REM Sleep Behavior Disorder

Review Article

Address correspondence to Dr Birgit Ho¨gl, Department of Rapid Eye Movement Neurology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria, Sleep Behavior Disorder [email protected]. Relationship Disclosure: Dr HPgl serves as associate and Other Rapid Eye editor of the Journal of Clinical Sleep Medicine and receives personal compensation for serving on the advisory Movement Sleep board of Mundipharma and UCB. Dr Ho¨gl has received honoraria for lectures for Parasomnias Abbvie, Eli Lilly and Company, Janssen Cilag, Lundbeck, Birgit Ho¨ gl, MD; Alex Iranzo, MD Mundipharma, Otsuka Pharmaceutical, and UCB, and as a consultant for Axovant and Benevolent Bio. Dr Ho¨gl ABSTRACT receives royalties from Cambridge University Press Purpose of Review: The most common rapid eye movement (REM) parasomnia and Springer. Dr Iranzo encountered by neurologists is REM sleep behavior disorder (RBD), and nightmares are has received personal so frequent that every neurologist should be able to differentiate them from the dream compensation for serving on the advisory board of and enactment of RBD. Isolated sleep paralysis is relatively common and is often mistaken as a lecturer for Otsuka for other neurologic disorders. This article summarizes the current state of the art in the Pharmaceutical and UCB. diagnosis of RBD, discusses the role of specific questionnaires and polysomnography in Unlabeled Use of the diagnosis of RBD, and reviews recent studies on idiopathic RBD as an early feature Products/Investigational Use Disclosure: of a synucleinopathy, secondary RBD, and its management. Recent diagnostic criteria Drs HPgl and Iranzo discuss and implications of nightmares and isolated sleep paralysis are also reviewed. the unlabeled/investigational Recent Findings: Idiopathic RBD can now be considered as part of the prodromal use of clonazepam and melatonin for the management stage of a synucleinopathy. Therefore, an accurate diagnosis is mandatory, and this of rapid eye movement sleep implies detection of REM sleep without atonia. The polysomnography montage, behavior disorder. including EMG of the submentalis and flexor digitorum superficialis muscles, provides * 2017 American Academy a high sensitivity and specificity for the diagnosis. The exact diagnosis is important for of Neurology. patient counseling and for future neuroprotective trials. Summary: REM parasomnias include RBD, sleep paralysis, and nightmares, which have distinct clinical characteristics and different implications regarding diagnostic procedures, management, and prognosis.

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INTRODUCTION RAPID EYE MOVEMENT SLEEP Rapid eye movement (REM) sleep be- BEHAVIOR DISORDER havior disorder (RBD), nightmares, and RBD has a low prevalence in young adults, Supplemental digital content: sleep paralysis are categorized among but is a more frequent parasomnia among Videos accompanying this article are cited in the text as parasomnias occurring specifically dur- the elderly, with an estimated prevalence Supplemental Digital Content. Y ing REM sleep. In the past few years, of probable RBD of up to 7.7%.1 3 The Videos may be accessed by clicking on links provided in important advances in research into recent interest in RBD by neurologists the HTML, PDF, and app these disorders have enriched the field, is because, beyond its classification as a versions of this article; the URLs are provided in the print particularly in RBD, which has been parasomnia, it has been recognized to version. Video legends begin linked to neurodegeneration. be an early form of a synuclein disease. on page 1031.

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KEY POINT h Although rapid eye Diagnostic Criteria dream enactment is occurring (the movement sleep The current diagnostic criteria for behaviors seem to mimic dream con- behavior disorder can RBD were published in the 2014 tent). Dream content is often elaborate, be suspected by the International Classification of Sleep typical for REM-sleep dreaming, in con- patient’s history, Disorders, Third Edition (ICSD-3) by trast to the more static imagery and polysomnography is the American Academy of Sleep Med- ruminations of non-REM dreamlike ex- required for a icine (AASM) (Table 5-1).4 These periences. In RBD, patients can be definite diagnosis. criteria require that sleep-related vo- awakened easily and are usually quickly calizations or complex motor behav- oriented. The vocalizations and behaviors plus pathologically increased iors show a very large intraindividual muscle tone during REM sleep on and interindividual variability in RBD. the polysomnogram (REM sleep with- This can be of some clinical help to out atonia) are present. Although RBD differentiate the dream enactment be- can be suspected by history, for a defi- haviors of RBD from the lower variabil- nite diagnosis of RBD, polysomno- ity of vocalizations in somniloquy and graphy is required. non-REM parasomnia or behaviors ob- While former ICSD criteria only served with periodic leg movements or required ‘‘excessive’’ submental or sleep-related epilepsy. If subjects are (upper or lower) limb EMG activity not awakened immediately after the during polysomnography for the di- RBD episode or do not wake up spon- agnosis of RBD, the current ICSD-3 taneously because of injury during an criteria list exact polysomnography episode, dream content is frequently no measures for scoring guidelines and longer remembered. The easy ability for are established on evidence-based awakening and reorientation in idio- data for detecting REM sleep without pathic RBD can help to clinically differ- atonia in the evaluation of RBD.5,6 entiate RBD from non-REM parasomnias Typical clinical characteristics of RBD and nocturnal wandering in dementia. include sleep-related complex motor Because REM sleep is more likely to behaviors and vocalizations that are occur and REM episodes last longer in associated with dreaming. Observers later parts of the night, RBD episodes have the impression that apparent often occur in the second half of the

TABLE 5-1 International Classification of Sleep Disorders, Third Edition, Diagnostic Criteria for Rapid Eye Movement Sleep Behavior Disordera

All criteria of the following must be met for a diagnosis of rapid eye movement (REM) sleep behavior disorder A. Repeated episodes of sleep-related vocalization and/or complex motor behaviors B. These behaviors are documented by polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep C. Polysomnographic recording demonstrates REM sleep without atonia D. The disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use a Reprinted with permission from the American Academy of Sleep Medicine.4 B 2014 American Academy of Sleep Medicine.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT night (whereas non-REM sleep para- ICSD-3 diagnostic standards. In other h Standardized protocols somnias often occur in the first hours words, polysomnographic features of and normative values of sleep). REM sleep without atonia alone are exist for making an not diagnostic of RBD. exact quantitative Clinical History Taking Polysomnography is mandatory for diagnosis of rapid eye Mild RBD probably often goes undiag- a definite and reliable diagnosis of RBD movement sleep nosed, as patients may be unaware of because other conditions may mimic behavior disorder. their nighttime behaviors or may ig- its symptoms. Standardized protocols nore that dream-associated behaviors and normative values exist for making reflect a pathology that should be an exact quantitative diagnosis of RBD. reported to their physician.7,8 Specific The hallmark of RBD is abnormally history taking for RBD should include increased activity on the surface EMG the bed partner whenever possible. of chin (mental and submental) and Useful screening questions for a part- upper or lower extremity surface ner can help determine if the patient EMG recordings during REM sleep on seems to ‘‘dream a lot’’ or if the polysomnography. Usually, this abnor- partner can observe what their partner mally increased EMG activity is sub- dreams about. If a partner is not divided into tonic and phasic or any available, questions to the patient EMG activity. Tonic EMG activity is should relate to whether they have characterized by a longer-lasting in- been told about such behaviors or if crease in the tone of the EMG (lasting injuries or falls out of bed have oc- longer than one-half of a 30-second curred during sleep (with or without epoch). Phasic EMG activity is charac- remembered dreaming). Specific his- terized by shorter, often twitchlike tory taking is necessary because RBD increases in EMG tone, lasting 0.1 to symptoms are often not spontaneously 5 seconds.11 While tonic EMG activity reported,9 and, specifically in idiopathic is usually only found in the mental/ RBD, only patients with more severe submental EMG, phasic activity is symptoms tend to be sent to the sleep present in mental/submental as well laboratory.10 as extremity muscles. Although differ- A history of dream enactment be- ent pathophysiologic pathways are havior alone is insufficient to diagnose thought to underlie tonic and phasic RBD, as this occurs frequently in the EMG activity in RBD, the term any general population and may point to EMG activity has been introduced for non-REM parasomnia (eg, somnambu- clinical reasons of quantification.6 lism, sleep terrors, hypnagogic halluci- Early during the course of the devel- nations), other sleep disorders where opment of polysomnographic methods abnormal behaviors may occur (eg, for the evaluation of RBD, Mahowald nocturnal epilepsy, vigorous periodic and Schenck12 suggested that arm limb movements, severe obstructive EMG should be recorded to accurately sleep apnea), or may be confused with diagnose RBD. Because some patients nightmares or visual hallucinations. have RBD behaviors mostly in the arms, and because EMG activity and Polysomnographic Diagnosis movements during REM sleep in leg Clinical diagnosis is always required muscles are less specific, it is highly in RBD, in addition to confirmatory recommended to perform an EMG polysomnographic features, along with recording from the upper extremities recorded dream enactment behavior or in combination with the chin EMG to complex behavior, according to current diagnose RBD (Supplemental Digital

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Content 5-1, links.lww.com/CONT/ montage, therefore, should include A221)(Figure 5-1).13 the mentalis or submentalis muscle Normative values for EMG activity and both upper extremities (right and that help to discriminate between left flexor digitorum superficialis). RBD and controls have been pub- Other published values refer to the lished for 11 striated muscles (surface chin alone, and recent work has EMG),6 and the most sensitive and demonstrated that a quantitative diag- specific, yet simple, EMG combination nosis of RBD with highly similar EMG was of the mental/submental and flexor values can also be feasible in poly- digitorum superficialis muscles in the somnography with tibialis anterior upper limbs.6 For accurate diagnosis EMG recordings only, and even in of RBD, the polysomnography EMG split-night polysomnography including

FIGURE 5-1 Examples from polysomnographic records (each panel is 10 seconds) from normal rapid eye movement (REM) sleep (left tracings) and REM sleep in a patient with REM sleep behavior disorder (RBD) (right tracings). The top four channels are horizontal and vertical electrooculography, the central six channels are EEG according to the American Academy of Sleep Medicine, and the bottom six channels represent mental and submental, left and right flexor digitorum superficialis, and left and right tibialis anterior muscles. Whereas in normal REM sleep, almost complete atonia is seen in all recorded muscle channels, in RBD, excessive phasic EMG activity is seen in both upper and lower extremity muscles. Note that in this epoch, the excessive muscle activity would not have been seen if chin EMG would have been recorded alone.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT continuous positive airway pressure tients who do not have enough min- h 14,15 For accurate (CPAP) titration. However, it is utes of REM sleep during the first polysomnographic preferable, whenever possible, to have night of polysomnography or when diagnosis of rapid eye either full-night diagnostic or CPAP REM sleep is markedly interrupted movement sleep treatment studies rather than split- by apneas. In some clinical settings, behavior disorder, night studies, especially for research the diagnosis of RBD may still have polysomnography purposes.7 The normative values to be determined purely on clinical should include an EMG require that any EMG activity (tonic, grounds, such as in developing re- montage using the phasic, or other) in the combined gions with scarce resources, in large- mentalis or submentalis recording of mentalis and right and scale epidemiologic studies where muscle and both upper left arm (flexor digitorum superficialis) polysomnography is infeasible or extremities (right and left flexor digitorum during REM sleep should be at least unaffordable, or when REM sleep superficialis). 27% in 30-second epochs for RBD and cannot be recorded or overall sleep 32% when a 3-second mini-epoch architecture is so disturbed that rec- scoring approach is applied.16 ognition of REM sleep is impossible. Because visual quantification of Sleep architecture is often highly increased EMG activity during REM disturbed in advanced parkinsonism sleep requires highly specific knowl- with underlying synucleinopathy, or edge and is time consuming, several sometimes in the setting of autoim- attempts have been made to develop munity, as in the recently described computerized methods for automatic IgLON5 autoimmunity syndrome,26,27 detection and quantification of EMG which is now called anti-IgLON5 dis- activity during REM sleep. A series of ease.28 However, polysomnographic different approaches and techniques confirmation of RBD diagnosis should have been validated and published.17Y20 be considered the standard of practice. Some of them require separate software and analysis after polysomnogra- Questionnaires for Diagnosis phy, while others can be run together Because polysomnography is some- with a regular polysomnographic anal- times not readily available, several ysis. Some rely on EMG activity analysis questionnaire-based instruments have for the chin only.21,22 Only one auto- been developed to screen for RBD, matic analysis software designed to namely, the REM Sleep Behavior Dis- quantify EMG activity during REM sleep order Screening Questionnaire, the includes other additional muscles.19 REM Sleep Behavior Disorder Ques- Nevertheless, with either automated tionnaire Hong Kong,29 the Mayo or visual scoring approaches, high Sleep Questionnaire,30 the Innsbruck technical quality of polysomnogram REM Sleep Behavior Disorder In- recordings and complete elimination ventory,31 and the International REM of artifacts that can confound EMG Sleep Behavior Disorder Study Group’s activity analysis (such as snoring arti- REM Sleep Behavior Disorder Single- facts) are necessary, and a visual plau- Question Screen.32 All of these have sibility check of all calculated values been validated with a reasonable with a cross-check of the original sensitivity and specificity in the con- polysomnogram is necessary to ensure text of the respective validation studies. the quality of the diagnosis of RBD.23 Nevertheless, some recent work has One night of polysomnography shown that the sensitivity and specificity recording is usually sufficient to make of diagnostic RBD questionnaires a diagnosis of RBD.24,25 Asecond strongly depend on the settings33;false night is sometimes necessary in pa- positives are very frequent if patients

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KEY POINTS h Patients with idiopathic have to complete the questionnaire presenting to sleep centers, the pro- rapid eye movement themselves, and false negatives occur dromal stage of a neurodegenerative sleep behavior disorder in patients who are unaware of their disease characterized by neuronal 19 have no motor or nocturnal behaviors. cell loss and abnormal deposits of cognitive symptoms. Therefore, it should be kept in !-synuclein in surviving cells. These h Most individuals initially mind that questionnaires are appro- diseases are termed synucleinopathies diagnosed with priate to make a diagnosis of probable and include PD, dementia with Lewy idiopathic rapid eye RBD only, and their usefulness and bodies (DLB), and multiple system movement sleep outcomes rely on the intervention of a atrophy (MSA), with disease subtypes behavior disorder are trained interviewer. For screening pur- defined by specific motor, cognitive, or eventually diagnosed poses, a multistep strategy including autonomic impairments at presen- with Parkinson disease, confirmatory polysomnography has tation. Longitudinal follow-up in pa- dementia with Lewy therefore been recommended.34 tients with idiopathic RBD diagnosed bodies, and, less Video-polysomnography is recom- in sleep centers shows that most frequently, with mended to diagnose RBD, but in individuals initially diagnosed with multiple system atrophy. contrast to EMG, where published idiopathic RBD are eventually diag- cutoff values exist, no cutoff values exist nosedwithPD,DLB,and,lessfre- for video analysis.35 Overall, the major- quently, with MSA. ity of motor events, even in severe Schenck and colleagues41 first RBD, are simple elementary move- showed that parkinsonism developed ments,36 and complex or violent be- in 11 of 29 (38%) subjects with haviors are much more rare and idiopathic RBD 4 years after the initiated during REM sleep with rapid diagnosis of the sleep disorder and eye movements in the majority of 13 years after the estimated onset of patients (compared to REM sleep with- RBD symptoms. After 16 additional out rapid eye movements).37 While years, 21 (81%) patients from this minor jerks during REM sleep exist in cohort were diagnosed with PD, DLB, the healthy population,35 it has been or MSA.42 Iranzo and colleagues43 suggested that apparently intentional found that 20 of 44 (45%) patients behaviors (so-called REM sleep behav- with idiopathic RBD developed a ioral events) at night could indicate the defined neurodegenerative syndrome future development of RBD in patients after a mean follow-up of 5 years. with early Parkinson disease (PD).38Y40 Clinical diagnoses were PD (n = 9), DLB (n = 6), MSA (n = 1), and mild Idiopathic Rapid Eye Movement cognitive impairment (n = 4). After Sleep Behavior Disorder 7 years of additional follow-up, 36 RBD can be divided into a primary (82%) developed PD (n = 16), DLB (idiopathic form) or secondary form (n = 14), MSA (n = 1), and mild when the parasomnia is linked to a cognitive impairment (n = 5). The second condition or situation. rates of phenoconversion from idio- Idiopathic rapid eye movement pathic RBD diagnosis were 35% at behavior disorder as an early feature 5 years, 73% at 10 years, and 92.5% of synucleinopathies. Patients with at 14 years.44 Similar results have been idiopathic RBD have no daytime mo- found in a large international multi- tor or cognitive symptoms. However, center cohort involving 279 subjects.45 three lines of evidence indicate that Overall, these observations indi- idiopathic RBD is not an innocent cate that RBD is usually not idiopathic sleep abnormality, but represents, at per se, but perhaps most properly least in most older adult cases termed a cryptogenic disorder that

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT represents an early stage of PD and dopaminergic uptake in the putamen h Patients with idiopathic DLB before the clinical onset of overt on functional imaging (Case 5-1). rapid eye movement parkinsonism and cognitive impair- Patients’ perceived time of onset of sleep behavior disorder ment. Interestingly, in the setting of RBD and nonmotor symptoms such show abnormalities RBD, the coexistence of mild cogni- as hyposmia, constipation, and depres- typical of Parkinson tive impairment indicates the progres- sion are highly variable. Clinical exami- disease such as sion to dementia in less than 5 years.46 nation may reveal facial akinesia, hyposmia, depression, Thus, in patients with RBD and comor- reduced arm swing, and other forms of constipation, and bid cognitive impairment, the disease subtle bradykinesia that still are not decreased dopaminergic should not be considered idiopathic. sufficient to disclose frank parkinson- uptake in the putamen Another important aspect is that the ism. Asymptomatic cognitive deficits in on functional imaging. coexistence of RBD in subjects with the executive, memory, and visuospatial cognitive impairment (either mild cog- domains are shown by neuropsycho- nitive impairment or dementia) indi- logical tests, while electroencephalo- cates that the underlying process is a graphy may demonstrate subtle cortical synucleinopathy (DLB or PD) and not slowing. Neuroimaging may show a Alzheimer disease or frontotemporal number of abnormalities, including de- dementia. creased metaiodobenzylguanidine up- Patients with idiopathic RBD show take in cardiac scintigraphy; decreased often subtle subjective or objective clin- putaminal dopamine uptake in dopa- ical abnormalities that are typical fea- mine transporter imaging; hyperecho- tures of the synucleinopathies. Patients genicity of the substantia nigra and with idiopathic RBD may show abnor- hypoechogenicity on the brainstem malities typical of PD such as hyposmia, raphe on transcranial sonography; loss depression, constipation, and decreased of intensity in the substantia nigra and

Case 5-1 A 69-year-old man presented with a 4-year history of abnormal behaviors during sleep, which were described by his wife. Upon awakening, he would not recall these behaviors, which consisted of violent activities such as punching, kicking, knocking over the nightstand, and grabbing his wife by the neck. These behaviors were performed with his eyes closed and mainly during the second half of the night. If awakened during one of the episodes, he reported dreaming that unknown intruders were attacking him or chasing him. One night he jumped out of bed while dreaming that he was fighting against a lion. Another night he hit the wall and broke his right arm. He had no symptoms of insomnia, excessive daytime sleepiness, snoring, restless legs syndrome, or seizures. He reported no cognitive or motor problems. The patient had a history of depression and was treated with venlafaxine. On examination, he had facial akinesia and reduced right arm swing, but limb bradykinesia, tremor, rigidity, and postural imbalance were absent. Video-polysomnography showed increased electromyographic activity during rapid eye movement (REM) sleep in all four limbs, but not in the mentalis, associated with jerks and raising the arms. Obstructive sleep apnea and periodic limb movements were absent. The patient was diagnosed with idiopathic REM sleep behavior disorder (idiopathic RBD), and clonazepam was started (1 mg at bedtime), which led to a dramatic decrease in dream-enacting behaviors. Continued on page 1024

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KEY POINT Continued from page 1023 h Dysfunction in During 5 years of follow-up, he developed constipation and loss of idiopathic rapid eye the sense of smell. Cognitive symptoms were still absent, but movement sleep neuropsychological testing showed executive dysfunction. After 6 years of behavior disorder is follow-up, he first reported motor slowness. Neurologic examination widespread and involves revealed shuffling gait, bilateral asymmetric bradykinesia, and rigidity, the olfactory system, the and he was diagnosed with Parkinson disease (PD). Dopamine transporter limbic system, the imaging showed decreased bilateral putaminal uptake. The patient autonomic system, started levodopa (750 mg/d), and motor examination showed improvement the nigrostriatal system, in bradykinesia and rigidity. the hippocampus, and the cortex. These Comment. This case illustrates that idiopathic RBD may be the first feature abnormalities do not of PD. It also shows that patients with idiopathic RBD have no motor or occur in all subjects cognitive symptoms and may be unaware of their symptoms as reported by the bed partner; these symptoms, which may result in injuries, respond to with idiopathic rapid eye clonazepam. Additionally, patients with idiopathic RBD have asymptomatic, movement sleep usually covert prodromal historical features of PD (eg, depression, constipation, behavior disorder, hyposmia), and their baseline examinations may show subtle parkinsonian and some individuals show only a few signs and asymptomatic neuropsychological dysfunction. In this patient, the abnormalities, while mentalis muscle was atonic on video-polysomnography, but diagnostic others have many. REM sleep atonia loss (REM sleep without atonia) was apparent only in the limbs, demonstrating the importance of recording EMG in the limbs, especially in the arms, where isolated REM atonia loss may be seen in the flexor digitorum superficialis muscles. Typically arising from idiopathic RBD, PD was characterized in this patient by the akinetic-rigid motor subtype that responded to conventional dopaminergic therapy.

locus coeruleus/subcoeruleus area on manifesting parkinsonism or cogni- 3T MRI; abnormal metabolic network tive decline, while others are not. characterized by increased activity in Researchers have sought to establish the pons and hippocampus and de- which abnormalities identify those creased activity in occipital and temporal subjects with idiopathic RBD with a areas by positron emission tomo- short-term risk for being diagnosed graphy (PET); decreased fractional an- with PD, DLB, or MSA. They found isotropy and increased mean diffusivity that decreased dopaminergic putami- in the midbrain and pontine nuclei that nal uptake and hyposmia identify regulate REM in sleep diffusion-tensor those subjects with idiopathic RBD imaging; and increased gray matter who have an increased short-term risk density in both hippocampi revealed (2.5 to 5 years) of being diagnosed with by voxel-based morphometry. a synucleinopathy.47,48 Patients with These findings indicate that dys- cortical electroencephalographic slow- function in idiopathic RBD is wide- ing tend to develop mild cognitive spread and involves the olfactory impairment and subsequent dementia. system, the limbic system, the auto- Hyperechogenicity of the substantia nomic system, the nigrostriatal sys- nigra alone and autonomic abnor- tem, the hippocampus, and the malities do not seem to identify the cortex. These abnormalities do not risk for short-term conversion. Re- occur in all subjects with idiopathic searchers have also evaluated if these RBD, and some individuals show only abnormalities change with time, re- a few abnormalities, while others have flecting an active neurodegenerative many. This indicates that some pa- process during the prodromal stage of tients with idiopathic RBD are close to the synucleinopathies. While dopamine

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS transporter imaging demonstrates pro- tures (amygdala), and pathways that h 49 In patients with gressive decline in putaminal uptake, modulate REM sleep atonia. Therefore, idiopathic rapid eye and tests show progressive cognitive RBDisfrequentinpatientswith movement sleep 50 deficits, smell impairment, dysautono- neurodegenerative diseases (eg, PD, behavior disorder, mic abnormalities, and the echogenic DLB, MSA) that affect these regions, abnormal deposits of size of the substantia nigra by transcranial but is rare in Alzheimer disease or phosphorylated sonography remain unchanged with time. frontotemporal dementia. For some !-synuclein are detected Abnormal deposits of phosphorylated conditions (eg, PD and MSA), RBD has in peripheral organs !-synuclein are detected in peripheral been well characterized in a number of outside the brain. organs outside the brain in patients publications, while for other conditions h Rapid eye movement with idiopathic RBD. (eg, Huntington disease, Machado- sleep behavior disorder The Sleep Innsbruck Barcelona Joseph disease, PD with parkin2 muta- may be secondary (SINBAR) group51 reported that co- tions, myotonic dystrophy, Wilson to established lonic biopsies detected phosphory- disease), RBD has been reported in neurodegenerative lated !-synuclein aggregates in the single or a few small case series diseases (eg, Parkinson disease, spinocerebellar submucosal nerve fibers or ganglia in involving small numbers of patients or ataxias), autoimmune four out of 17 patients with idiopathic in anecdotal reports (eg, attention diseases (anti-IgLON5 RBD and in none of the 14 controls. In a deficit hyperactivity disorder). In some disease, narcolepsy, second study, biopsy of the submandib- instances, RBD may be an important paraneoplastic ular gland detected phosphorylated clinical feature, while in others it is not syndromes), focal !-synuclein deposits in greater than significant and is overlooked by other brainstem lesions 85% of the subjects with idiopathic features (eg, dementia, parkinsonism, (ischemic infarct, RBD, and in none of the controls, in confusion, seizures). When RBD is tumors), and may be whom glandular parenchyma was associated with a neurodegenerative induced by medications obtained by the procedure.52 disease, the parasomnia may occur (antidepressants). before or after the onset of the classic Secondary Rapid Eye Movement symptoms of the disease (eg, demen- Sleep Behavior Disorder tia, parkinsonism). In idiopathic PD, Aside from the idiopathic form of RBD is linked to a specific phenotype RBD, the parasomnia can be found in where male sex, the rigid-akinetic association with other medical con- motor subtype, dysautonomia, and ditions or with the introduction of cognitive impairment predominate.54 some medications and is referred to RBD occurs in the majority of patients as secondary RBD. with MSA, if not all, but only about Diagnosis. Confirmation with video- one-half of them are aware of their polysomnography is mandatory to es- vigorous dream-enacting behaviors. tablish the association between RBD RBD in DLB (and in all dementias) and other conditions. RBD may be sec- should be distinguished from visual ondary to established neurodegenera- hallucinations resembling nightmares, tive diseases (eg, PD, spinocerebellar and both confusional awakenings ataxias), autoimmune diseases (eg, anti- and episodes of nocturnal agitation IgLON5 disease, narcolepsy, paraneo- can mimic the dream-enacting be- plastic syndromes), focal brainstem haviors seen in RBD. Denervation of lesions (eg, ischemic infarct, tumors), the amygdala and the brainstem by or induced by medications (eg, antide- hypocretin/orexin deficiency explains pressants) (Table 5-2).53 why RBD may occur in narcolepsy. The link is established when the However, in narcolepsy, RBD is not underlying condition impairs the brain- very common and is usually not a stem (pons and medulla), limbic struc- bothersome symptom compared with

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TABLE 5-2 Conditions Associated With Rapid Eye Movement Sleep Behavior Disorder

b Neurodegenerative Diseases Idiopathic Parkinson disease (25%Y58% of the cases) Parkinson disease with LRRK2 mutation (15%) Parkinson disease with parkin2 mutation (a few descriptions) Dementia with Lewy bodies (50%Y70% of the cases) Multiple system atrophy (90%Y100% of the cases) Mild cognitive impairment (a few descriptions) Pure autonomic failure (a few descriptions) Alzheimer disease (anecdotal cases) Progressive supranuclear palsy (a few descriptions) Guadeloupean parkinsonism (a few descriptions) Frontotemporal dementia (anecdotal descriptions) Corticobasal syndrome (anecdotal descriptions) DJ1 mutations and parkinsonism-dementiaYamyotrophic lateral sclerosis complex (anecdotal descriptions) Amyotrophic lateral sclerosis (a few descriptions) Neurodegeneration with brain accumulation type 1 (anecdotal descriptions) Wilson disease (a few descriptions) Huntington disease (a few descriptions) Spinocerebellar ataxia type 3 (a few descriptions) Spinocerebellar ataxia type 2 (a few descriptions) b Autoimmune Disorders Narcolepsy (30% of the cases) Limbic encephalitis associated with antibodies to voltage-gated potassium channels/LIG1 (a few descriptions) AntiYN-methyl-D-aspartate (NMDA) encephalitis (anecdotal descriptions) Anti-Ma1 and anti-Ma2 encephalitis (anecdotal descriptions) Anti-IgLON5 disease (100%) Guillain-Barre´ syndrome (anecdotal descriptions) b Other Neurologic Conditions Myotonic dystrophy type 2 (anecdotal descriptions) Autism (anecdotal descriptions) Tourette syndrome (anecdotal descriptions) Chiari malformations (anecdotal description) Smith-Magenis syndrome (anecdotal description) Mo¨ bius syndrome (anecdotal description) Attention deficit hyperactivity disorder (anecdotal description) Posttraumatic stress disorder (a few descriptions) Continued on page 1027

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS h TABLE 5-2 Conditions Associated With Rapid Eye Movement Sleep Antidepressants including Behavior Disorder Continued from page 1026 tricyclics, selective serotonin reuptake b Structural Brain Lesions (Anecdotal Descriptions) inhibitors, and Ischemic infarct serotonin norepinephrine reuptake inhibitors Hemorrhage from cavernoma can induce rapid eye Tumors (astrocytoma, neurinoma, lymphoma) movement sleep Demyelinating plaques in multiple sclerosis behavior disorder. Limbic encephalitis Lipophilic beta-blockers Autosomal dominant leukodystrophy such as bisoprolol may b Drugs That Can Cause or Worsen Rapid Eye Movement Sleep Behavior also trigger rapid eye Disorder movement sleep behavior disorder. Antidepressants (especially selective serotonin reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors [SNRIs]) h Rapid eye movement Beta-blockers sleep behavior disorder has been described in the new entity, anti-IgLON5 disease, hypersomnia, cataplexy, and sleep frag- amination shows a tauopathy involv- characterized by mentation. RBD occurs in autoimmune ing the brainstem and hypothalamus. the presence of disorders, paraneoplastic syndromes, From a clinical point of view, there autoantibodies against tumors, strokes, and multiple sclerosis are a variety of neurologic (eg, gait IgLON5 (a neuronal cell when the structures that regulate REM instability, dysphagia, chorea, demen- adhesion protein), sleep atonia (medial magnocellular nu- tia, tiredness, hoarseness, dystonia, and postmortem cleus, subcoeruleus nucleus, amygdala) upward gaze palsy) and sleep (eg, examination shows a are damaged. insomnia, stridor, dream-enacting be- tauopathy involving Antidepressants including tricyclics, haviors, hypersialorrhea during sleep, the brainstem and hypothalamus. selective serotonin reuptake inhibitors hypersomnia) abnormalities. Video- (SSRIs), and serotonin norepineph- polysomnography shows a very com- rine reuptake inhibitors (SNRIs) can plex sleep pattern characterized by induce RBD. Lipophilic beta-blockers sleep-breathing abnormalities (obstruc- such as bisoprolol may also trigger tive sleep apnea and inspiratory stridor RBD. Discontinuation of the offending secondary to vocal cord palsy) and by drug is usually associated with the abnormal sleep architecture. Abnormal elimination of the clinical and video- sleep architecture includes infrequent polysomnographic features of RBD, normal N1 and N2 sleep, normal N3 suggesting that the parasomnia was sleep with delta waves only in the simply a side effect of these drugs. second half of the night, periods of However, in other cases, RBD persists, diffuse delta activity typical of normal suggesting that the antidepressant N3 sleep mixed with spindles, poorly may have unmasked an otherwise structured stage N2 sleep with spindles latent neurodegenerative process. and K complexes, vocalizations and RBD has been described in the new apparently intentional behaviors in entity, anti-IgLON5 disease.26,27 This non-REM sleep, and RBD of mild inten- neurologic disorder is characterized by sity characterized by very frequent limb the presence of autoantibodies against and body jerks, but no vocalizations and IgLON5 (a neuronal cell adhesion pro- no complex or finalistic (apparently tein) and the haplotypes DQB1*0501 goal-directed) behaviors. This entity and DRB1*1001, and postmortem ex- affects people of both sexes older than

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KEY POINTS h First-line drug treatment the age of 50 and does not respond to rate counseling. Physicians should in- of rapid eye movement immunotherapy. form patients with caution but with a sleep behavior disorder Management. To minimize the risk determined attitude. The conversation symptoms are of injury, protection measures are should focus on the goals of good clonazepam or recommended to improve the safety medical care, commitment, and en- melatonin at bedtime. of the sleep environment, such as couraging periodic follow-up visits. h Patients with sleeping in separate beds or bed- Patients should learn that these routine idiopathic rapid eye rooms, removing dangerous objects visits will allow the earliest identifica- movement sleep from the bedroom, installing bed rails, tion of parkinsonism and cognitive behavior disorder are or placing cushions on the floor next impairment and will enable appropriate candidates for to the bed. First-line drug treatments management for enhancing quality of enrollment in of RBD symptoms are clonazepam and life. Also, patients should be informed neuroprotective trials. melatonin at bedtime, and either is that clinicians and researchers aim to h Nightmares are usually effective in reducing dream-enacting design disease-modifying drug trials in benign when isolated, intensity and frequency, but they do the idiopathic RBD population, and but may be one of the not impact, in idiopathic RBD cases, patients with idiopathic RBD are candi- features of several the risk for developing PD and DLB. dates to be considered for enroll- conditions such as rapid The typical effective doses are clonaz- ment in neuroprotective trials. eye movement sleep epam 0.25 mg to 2 mg and melatonin Of course, physicians do not need behavior disorder, 3 mg to 12 mg at bedtime. Dopami- to give all this information at the initial narcolepsy, sleep 55 terrors, depression, nergic agents are not effective. visit, but can provide it on subsequent posttraumatic stress It is debatable if physicians should follow-up visits, depending on each disorder, and the effect inform the patient with idiopathic individual patient. of some medications. RBD that the parasomnia is associated with a risk for developing parkinson- NIGHTMARES ism and dementia. The issue raises Contrary to popular belief, dreams ethical and practical considerations. It occur not only during REM sleep but is important to remark that (1) pa- also during all stages of non-REM sleep. tients with idiopathic RBD feel well Thus, nightmares (repeated occur- and have no motor or cognitive prob- rences of extended, dysphoric, and lems, (2) no interventions exist to well-remembered dreams that usually stop the neurodegenerative process, involve threats to survival, security, or and (3) the risk for conversion is physical integrity) may occur in all sleep not absolute and not imminent. For stages. An important feature of night- these reasons, some physicians argue mares is that, upon waking, the person against disclosing information that remembers the unpleasant dream and would lead to years of worry. If physi- is fully oriented and alert. Particularly in cians are reluctant to disclose infor- children, nightmares are isolated, tran- mation, it is very likely that newly sient, and benign. In these cases, edu- diagnosed patients with idiopathic cation and reassurance that nightmares RBD or their relatives will search on are harmless conditions are sufficient. the Internet and find out the strong See Table 5-3 for the ICSD-3 diagnostic link between their parasomnia and a criteria for nightmares. neurodegenerative disease. Patients Nightmares are usually benign when may then think that their physician isolated but may be one of the features withheld important information re- of several conditions such as RBD, garding their health. The authors be- narcolepsy, sleep terrors, depression, lieve that early disclosure of the risk is posttraumatic stress disorder, and the an optimal approach to provide accu- effect of some medications.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 5-3 International Classification of Sleep Disorders, Third Edition, Diagnostic Criteria for Nightmaresa

Criteria A through C must be met for a diagnosis of nightmares A. Repeated occurrences of extended, extremely dysphoric, and well-remembered dreams that usually involve threats to survival, security, or physical integrity B. On awakening from the dysphoric dreams, the person rapidly becomes oriented and alert C. The dream experience, or the sleep disturbance produced by awakening from it, causes clinically significant distress or impairment in social, occupational, or other important areas of functioning as indicated by the report of at least one of the following: 1. Mood disturbance (eg, persistence of nightmare affect, anxiety, dysphoria) 2. Sleep resistance (eg, bedtime anxiety, fear of sleep/subsequent nightmares) 3. Cognitive impairments (eg, intrusive nightmare imagery, impaired concentration, or memory) 4. Negative impact on caregiver or family functioning (eg, nighttime disruption) 5. Behavioral problems (eg, bedtime avoidance, fear of the dark) 6. Daytime sleepiness 7. Fatigue or low energy 8. Impaired occupational or educational function 9. Impaired interpersonal/social function

a Reprinted with permission from the American Academy of Sleep Medicine.4 B 2014 American Academy of Sleep Medicine.

Nightmares can be the side effect parking lot or not finishing tasks at of medications (eg, beta-blockers, an- work) or, in the case of sleep apnea, tidepressants, nicotine, or varenicline sometimes suffocation or drowning. patches) or the effect of substance Therapy is warranted when recur- withdrawal (eg, alcohol). In RBD, rent nightmares cause significant stress dream content consists of situations and impairment in social, occupational, where the patient is attacked or and other areas of functioning (eg, an- chased. The same content may occur xiety, fear of sleep, fatigue). For night- in subjects with severe obstructive mares associated with posttraumatic sleep apnea (Case 5-2) and periodic stress disorder, prazosin 1 mg to 3 mg limb movement disorder, although nightly has been shown to be benefi- they usually occur in N2 sleep. Night- cial, leading to its adoption for treat- mares in sleep terrors occur in N2 ment of nightmares more broadly, and N3 sleep and involve threats and although evidence for treatment of the need to escape from something nightmares unassociated with post- like a fire or a small room. Depression traumatic stress is not established.55 and obstructive sleep apnea are asso- A mindfulness-based intervention known ciated with nightmares consisting of as dream image rehearsal therapy has frustration (eg, not finding the car in a also been reported to be successful in

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KEY POINTS h Isolated sleep paralysis is Case 5-2 a benign condition but A 66-year-old man presented to a sleep center with a 3-year history of can be a highly dream-enacting behaviors. He had been diagnosed with Parkinson disease frightening situation 7 years earlier and was taking 2 carbidopa/levodopa 25 mg/100 mg tablets when it first occurs. 3 times daily (total levodopa dosage of 600 mg/d) and the rotigotine patch Secondary sleep (8 mg). Behaviors witnessed by his wife while the patient slept included paralysis is a feature of gesturing, pointing out, smacking, kicking, talking, and shouting. He narcolepsy. Relevant recalled having disturbing dreams such as fighting someone or having neurologic and medical trouble finding his car keys. These abnormal behaviors and nightmares differential diagnoses did not change after being treated with clonazepam (3 mg at bedtime) must be ruled out. for 6 months. He was a habitual loud snorer and admitted to dozing off h Sleep paralysis is termed while watching television and reading magazines. He denied cognitive hypnagogic when impairment. Neurologic examination was unremarkable. it occurs upon Video-polysomnography showed an apnea-hypopnea index of 57 per hour, falling asleep and an arousal index of 65, minimal oxyhemoglobin saturation of 64%, and a hypnopompic decrease in slow-wave sleep percentage. Videotape analysis disclosed abnormal when it occurs behaviors that appeared to be acting out a dream (ie, gesturing, kicking, talking) upon awakening. that only occurred during arousals at the end of most obstructive sleep apneic events. Behaviors displayed from arousals in rapid eye movement (REM) sleep were indistinguishable clinically from those occurring in non-REM sleep. REM sleep was characterized by muscle atonia. No increased tonic or phasic EMG activity occurred in the mentalis and four limb muscles. Epileptiform activity was not detected. The patient accepted treatment with continuous positive airway pressure (CPAP). A second polysomnographic study showed that CPAP titration eliminated snoring, apneic events, arousals, and oxyhemoglobin desaturations with an optimal pressure of 9 cm of H20. A second video-polysomnography study also found normal REM sleep atonia. During follow-up visits, the patient reported good CPAP compliance, using the machine every night, with complete cessation of his abnormal sleep behaviors, unpleasant dreams, snoring, and daytime hypersomnolence. Comment. Severe obstructive sleep apnea can mimic the characteristic symptoms of RBD. Video-polysomnography should be performed in subjects with suspected RBD to confirm or to exclude the presence of this parasomnia.

the management of nightmare disorder. atonia, otherwise a hallmark of physi- Image rehearsal therapy involves ‘‘rewrit- ologic REM sleep, persists and extends ing’’ the storyline, theme, or conclusions into wakefulness. Isolated sleep paral- of a typical distressing nightmare to a ysis is a benign condition but can be more positive conclusion during wake- experienced as a highly frightening fulness for 10 to 20 minutes daily, with situation when it first occurs. Second- hopes that this strategy improves the ary sleep paralysis is a feature of nightmarish dream content.55 narcolepsy, and relevant neurologic and medical differential diagnoses RECURRENT ISOLATED SLEEP (eg, hypokalemic periodic paralysis) PARALYSIS must be ruled out. Whereas in RBD, persisting muscle Sleep paralysis is termed hypnago- tone during REM sleep permits the gic when it occurs upon falling asleep occurrence of RBD behaviors, in re- and hypnopompic when it occurs current isolated sleep paralysis, it is upon awakening. The characteristic assumed that REM sleep muscle clinical feature of sleep paralysis is

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS the complete inability to move (not mares. Video-polysomnography is h Ancillary respiratory only heaviness) in the presence of needed to establish its diagnosis, show- muscles are also full wakefulness. Ancillary respiratory ing abnormal behaviors and REM sleep affected from rapid eye muscles are also affected from REM without atonia. An optimal video- movement sleep atonia, sleep atonia, and the diaphragm is the polysomnographic montage should in- and the diaphragm is only respiratory muscle continuing to clude audio and EMG recording of the the only respiratory function during REM sleep. A sensa- mental/submental and flexor digitorum muscle continuing to tion of difficulty breathing, sometimes superficialis muscles in the upper limbs. function during rapid associated with hallucinatory experi- Correct diagnosis is important because eye movement sleep. ences, have contributed to the fact other conditions may mimic RBD symp- h The differential diagnosis that sleep paralysis is recognized in toms, and the idiopathic form may for recurrent isolated different popular cultures.56 Extrinsic herald PD and DLB. Patients with idio- sleep paralysis may eye muscles are unaffected. While no pathic RBD are candidates for testing include hypokalemic specific medical treatment beyond reas- neuroprotective medications to halt the periodic paralysis, surance as to its ultimately physiologic degenerative process and prevent the complex nocturnal visual hallucinosis, panic and benign nature is recommended onset of parkinsonism and dementia. attacks, obstructive or for recurrent isolated sleep paralysis, Recurrent sleep paralysis and night- central sleep apnea, and frequent triggers (eg, sleep deprivation, mares are usually benign conditions, transient ischemic jet lag, comorbid obstructive sleep but, in some cases, are components of attack. However, the apnea triggering arousal) should be sleep disorders such as in narcolepsy, characteristic features of recognized and corrected or avoided. sleep terrors, and RBD. recurrent, short-lived, Differential diagnosis may include hy- symmetrical paralysis pokalemic periodic paralysis, complex VIDEO LEGEND with rapid recovery and a nocturnal visual hallucinosis, panic at- Supplemental Digital benign clinical course Content 5-1 tacks, obstructive or central sleep ap- experienced only upon nea, and transient ischemic attack. Rapid eye movement sleep behavior awakening from sleep However, the characteristic features of disorder. A 63-year-old man with are diagnostic historical features for recurrent recurrent, short-lived, symmetrical pa- idiopathic rapid eye movement (REM) isolated sleep paralysis. ralysis with rapid recovery and a benign sleep behavior disorder showing typi- clinical course experienced only upon cal prominent jerks during REM sleep. awakening from sleep are diagnostic links.lww.com/CONT/A221 historical features for recurrent isolated B 2017 American Academy of Neurology. sleep paralysis. While sleep paralysis is listed among the REM-related parasom- ACKNOWLEDGMENT nias in the ICSD-3,itshouldbealso The authors acknowledge Heinz Hackner, noted that even in healthy persons, board-certified polysomnography tech- sleep paralysis may sometimes go nician, for his technical advice with along with hallucinatory experiences, Figure 5-1. namely, visual, acoustic, or tactile hallucinations of the perception of a REFERENCES person’s presence. However, hypnago- 1. Mahlknecht P, Seppi K, Frauscher B, et al. gic hallucinations are listed among the Probable RBD and association with other parasomnias. In some cases, neurodegenerative disease markers: a population-based study. Mov Disord 2015; rudimentary low-volume vocalizations 30(10):1417Y1421. doi:10.1002/mds.26350. are also uttered during sleep paralysis. 2. Boot BP, Boeve BF, Roberts RO, et al. Probable rapid eye movement sleep behavior CONCLUSION disorder increases risk for mild cognitive impairment and Parkinson disease: a RBD is clinically characterized by population-based study. Ann Neurol dream-enacting behaviors and night- 2012;71(1):49Y56. doi:10.1002/ana.22655.

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