Rapid eye movement sleep behavior disorder
Sep. 01, 2022
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Sleep terrors consist of abrupt arousals out of sleep stage 3 NREM, primarily in the first third of the night, with disordered motor agitation, screaming, fear, and autonomic activation. Sleep terrors affect between 1% to 6% of prepubertal children with a peak incidence between 5 and 7 years of age and a strong familial clustering. Sleep terrors are usually benign and tend to spontaneously decrease in frequency or cease during adolescence. However, since the early 2000s, it has been shown that sleep terrors can persist in adulthood in predisposed individuals or even appear de novo in some cases. In this update, the author addresses the latest clinical and polygraphic criteria for the differential diagnosis between sleep terrors and other motor phenomena occurring during sleep, focusing on sleep-related hypermotor epilepsy in which the differential diagnosis poses particular problems.
• Sleep terrors are sudden, partial awakenings from deep non-REM sleep, associated with intense motor behavior and strong autonomic responses.
• Sleep terrors are mainly a childhood phenomenon, with peak prevalence at 5 to 7 years of age.
• During the episodes, children have a terrified expression but do not respond to family members trying to console them.
• Sleep terrors are usually benign with a tendency for spontaneous resolution, but they can persist in adulthood in predisposed individuals or even appear de novo in some cases.
• Safety measures are of primary importance to protect the patient from injury, but treatment with medications is not usually necessary.
Sleep terrors (also called "pavor nocturnus" in children and "incubus" in adults) have commanded attention for centuries. It was not until 1949, when Jones wrote On The Nightmare, that sleep terrors were differentiated from terrifying dreams (16).
Gastaut described sleep terrors in a single subject, which originated in slow-wave sleep (13). Broughton first suggested that sleep terror is a "disorder of arousal" rather than an epileptic phenomenon (04). Fisher confirmed that sleep terrors begin in stage 3 or 4 sleep (now N3), generally in the first cycle (12). In the International Classification of Sleep Disorders, sleep terrors are classified as a disorder of arousal (from NREM sleep) within the class of parasomnias (01).
• Sleep terror has an explosive onset that may consist of an abrupt arousal and a sudden scream or series of screams followed by incoherent verbalizations. The heart rate rises; tachypnea and increased respiratory amplitude are common.
• The individual then enters a state characterized by autonomic and behavioral manifestations of intense fear.
• Patients do not usually leave the bed, but sometimes patients jump out of bed and run through the house, the sleep terror episode resulting in somnambulism proper.
• Attacks usually arise during the first third of the night.
• The episodes generally last 1 to 5 minutes, during which the patient is unresponsive or partially responsive with confusion, disorientation, and agitation.
Other clinical features include flushing of the skin, diaphoresis, and mydriasis. The heart rate rises; tachypnea and increased respiratory amplitude are common (36; 02; 26).
The patient may feel anxious, fearful, or terrified and is generally inconsolable until the intense agitation dissipates. A sense of respiratory oppression or of doom or impending death may accompany the episode. As the patient calms down at the end of the episode, sleep follows easily, and the episodes usually do not occur more than once per night (36).
Recall of the episode either immediately after or the next morning is usually absent or limited to a single frightening image, such as suffocation or being buried alive, although occasionally patients may recall more elaborate dream-like experiences. The degree of retrograde amnesia varies with the child’s age, the time that elapses between the event and the report (whether the report is given just after the event or the next morning) and the severity of the child’s confusion during the event.
In a study of 25 adults and 20 children with a diagnosis of disorders of arousal, more than two-thirds of the children could not recall any mental activity associated with their episodes, whereas more than two-thirds of adults recalled at least one mental experience. The content of the collected reports was dominated by dynamic actions acted out from a self-perspective, often with apprehension and in response to misfortune and danger, in a home-setting environment (07).
Uguccioni and colleagues compared dream recall in patients with sleep terror (ST) and sleepwalking (SW) and in patients with REM sleep behavior disorders (RBD) (34). The authors found that the majority of patients remembered an enacted dream. These dreams were more complex and less bizarre, with a higher level of aggression in the RBD than in SW/ST subjects. As many as 70% of enacted dreams in SW/ST and 60% in RBD involved a threat; there were more misfortunes and disasters in the SW/ST dreams, whereas there were more human and animal aggressions in the RBD dreams.
In extreme cases, probably due to the severe manifestation of the patient’s parasomnia, traumatic events associated with a family member’s sleep disorder can also have profound, sometimes chronic, psychological effects on his or her family members.
Less severe episodes accompanied by brief screams, inconsolable crying, and mild agitation overlap with confusional arousals.
Sleep terror episodes can be precipitated by fever, sleep deprivation, or the use of central nervous system depressant medications (26). Attacks can often be triggered by forced arousals in slow-wave sleep. Young children (1 to 4 years) with poorly controlled asthma had more sleep disruptions, including frequent sleep terrors, in comparison to children without asthma (25).
In children, sleep terrors are usually benign and become less frequent with age, tending to resolve spontaneously during adolescence, perhaps because the amount of time spent in delta-wave sleep decreases with age (26). When sleep terror episodes include sleepwalking activity, the risk of injury is increased. The sleepwalking associated with sleep terrors is more vigorous and frantic than merely somnambulistic episodes; sometimes persons with sleep terrors bolt out of bed and run about frightened and confused.
A multicenter study confirmed the hypothesis that behavioral or emotional problems are surprisingly common in children and adolescents with disorders of arousal, and the severity of emotional or behavioral problems is positively correlated with the severity of the nocturnal episodes (10).
A 7-year-old child presented with a 3-year history of sudden awakenings, usually 1 hour after sleep onset. The child’s medical history was unremarkable. Family history revealed that a maternal cousin had experienced sleep terror episodes in the past. During the episodes the patient sat up with a fearful expression and glassy eyes, vocalized, screamed, and shook; his body seemed fighting against an unknown danger. He was usually inconsolable, unresponsive to external stimuli, and was difficult to waken and calm. He had tachycardia, tachypnea, flushing of the skin, and mydriasis. The patient was confused and disoriented if awakened. Often the child might be able to provide only an indication of fear, but return to sleep might occur without achieving full waking consciousness, and morning amnesia for the whole event was the rule. The episodes occurred twice monthly, lasting 3 to 5 minutes; during febrile illness, they were more frequent and prolonged. Neurologic examination was negative. Based on the characteristic history, he was diagnosed with sleep terrors. No pharmacologic treatment was begun because the attacks did not produce harm or injury; parents and child were reassured that the episodes are generally self-limiting, decreasing in frequency, and cease during adolescence or young adulthood.
A number of genetic, developmental, psychological, and organic risk factors have been identified for sleep terrors.
• Genetic factors: Many patients have a family history of sleep terrors, sleepwalking, or both, supporting the hypothesis that sleepwalking and night terrors share a common genetic predisposition (28). Studies of twins strongly support the heritability of sleep terrors.
• Developmental factors: The common pattern of onset is in childhood, and termination by late adolescence implicates a developmental factor.
• Psychological factors: Sleep terrors are common in patients with posttraumatic stress disorder and are probably increased in children raised in violent, abusive families. Some studies reported a significant association between anxiety level and sleep terror episodes, but psychopathology is extremely rare in children despite the impressive intensity of the attacks.
Organic factors. Sleep terrors occur more often in children with sleep-disordered breathing than in normal children and are increased in persons with obstructive sleep apnea, especially during nasal continuous positive airway pressure therapy, and in those who consume alcohol at bedtime. The prevalence of parasomnias, including sleep terrors, is greater among children with neurodevelopmental disorders, such as Down syndrome and cerebral palsy. These patients are more vulnerable to upper airway obstruction that can cause repeated arousals from sleep, triggering arousal disorders. Nevsimalova and colleagues suggested that childhood parasomnias, including sleep terror, can be regarded as a disorder of sleep maturation because they are frequently associated with perinatal risk factors and developmental comorbidities (27).
Sleep terrors starting in adulthood can be symptomatic of neurologic diseases. There are isolated documented cases of sleep terrors caused by a brainstem lesion or a thalamic tumor.
The pathogenesis of sleep terrors is unknown. Sleep terror is classified as a disorder of arousal based on the concept that disordered arousal mechanisms lead to behavioral and emotional activation but not to a full awakening (08; 26). Sleep disorders that are known to trigger arousals, like sleep-disordered breathing, may cause sleep terror in children. Episodes usually occur during deep non-REM sleep (stage 3). High-voltage slow-wave activity may be seen immediately prior to the episode, and the EEG during an episode may show diffuse, hypersynchronous rhythmic delta, diffuse delta with intermixed faster frequencies in the theta and alpha range, or prominent alpha and beta activity.
Some authors failed to find a “delta wave build-up” prior to an arousal disorder, suggesting that this EEG pattern does not appear to be specific for an arousal disorder episode (32). Intracerebral EEG studies suggest that arousal disorders could be dissociated arousal states due to the coexistence of different, local, cerebral states of being (32; 02). Scalp EEG analysis reveals a localized decrease in slow wave activity over centro-parietal regions relative to the rest of the brain in patients with arousal disorders compared to good-sleeping healthy controls; also, these differences in local sleep were present in the absence of any detectable clinical or electrophysiological signs of arousal (09). These topographical changes in local EEG power persist during REM sleep and wakefulness, suggesting a trait-like functional change that crosses the boundaries of NREM sleep.
Studies on adults suggest that an abnormal deep sleep associated with a high slow-wave sleep fragmentation might be responsible for the occurrence of sleep terror episodes (22). A video-polysomnographic (V-PSG) assessment to quantify slow-wave sleep interruptions (slow-wave sleep fragmentation index, slow/mixed and fast arousal ratios, and indexes per hour) and the associated behaviors in 60 adult patients with disorder of arousal showed that slow-wave sleep fragmentation index and the mixed, slow, and slow/mixed arousal indexes and ratios were higher in patients with disorders of arousal than controls (22). Usually, the increased slow-wave sleep fragmentation observed in patients with sleep terrors is not associated with the level of daytime sleepiness (21). In fact, daytime sleepiness in adult patients with sleep terrors and sleepwalking episodes seems to be associated with a specific polygraphic phenotype (rapid sleep onset, long sleep time, lower numbers of awakenings on N3), which is suggestive of a higher sleep propensity that may contribute to incomplete awakening from deep sleep (06).
Evaluating autonomic reactions in a small group of adult patients with sleepwalking and sleep terrors, Ledard and colleagues found an autonomic arousal occurring 4 seconds before motor arousal from N3 sleep (with a higher adrenergic reaction than in controls), suggesting that an alarming event during sleep (possibly a worrying sleep mentation or a local subcortical arousal) causes the motor arousal (17).
Approximately 1% to 6% of prepubertal children have recurrent sleep terrors, with a peak incidence between 5 and 7 years of age (18). Episodes tend to decrease in frequency or cease during early adolescence such that 50% of children no longer have attacks by the age of 8 and 36% continue to have attacks into adolescence, suggesting a disorder of maturation of the nervous system. However, in some patients, episodes begin in adolescence or early adulthood (02; 26). The prevalence of disorders of arousal was 7.1% among boys and 7.7% among girls in a nationwide survey conducted among Japanese adolescents (15). The prevalence in adults is about 1%; in most instances this represents a continuation of episodes after adolescence. Sex and racial or cultural differences do not appear to affect prevalence.
Many individuals share the condition with one or more family members, and the increased prevalence in first-degree relatives suggests an autosomal dominant pattern of inheritance. Again, these findings predate the discovery of autosomal-dominant nocturnal frontal lobe epilepsy and may refer to misdiagnosed seizures.
Sleep deprivation, a big delay in sleep/wake schedule such as that of confinement due to COVID-19, emotional stress, alcohol use at bedtime, and febrile illness can influence the frequency and severity of episodes in susceptible individuals (23; 05). voidance of these precipitants may help to prevent sleep terrors. In some patients, the premenstrual period may be associated with more frequent episodes (23; 26).
The differential diagnosis includes sleep-related epilepsy, REM sleep behavior disorder, nightmares, confusional arousals, nocturnal panic attacks, nocturnal delirium, and other sleep disorders that produce anxiety, including obstructive sleep apnea and nocturnal cardiac ischemia. Sleep terrors pose particular problems in their differential diagnosis with the sleep-related epileptic seizures, particularly sleep-related hypermotor epilepsy in which attacks commonly occur without scalp EEG epileptic abnormalities (33; 19; 26). Generally, the distinction between sleep terrors and epileptic seizures is based on clinical criteria. Features favoring the diagnosis of sleep-related hypermotor epilepsy rather than sleep terrors are a high rate of same-night recurrence, the presence of dystonic-dyskinetic motor pattern during the attacks, their stereotypical motor behavior, their response to antiepileptic medication, and onset or persistence into adulthood (30; 33; 26). Sleep terrors typically occur within the first few hours of sleep, whereas seizures may occur throughout the night (see Table 1). Nocturnal complex partial seizures may also be associated with fearful appearance, screaming, running, tachycardia, and vague frightening perceptions. However, it is not always possible to distinguish sleep terrors from seizures on the basis of history alone, and video-polysomnographic recording is mandatory in cases in which episodes are frequent and persisting in young adulthood with a violent motor behavior (26). In association with the episodes’ semeiological features, sleep stage and the relative time of occurrence of minor and major motor manifestations during sleep represent useful criteria to discriminate sleep-related hypermotor epilepsy and disorders of arousal (29; 19). Analyzing the "event distribution index" during video-polysomnography recordings of 89 patients with a definite diagnosis of disorders of arousal (59) or sleep-related hypermotor epilepsy (30), the occurrence of at least one major event outside N3 was highly suggestive for sleep-related hypermotor epilepsy. The occurrence of at least one minor event during N3 was highly suggestive for disorders of arousal (29).
Sleep terrors usually occur within the first few hours of sleep and arise out of NREM sleep stages 3 (N3), whereas nightmares occur out of REM sleep during the middle or latter half of the night. Nightmares are not usually accompanied by major motor activity or severe anxiety, vocalization, and autonomic discharge, and they are less likely to begin with an intense scream than sleep terrors. The sleeper is more easily aroused and, when awakened from a nightmare, exhibits good intellectual function. Afterward, dream content can be recalled in vivid detail (see Table 1). Some patients, however, have clinical features that overlap between nightmares and sleep terrors.
• Age at onset: 3 to 8 years
• Age at onset: any age
Sleep-related hypermotor epilepsy
• Age at onset: any age
Confusional arousals are awakenings from slow-wave sleep without terror or ambulation. Patients may fumble with bedclothes and mumble incoherently but do not exhibit intense autonomic arousal or flight reactions. The features of sleep terrors, sleepwalking, and confusional arousals often overlap. For example, sleepwalking episodes and confusional arousals may be associated with whimpering or crying, fearful behavior, and mild autonomic arousal.
In nocturnal dissociative disorder, the patient is awake when the episode begins and behavior is purposeful, more complex, and longer lasting. The EEG is consistent with wakefulness.
REM sleep behavior disorder may be associated with violent behavior, running, or screaming; however, autonomic activation is usually absent or mild with, for example, little or no tachycardia. Episodes tend to occur later in the night and are often associated with dream recall. Observers often report that patients seem to be "acting out" their dreams. In some patients, however, behavior may be similar to that observed with sleep terrors, and some patients have an "overlap syndrome” (parasomnia overlap disorder) with elements of sleep terrors, somnambulism, and REM sleep behavior disorder (35).
Nocturnal panic attacks may at times clinically resemble sleep terrors, and episodes may arise out of NREM sleep, usually stage 2 or 3. Psychopathology is common, and there are always similar episodes in daytime wakefulness, which is not true in patients with sleep terrors.
In a single case, screaming/yelling episodes were due to a sporadic insulinoma, suggesting the inclusion of hypoglycemia in the differential diagnosis of new-onset or worsening seizures or night terrors (03).
For otherwise normal children with typical behaviors occurring during the first third of the night, the diagnosis can usually be made based on clinical criteria. The International Classification of Sleep Disorders, third edition, criteria are adequate for a reliable diagnosis of disorders of arousal in adulthood, too (20). When the diagnosis is uncertain, video-polygraphic monitoring is indicated, particularly if the events are occurring several times per week. If nocturnal seizures are a diagnostic consideration, multiple EEG channels should be included in the recording montage, and the paper speed could be sufficient to identify epileptiform and ictal EEG activity (15 to 30 mm per second). A synchronized video recording of the patient is useful to observe the clinical manifestations of the motor attacks and their stereotypy if more than one episode is recorded (30; 26). Standard polysomnographic recording techniques used for identifying sleep apnea are generally insufficient when complex partial seizures are a consideration.
Polysomnographic monitoring usually demonstrates that sleep terrors consist of sudden and incomplete arousal from deep sleep. The onset of sleep terror episodes is usually within the first few hours of sleep, during stage 3 sleep. Prior to a sleep terror episode, the EEG may show high-voltage, generalized symmetrical, hypersynchronous slow-wave activity. During the episode, it often shows a regular, rhythmic delta activity pattern, associated with a marked increase in muscle tone and change in respiratory and heart rate. In these patients beyond full sleep terrors, partial arousals from slow-wave sleep without full terror are also common, and tachycardia usually occurs during both clinical episodes of sleep terror and partial arousals. Psychogenic dissociative episodes are associated with a waking EEG pattern.
Psychiatric or psychological evaluation may be indicated in selected patients.
• Attempts to interrupt sleep terror episodes should be avoided because they often confuse and frighten the patient more and may result in more violent behavior.
• Safety measures are of primary importance to protect the patient from injury. These include locating the patient's bedroom on the ground floor and providing special bolts for windows and doors.
• The patient should be counseled to avoid sleep deprivation.
• Treatment with medications is not usually necessary for the younger child because psychological disturbances are infrequent, and the disorder is usually outgrown by late adolescence (02; 18).
As frightening as they are, parents and children usually only need to be reassured that the episodes are generally self-limiting and that the attacks rarely produce harm or injury. Attempts should be made to alleviate whatever stress may be going on in the child’s environment and to ensure that the child is getting adequate rest. When the behavior has the potential of injury or causes major disruption of family life, treatment with benzodiazepines, imipramine, mirtazapine, or ramelteon may be beneficial (14; 31; 11; 24). Clonazepam treatment at 1 mg/day or melatonin 5 mg are beneficial in some patients.
For adults, psychotherapy may be helpful when the disorder is linked to significant psychopathology although studies evaluating the efficacy of different psychological approaches in adults (hypnosis, relaxation therapy, or cognitive behavioral therapy) provided contrasting results (24). Benzodiazepines are also helpful and can be used for long intervals with few complications in most patients; however, when the drug is withdrawn, the relapse rate is high. Diazepam (5 to 10 mg before retiring) could be useful, but to avoid daytime sedation due to the long half-life of diazepam and its metabolites, better results have been reported with shorter-acting benzodiazepines such as midazolam, oxazepam, and especially clonazepam, at the usual evening doses of 10 to 20 mg, 10 to 20 mg, and 0.5 to 2 mg, respectively. Imipramine 50 to 100 mg at bedtime is sometimes effective, and hypnosis or other behavioral treatment may be helpful for some patients. A 6-month course of medication, followed by gradual withdrawal, is a typical program. In the wake of the hypothesis that manifestations of arousal disorders such as sleep terrors may be due to a conflict between the mechanisms generating slow-wave sleep and arousal, dependent on a dysfunction in the serotoninergic system, L-5-hydroxytryptophan, a precursor of serotonin, (2 mg/Kg at bedtime) has been proposed as highly effective in reducing the number of sleep terror episodes.
Stress reduction through such techniques as relaxation therapy and autogenic training may be helpful in adults with psychopathology.
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Italfarmaco and Pfizer.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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