Sleep Disorders Milena K

ARTICLE IN PRESS REVIEW (NEW LINE)NEUROLOGY SERIES EDITOR, WILLIAM J. MULLALLY, MD

Sleep Disorders Milena K. Pavlova, MD, Veronique Latreille, PhD Department of Neurology, Brigham and Women’s Hospital, Boston, Mass.

ABSTRACT

Sleep disorders are frequent and can have serious consequences on patients’ health and quality of life. While some sleep disorders are more challenging to treat, most can be easily managed with adequate interventions. We review the main diagnostic features of 6 major sleep disorders (insomnia, circadian rhythm disorders, sleep-disordered breathing, hypersomnia/narcolepsy, parasomnias, and restless legs syndrome/periodic limb movement disorder) to aid medical practitioners in screening and treating sleep disorders as part of clinical practice. Ó 2018 Elsevier Inc. All rights reserved. The American Journal of Medicine (2018) 000:1−8

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

INTRODUCTION impaired attention, mood disturbances) for at least 3 nights 4 Sleep is a universal function of living species, comprising per week and last for more than 3 months. Although several one-third of human life. Poor or insufficient sleep has been insomnia subtypes have been delineated (eg, idiopathic, psy- associated with a wide variety of dysfunction in most body chophysiological, and paradoxical), diagnosis and treatment systems, including endocrine,1 metabolic,2 higher cortical is similar. function,3 and neurological disorders. Disorders of sleep The precise pathophysiological mechanisms underlying can manifest as complaints of either insufficient sleep, insomnia have not been identified yet, but some neurobio- excessive amount of perceived sleep, or abnormal move- logical and psychological models have been proposed. Con- ments during sleep. This review article focuses on the most tributing factors include behavioral, cognitive, emotional, 5 commonly seen sleep disorders in neurological practice and genetic factors. These are often conceptually classified 6 (Table). into predisposing, precipitating, and perpetuating factors. Available treatments for insomnia include pharmacological and nonpharmacological therapies. Treatment should MAJOR SLEEP DISORDERS consider other comorbidities that lead to sleep disruption, including other primary sleep disorders (eg, sleep apnea Insomnia and periodic limb movement in sleep). Initial counseling More than one-third of adults experience transient insomnia and education about good sleep practices is usually helpful, at some point in their lives. In about 40% of cases, insomnia and often sufficient to reduce insomnia symptoms. Good can develop into a more chronic and persistent condition.4 sleep habits include: keeping regular wake times (and The diagnosis of insomnia is made when the patient reports explaining that duration of wakefulness and circadian dissatisfaction with sleep (sleep-onset or sleep-maintenance rhythms both affect sleep onset), limiting time in bed to insomnia) as well as other daytime symptoms (eg, sleepiness, sleep time, use of bed for sleep/intimacy only, avoid afternoon caffeine and limit alcohol intake, and avoiding day- Funding: None. time napping (otherwise these should be very brief, < 30 Conflict of Interest: MP has received research grants from Biomobie, minutes, and taken in the early afternoon at latest). In cases Inc. and Lundbeck, Inc. VL is supported by a scholarship from the Cana- of persistent insomnia, cognitive behavioral therapy may dian Institutes of Health Research. Authorship: Both authors contributed to the literature search and the prove very helpful. Studies have shown that cognitive writing of the manuscript. behavioral therapy for insomnia may have equal or better Requests for reprints should be addressed to Milena Pavlova, MD, effect than pharmacological treatment, and that the effect is Department of Neurology, Brigham and Women’s Faulkner Hospital, longer lasting.7−11 Other behavioral treatment methods 1153 Centre Street, Boston, MA 02130. include sleep restriction and relaxation-based interventions. E-mail address: [email protected]

Pharmacological therapy may be appropriate when treat- endogenous circadian system.15 Normally, the sleep phase ment is anticipated to be short (eg, insomnia in the setting of of the circadian rhythm occurs about 2 hours after the onset stress), or in addition to behavioral treatments. The choice of of melatonin secretion. It may occur later or earlier than agent should consider: 1) predominant type of complaints society-driven scheduled sleep time, resulting in a delayed −sleep initiation or sleep maintenance; 2) frequency of or advanced sleep−wake phase disorder. insomnia symptoms (nightly vs intermittent); 3) length of Circadian rhythm sleep−wake disorders are common.4 treatment anticipated; 4) age and comorbidities of the patient. In delayed sleep−wake phase disorder, sleep occurs sys- Sleep initiation insomnia may tematically later than needed, whereas respond well to short-acting medi- in advanced sleep−wake phase disor- cations, and these can be used as CLINICAL SIGNIFICANCE der, sleep occurs systematically earlier needed if the condition is intermit- than needed. Yet in both cases, sleep tent−in this case the choice of hyp- Sleep disorders are common and may length is normal and the patient is notic should depend on adversely affect health and well-being. refreshed when sleeping according to comorbidities. Nightly sleep main- his/her desired time. Delayed sleep While some sleep disorders are more − tenance insomnia may need nightly challenging to treat, most can be easily wake phase disorder is thought to longer-acting medications, such as account for 10% of patients with managed with adequate interventions. eszopiclone or suvorexant. Patients chronic insomnia and is particularly with comorbid anxiety or depres- Sleep disorders are often briefly common in adolescents and young 4 sive symptoms may benefit from addressed during standard medical adults, occurring in 7%-16%. − antidepressant treatment, such as training. This review will provide a cur- Advanced sleep wake phase disorder mirtazapine or trazodone. A history rent practical overview of the most com- is estimated to occur in 1% of middle- of sleepwalking as a child should aged adults and even more commonly mon sleep disorders. be considered a caution when using in older populations. Non-24-hour cir- zolpidem, as it may cause complex cadian rhythm disorder is thought to behaviors in sleep.12−14 Other fac- occur in > 50% of blind individuals, tors such as the patient’s age and sex should also be consid- and up to 80% of this population complains of sleep distur- ered before starting pharmacological treatment for insomnia. bances. Twenty percent of the workforce engages in shift In 2013, the US Food and Drug Administration (FDA) issued work and 10%-38% of this population is estimated to suffer a warning, recommending that a lower dose of hypnotics be from shift work circadian rhythm disorder.4 used to prevent next-morning impairment due to residual The diagnosis and treatment of circadian rhythm sleep effect. Women appear to be more susceptible to this risk (by −wake disorders are sometimes difficult without an accu- FDA site, see Appendix, available online). rate assessment of the patient’s circadian phase. In research Overall, medications most frequently used in the treat- conditions, plasma measurements of melatonin, and core ment of insomnia include: 1) Benzodiazepines: they have body temperature, are commonly used.16 However, these the advantages of being cheap and ubiquitous, however, are labor-intensive, expensive, require special settings, and they are associated with various problems: excessive seda- are, therefore, impracticable for routine clinic use. More tion, high frequency of falls (due to nonselective gamma- feasible assessment parameters include salivary and urine aminobutyric acid effects), hypotension, tendency to lose melatonin measures.17−20 Despite their high prevalence, efficacy after longer use, muscle relaxant effect, and signifi- circadian rhythm sleep−wake disorders are commonly mis- cant cognitive effects. 2) Other hypnotics include: zolpi- diagnosed as insomnia or, in some situations, hypersomnia. dem, zolpidem CR, Intermezzo (Purdue Pharma, Stamford, A recent study of patients diagnosed with primary insomnia CT; zolpidem ultrashort acting, 1.75-3 mg), zaleplon, and demonstrated that 10%-22% had a bedtime out of phase eszopiclone. The advantages of these hypnotics are that with their circadian sleep time, suggesting a circadian etiol- some are very short acting (Intermezzo, zaleplon), and are ogy for their sleep problems.21 This misdiagnosis may lead FDA-approved for chronic insomnia treatment (eszopi- to unsuccessful, expensive, and sometimes harmful conse- clone, zolpidem CR). However, frequent problems include quences. common side effects such as parasomnia, and over-seda- Treatment of circadian rhythm sleep disorders are based tion, and some also have a potential to lose efficacy. 3) on timed bright or blue light (morning for delayed and after- Other options for insomnia treatment include: melatonin noon for advanced phase disorders) and melatonin (1 hour agonists (ramelteon, tasimelteon), orexin antagonist (suvor- prior to required bedtime in delayed phase disorder).16 For exant), antidepressants (mirtazapine, trazodone, amitripty- non-24-hour sleep−wake phase disorder, in blind individu- line), antihistamines, and other substances (eg, herbal). als, Tasimelteon has been recently found helpful. It is also helpful to counsel patients that the accuracy of the timing of any interventions for delayed sleep−wake phase disorder Circadian Rhythm Sleep Disorders may be crucial to successful treatment. The effect of light, The timing of sleep and wakefulness is maintained on one for example, depends on the light spectrum/wavelength, end by homeostatic factors, and on another by the intensity, prior light exposure, and, most importantly, ARTICLE IN PRESS K. Pavlova and Latreille Sleep Disorders 3

Table Common Sleep Disorders in Neurology Condition Defining Features Confirmatory Evaluations Treatment Insomnia Difficulty with: Primary: clinical history Hypnotics Sleep initiation or Ancillary: sleep log Antidepressants Sleep maintenance Melatonin agonists Results in: Orexin antagonists Fatigue/malaise Mood disturbance/irritability Reduced productivity Chronic: > 3 times/week and > 3 months DSWPD Sleep occurs systematically later tha Sleep log Melatonin 0.3-3 mg − evening needed Actigraphy* (5 h before habitual bedtime) Sleep length is normal and the patient is Melatonin* Combined with morning blue refreshed when sleeping according to his/ light her desired time ASWPD Sleep occurs systematically earlier that Sleep log Evening blue light needed Actigraphy* Sleep length is normal and the patient is Melatonin* refreshed when sleeping according to his/ her desired time OSA Snoring/apneas/gasping upon awakening Home sleep testing Continuous or bilevel positive Other nonspecific symptoms Polysomnography airway pressure - Morning headache In both cases, diagnosis Dental − oral appliances - Attention deficits requires: Surgery − for select cases - Mood disturbance Apnea-Hypopnea Index Conservative measures − to use - Nocturia, night sweats > 5/h with symptoms or with another treatment or for - Aggravation of other disease Index > 15/h regardless few symptoms and Apnea-Hypo- of symptoms pnea Index < 20 Sleep position Weight loss Avoidance of “relaxants” close to bedtime Narcolepsy Classic tetrad: Multiple sleep latency test Sleepiness: Sleepiness Sleep latency < 8 min Modafinil Sleep paralysis 2 Sleep-onset REM or Armodafinil Hypnagogic hallucinations 1 SOREM and first REM on Methylphenidate Type 1: Cataplexy polysomnography < 15 Amphetamine salts Type 2: Without cataplexy min Sodium oxybate Type 1: Cataplexy: Cerebrospinal fluid: low Sodium oxybate orexiny SSRI HLA DQB1*0602 REM behavior disorder Abnormal behaviors, emerging from REM Clinical history Clonazepam sleep Polysomnography: REM Other benzodiazepines Occur in the later parts of the night without atonia Melatonin Typical behaviors: talking, screaming, Treatment of associated disor- punching, kicking ders Associated with a vivid dream recall Safety measures NREM parasomnia Large variety of behaviors (hallucinations, Clinical history Counseling eating, locomotion, aggression, sex, - Precipitating factors terrors) (eg, sleep deprivation, Frequent amnesia for the event stress, fever, medications/ Behaviors may be from the same group substances) (usually eating or talking), but variable in Benzodiazepines presentation (eg, saying different Antidepressants phrases) ARTICLE IN PRESS 4 The American Journal of Medicine, Vol 000, No 000, && 2018

Table (Continued) Condition Defining Features Confirmatory Evaluations Treatment Several different behaviors can co-occur Distinction from seizures/postictal confusion is crucial RLS/PLMS RLS: Clinical history Dopamine-agonists Indescribable uncomfortable sensations Polysomnography may - Pramipexole starting at 0.125- that make the patient move limbs confirm PLMS 0.25 mg or Difficulty with sleep initiation due to the PLMS - Ropinirole 0.25-0.5 mg above sensations and urge to move PLMS > 15/h with - The dose of dopamine agonists Often associated with PLMS symptoms should be kept low Fragmented sleep, discomfort Gabapentin enacarbil Daytime sleepiness Fe supplementation if indicated (ferritin < 50), to be continued until > 100 Opiates and benzodiazepines (more limited use) ASWPD = advanced sleep−wake phase disorder; DSWPD = delayed sleep−wake phase disorder; NREM = non-rapid-eye movement; OSA = obstructive sleep apnea; PLMS = periodic limb movement of sleep; REM = rapid-eye movement; RLS = Restless legs syndrome; SSRI = selective serotonin reuptake inhibitor. *Not covered by most insurances in the US. yNot commercially available in the US. timing.22 The same light intensity may delay the sleep phase apnea; P: high blood pressure), as well as 4 items related to of the circadian cycle if administered prior to the core body the well-known sleep apnea risk factors (B: body mass temperature minimum, or advance it if administered after index > 35; A: Age > 50 years; N: Neck circumference it.16 For the same reasons, administration of exogenous mel- > 40 cm; G: male gender). A patient is at high risk of sleep atonin should also be timed by circadian phase. apnea if 3 or more questions are positively answered.24 In the general middle-aged population, moderate to severe sleep apnea can be found in about 30%-50% of men Sleep-Disordered Breathing: Obstructive Sleep and 11%-23% of women.25,26 Clinical symptoms include Apnea and Central Sleep Apnea most often loud snoring, choking/gasping, apneas witnessed Sleep apnea is a primary sleep disorder characterized by by the bed partner, excessive sleepiness and fatigue, and pauses of breathing during sleep. There are 3 main types of morning headache. Sleep apnea has debilitating effects on sleep apnea: obstructive sleep apnea, central sleep apnea, the patient and their family’s quality of life. When left and complex sleep apnea. An obstructive apnea is defined untreated, sleep apnea can also have major negative health as a cessation of airflow for at least 10 seconds, and results consequences; it increases the risk of hypertension, type 2 from the collapse of the upper away during sleep. By con- diabetes, and cardiovascular diseases.27 In a large cohort trast, during a central apnea, the interruption of airflow study, risk of stroke in men with moderate to severe occurs when there is a lack of effort to breathe−usually obstructive sleep apnea increased incrementally with each arising from the brain respiratory centers to the muscles unit of increased severity.28 Sleep apnea is also a well- that control breathing. Some patients present with a combi- known risk factor for cognitive deficits.29 The negative con- nation of both obstructive and central apnea, which is sequences of sleep apnea can be, at least partially, reversed termed complex sleep apnea. by consistent and accurate treatment. Sleep apnea can be diagnosed during polysomnography, Several treatment options are available. For mild cases where the severity of sleep apnea is quantified by the num- of obstructive sleep apnea, conservative therapies such as ber of respiratory events per hour of sleep. Along with clini- weight loss and avoiding supine position (for positional cal symptoms, at least 5 events per hour (Apnea-Hypopnea sleep apnea) can be helpful. The most widely used and cur- Index ≥ 5) are required for a diagnosis of sleep apnea.23 rently first-line treatment for obstructive sleep apnea is pos- According to prevalent criteria, an Apnea-Hypopnea Index itive airway pressure therapy. Continuous positive airway between 5 and 14 will be considered mild sleep apnea, pressure consists of a continuous flow of air into the nose, between 15 and 29 moderate sleep apnea, and more than 30 while bilevel therapy provides a higher pressure on inspira- events per hour is considered severe sleep apnea. Several tion and lower level on expiration. The latter is sometimes screening scales for sleep apnea have been developed to more comfortable with higher pressures. Auto-titrating identify at-risk patients. One of the most frequently used in machines have been very helpful to expedite treatment. clinic is the STOP-BANG questionnaire,24 which contains Adaptive servo-ventilation can also be used to treat com- 4 yes-or-no questions that relate to clinical signs of sleep plex sleep apnea. Continuous positive airway pressure ther- apnea (S: snoring; T: tiredness during daytime; O: observed apy in obstructive sleep apnea individuals has been found ARTICLE IN PRESS K. Pavlova and Latreille Sleep Disorders 5 to reduce subjective daytime sleepiness, improve cognitive functioning, as well as mood and quality of life.30−33 It also can improve blood pressure and glucose control.34 Oral appliances such as mandibular advancement devices may also help to improve mild to moderate cases of obstructive sleep apnea that are not associated with any significant risk factors, or for patients who are intolerant to positive airway pressure therapy. Surgical treatment methods include, most commonly, soft palate surgery, nasal surgery, and maxillo- mandibular surgery. These may help sleep apnea severity, Figure Example of a multiple although they generally do not cure sleep apnea. sleep latency test in a patient with narcolepsy. “W” delineates waking stage, N1-3 the non-rapid eye move- Hypersomnia: Narcolepsy and Idiopathic ment stages 1-3, respectively, and Hypersomnia the black solid bars indicate rapid When evaluating hypersomnia, the following issues should eye movement sleep. The green bars be considered: Is there enough sleep opportunity? In adults, delineate each nap opportunity. typical sleep need is more than 7 hours, with adequate, con- Sleep is seen in all 5 nap opportunities, occurs within a few minutes of sistent timing. Are there factors that impair sleep quality the lights out, and rapid eye move- and, as a result, lead to insufficient/poor quality sleep? ment sleep occurs in 3 of the 5 naps. These include medications and environmental factors, as well as primary sleep disorders such as sleep apnea and sleep-related movement disorders. Does it recur more than 3 times per week, for more than 3 months? Disorders causing central hypersomnia are rare. They Treatment of the sleepiness typically starts with modafi- include narcolepsy type 1 (with cataplexy), narcolepsy type nil or armodafinil. If these are not tolerated or ineffective, 2 (no cataplexy), idiopathic hypersomnia (with long sleep stimulants (methylphenidate or amphetamine/dextroam- time or without long sleep time), and recurrent hypersom- phetamine) can be used. Cautions should include monitor- nia (such as Kleine-Levin syndrome). Narcolepsy is a disor- ing blood pressure and evaluating for arrhythmias, which der of rapid eye movement sleep regulation.4 Classic can be worsened by these medications. None of these have symptoms include sleepiness, sleep paralysis, and hypnago- been approved for use in pregnancy. Cataplexy responds to gic hallucinations. Cataplexy in narcolepsy type 1 consists antidepressants (typically selective serotonin reuptake of a loss of muscle tone, provoked typically by positive inhibitors [SSRI]) or sodium oxybate. Common comorbid- emotions, classically, laughing or telling a joke. Occasion- ities of narcolepsy include rapid eye movement behavior ally, surprise or anger can be a trigger. Classically, in nar- disorder, present in as much as 10% of narcolepsy colepsy, any daytime naps are short (15-40 minutes) and patients,37 as well as periodic limb movement of sleep. refreshing. There is a common genetic association Both may be worsened by SSRI, including the ones used (DQB1*0602 haplotype), and patients with narcolepsy type for the cataplexy treatment. 1 may also have lower orexin measured in cerebrospinal Hypersomnia can sometimes be seen after head trauma, fluid.35,36 in some reports affecting as much as half of the patients The diagnosis is made first clinically; however, an objec- with traumatic brain injury,38 and a quarter of these patients tive documentation using multiple sleep latency test is may have sleep-disordered breathing. Treatment of sleep- needed to confirm the sleepiness. This test is typically per- disordered breathing may be helpful, and use of any sedat- formed on the day after a polysomnography and consists of ing medications should be judicious. 5 nap opportunities. Most narcolepsy patients fall asleep In rare conditions, hypersomnia can be idiopathic. This within minutes of being given the opportunity, and thus a condition typically presents with long, nonrefreshing naps. short sleep latency (average of < 8 minutes over the 5 Two types exist: 1) with a long sleep time, and 2) without naps), as well as rapid eye movement sleep during these long sleep time. The criteria for diagnosis include the clini- naps would be supportive of narcolepsy (see Figure). Cur- cal presentation, as well as supportive evidence from the rent criteria require that rapid eye movement sleep is either multiple sleep latency test: a sleep latency < 8 minutes, no seen in 2 or more naps or that rapid eye movement is seen sleep-onset rapid eye movement. Treatment is often chal- in one nap along with a rapid eye movement latency < 15 lenging, modafinil or armodafinil at higher doses can be minutes on the preceding polysomnogram. Haplotype typ- used, and sometimes other stimulants can be helpful. In ing may be performed; however, it is difficult to interpret another rare condition, Kleine-Levin syndrome, hypersom- and depends on genetics. Cerebrospinal fluid measurements nia is recurrent. Kleine-Levin syndrome typically presents of hypocretin are performed in many European countries in adolescence or the early 20s, and consists of periods that but are not currently commercially available in the US. last for approximately 2 weeks, during which patients ARTICLE IN PRESS 6 The American Journal of Medicine, Vol 000, No 000, && 2018 exhibit very long sleep (often 12-21 hours per day), and conversion disorders, and seizures. Unlike seizures, rapid during the waking periods individuals exhibit cognitive eye movement behavior disorder events are directed, and are abnormalities (eg, major apathy, confusion, slowness, not stereotypic. Identifying association with a dream is also amnesia), dream-like behavior, hyperphagia, or hypersexu- very helpful. ality. Between episodes, individuals have a normal level of The most commonly used agent for treating rapid eye functioning. Treatment with lithium may decrease the fre- movement behavior disorder is clonazepam,44 which has to quency of episodes, while stimulants have a marginal effect be used with caution in patients with dementia and may during the events.39,40 lead to excessive sedation. Due to the strong association with neurodegenerative conditions, patients are likely to have contraindications for benzodiazepine treatment. Parasomnias: Non-Rapid Eye Movement Another option is melatonin−an inexpensive and safer Parasomnias and Rapid Eye Movement Behavior option.45−47 In one recent study, melatonin was found to be Disorder equally effective as clonazepam for reducing the frequency Parasomnias can be grouped by type of behavior seen, or of dream-enactment episodes.48 based on sleep stage from which they occur. The most common non-rapid eye movement parasomnias include somnambulism, confusional arousals, and night terrors. These Restless Legs Syndrome and Periodic Limb parasomnias are characterized by a wide variety of behav- Movements of Sleep iors, but they mostly occur from slow-wave sleep, and as Restless legs syndrome is characterized by an uncomfortable such, they typically arise in the first half of the night. They sensation, leading to an urge to move the limbs that occurs most commonly manifest with directed behaviors. They are or worsens while at rest, with consistent evening predomi- not stereotypic and may have a variable duration. Upon nance, associated with dysesthesia, and is partially relieved awakening, the patient does not have any vivid dream by physical activity. Patients often describe the sensation as recall. If any dream mentation is recalled, it is very brief or “creeping, crawling tingling” or shock-like feelings, or sim- fragmented. The pathophysiology of non-rapid eye move- ply indescribable discomfort. Over the course of the disease, ment parasomnias is not well understood, although the the sensations can spread to the arms or trunk. One of the hypothesis of dysregulated slow-wave sleep has been pro- major characteristics of restless legs syndrome is its worsen- posed.41 Treatment may involve benzodiazepines, or in ing in the evening and at night, which results in difficulty ini- some cases, tricyclic antidepressants. Clinicians should be tiating sleep, as patients often get up and pace around the aware that some medications may induce somnambulism; room to relieve the discomfort. In turn, poor sleep often leads according to a recent review, the strongest evidence for to fatigue and daytime sleepiness. medication-induced sleepwalking was found for zolpidem Restless legs syndrome is one of the most common and sodium oxybate.42 sleep-related movement disorders, affecting about 15% of Rapid eye movement parasomnias, particularly rapid adults.49 Generally, it affects women more than men, and eye movement sleep behavior disorder, have been stud- prevalence is also higher with advancing age.49 The cause ied more extensively. Typically, the patient with rapid can be idiopathic or secondary. In its idiopathic form, there eye movement behavior disorder will present with is no known cause, but most patients will have a family his- abnormal behaviors during rapid eye movement sleep. tory. Secondary restless legs syndrome most often has a Dream enactment behaviors result from the loss of the later-onset course, and is associated with various neurologi- normal muscle atonia seen during this sleep stage. They cal disorders (eg, multiple sclerosis, Parkinson disease), occur mostly in the latter part of the night and consist iron deficiency (low ferritin level), or pregnancy. of a wide variety of motor activity that appears to be The diagnosis is made by clinical history. Restless legs related to a dream. If the patient awakens during that syndrome and periodic limb movement of sleep frequently time, he/she would be frequently able to recall the co-occur; the latter is present in 80% to 90% of patients dream, which is consistent with the behavior exhibited, diagnosed with restless legs syndrome. The presence of and is often elaborate. The type of behavior that most periodic limb movement in sleep is also supportive for the commonly brings the patient to medical attention is diagnosis of restless legs syndrome. Periodic limb move- often violent, such as screaming, punching, kicking, or ment of sleep can be diagnosed by clinical history, but a other such movements, however, nonviolent activity can polysomnography may be useful to confirm the diagnosis, be seen as well. particularly in patients with unexplained symptoms of Along with a history of recurrent dream-enactment insomnia or hypersomnia. behaviors, the diagnosis is confirmed by nocturnal polysom- Multiple studies highlight an important role of brain iron nography, which shows typical muscle activations during levels in the pathology of restless legs syndrome and peri- rapid eye movement sleep or in some cases may record the odic limb movement of sleep, but these are usually lower in abnormal events. This sleep disorder is frequently linked patients with restless legs syndrome.50 Dysfunction of the with neurodegenerative conditions, particularly synucleino- dopaminergic system has also been demonstrated as a pathies.43 Differential diagnosis includes other parasomnias, potential pathophysiological mechanism for restless legs ARTICLE IN PRESS K. Pavlova and Latreille Sleep Disorders 7 syndrome. Evaluation of serum ferritin level is recom- controlled trial and direct comparison. Arch Intern Med. 2004;164 mended. If ferritin is below 50 ug/L, replacement of iron (17):1888–1896. should be considered. Otherwise, pharmacological treat- 10. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: ment of restless legs syndrome may start with either dopa- a randomized controlled trial. JAMA. 2006;295(24):2851–2858. mine agonists or gabapentin or gabapentin enacarbil. 11. 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