/ 44. Winterfeld U, Merlob P, Baud D, et al. 14651858.CD006009.pub2. Pregnancy outcome following maternal exposure to pregabalin may call for concern. 35. Allen RP. Restless leg syndrome/Willis-Ekbom Neurology 2016;86(24):2251Y2257. disease pathophysiology. Sleep Med Clin doi:10.1212/WNL.0000000000002767. 2015;10(3):207Y214, xi. doi:10.1016/ j.jsmc.2015.05.022. 45. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole 36. Earley CJ, Connor J, Garcia-Borreguero D, for restless legs syndrome. N Engl J Med et al. Altered brain iron homeostasis and 2014;370(7):621Y631. doi:10.1056/ dopaminergic function in restless legs NEJMoa1303646. syndrome (Willis-Ekbom disease). Sleep Med 2014;15(11):1288Y1301. doi:10.1016/ 46. Trenkwalder C, Benesˇ H, Grote L, et al. j.sleep.2014.05.009. Prolonged release oxycodone-naloxone for treatment of severe restless legs 37. Bayard M, Bailey B, Acharya D, et al. syndrome after failure of previous Bupropion and restless legs syndrome: a treatment: a double-blind, randomised, randomized controlled trial. J Am Board placebo-controlled trial with an Fam Med 2011;24(4):422Y428. doi:10.3122/ open-label extension. Lancet Neurol jabfm.2011.04.100173. 2013;12(12):1141Y1150. doi:10.1016/ 38. Aukerman MM, Aukerman D, Bayard M, S1474-4422(13)70239-4. et al. Exercise and restless legs syndrome: a 47. Walters AS, Winkelmann J, Trenkwalder C, randomized controlled trial. J Am Board et al. Long-term follow-up on restless legs Y Fam Med 2006;19(5):487 493. doi:10.3122/ syndrome patients treated with opioids. jabfm.19.5.487. Mov Disord 2001;16(6):1105Y1109. 39. Burbank F, Buchfuhrer M, Kopjar B. Sleep doi:10.1002/mds.1214. improvement for restless legs syndrome 48. Dowell D, Haegerich TM, Chou R. CDC patients. Part I: pooled analysis of two guideline for prescribing opioids for chronic prospective, double-blind, sham-controlled, painYUnited States, 2016. JAMA 2016; multi-center, randomized clinical studies of 315(15):1624Y1645. doi:10.1001/ the effects of vibrating pads on RLS jama.2016.1464. symptoms. J Parkinsonism Restless Legs Syndr 2013;3:1Y10. 49. El-Tawil S, Al Musa T, Valli H, et al. Quinine for muscle cramps. Cochrane Database Syst 40. Trotti LM, Goldstein CA, Harrod CG, et al. Rev 2015;(4):CD005044. doi:10.1002/ Quality measures for the care of adult 14651858.CD005044.pub3. patients with restless legs syndrome. J Clin Sleep Med 2015;11(3):293Y310. doi:10.5664/ 50. Brown TM. Sleep-related leg cramps: a jcsm.4550. review and suggestions for future research. Sleep Med Clin 2015;10(3):385Y392, xvi. 41. Silber MH, Becker PM, Earley C, et al. doi:10.1016/j.jsmc.2015.05.002. Willis-Ekbom Disease Foundation revised consensus statement on the management 51. Hallegraeff JM, van der Schans CP, de Ruiter R, de Greef MH. Stretching of restless legs syndrome. Mayo Clin Proc 2013;88(9):977Y986. doi:10.1016/ before sleep reduces the frequency and j.mayocp.2013.06.016. severity of nocturnal leg cramps in older adults: a randomised trial. 42. Trotti LM, Bhadriraju S, Becker LA. Iron for J Physiother 2012;58(1):17Y22. restless legs syndrome. Cochrane Database doi:10.1016/S1836-9553(12)70068-1. Syst Rev 2012;5:CD007834. doi:10.1002/ 52. Manfredini D, Ahlberg J, Winocur E, 14651858.CD007834.pub2. Lobbezoo F. Management of sleep bruxism 43. Garcia-Borreguero D, Silber MH, in adults: a qualitative systematic literature Winkelman J, et al. Guidelines for the review. J Oral Rehabil 2015;42(11):862Y874. first-line treatment of restless legs doi:10.1111/joor.12322.

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