Clinical manifestations

Presentation and course

According to the International Classification of Sleep Disorders (ICSD-3-TR) parasomnias are characterized as a group of “undesirable physical events or experiences that occur during entry into sleep, within sleep, or during arousals from sleep” (01). Some are associated with violent motor and autonomic activity, whereas others, such as nightmares, have minimal muscle activation. Parasomnias may be categorized in various ways. The International Classification of Sleep Disorders divides parasomnias into four categories: (1) NREM- related parasomnias, including disorders of arousal (confusional arousals, sleep terror, and sleepwalking) and sleep-related eating disorder; (2) REM-related parasomnias, including nightmare disorder, recurrent isolated sleep paralysis, and REM sleep behavior disorder; (3) other parasomnias, including exploding head syndrome, sleep-related hallucinations, sleep-related urologic dysfunction, parasomnia unspecified, parasomnia due to a medication or substance, and parasomnia due to a medical disorder; and (4) isolated symptoms and normal variants, including sleeptalking (01).

Nightmares are common sleep-related parasomnias arising from REM sleep, associated with a frightening dream from which precise details are recalled. Nightmares generally occur in the last half of the night when REM sleep predominates, and in contrast to sleep terror, no confusion or disorientation is present. Nightmares are extended, extremely dysphoric, and well-remembered dreams that usually involve threats to survival, security, or physical integrity. They are experienced occasionally by many persons during their lifetime, occurring as a primary complaint without other comorbidities or in the context of other sleep, neurologic, or psychiatric disorders or systemic diseases. Nightmare disorder refers to nightmares causing clinically significant distress or impairment in social, occupational, or other important areas of functioning. According to the International Classification of Sleep Disorders (ICSD-3-TR) the diagnosis of nightmare disorder consists of the following three criteria: (1) repeated occurrence of extended, extremely dysphoric, and well-remembered dreams that usually involve threats to survival, security, or physical integrity; (2) on awakening from the dysphoric dreams, the person rapidly becomes oriented and alert; and (3) 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 (01).

Sleep paralysis is a relatively common but under-researched phenomenon, with terms for sleep paralysis existing in over 100 cultures (eg, in Hong Kong it is called “the ghost oppression phenomenon”) (46; 44). Sleep paralysis occurs when the atonia of REM sleep persists into wakefulness; thus, patients awaken finding themselves completely paralyzed and frequently feeling as if they are in danger of imminent death. Similar to the atonia in REM sleep, muscle atonia during sleep paralysis includes striated muscles under voluntary control except for the diaphragm, external eye muscles, and stapedius (46). The experience of a full-body paralysis despite subjective alertness is overwhelmingly unpleasant and frightening, especially when occurring for the first time and when accompanied by feelings of suffocation (06; 44). Sleep paralysis can be accompanied by visual and auditory hallucinations such as a sense of an evil presence (known as intruder hallucinations), pressure felt on the chest (incubus hallucinations), and illusory feelings of movement (vestibular-motor hallucinations) (10). The episodes last from a few seconds to several minutes disappearing spontaneously or on external stimulation. Sleep paralysis can occur as an isolated sporadic phenomenon, or it may be associated with narcolepsy.

According to the International Classification of Sleep Disorders (ICSD-3-TR), the diagnostic criteria for recurrent isolated sleep paralysis, all of which must be met, include: (1) a recurrent inability to move the trunk and all of the limbs at sleep onset or on awakening from sleep; (2) each episode lasts seconds to a few minutes; (3) episodes cause clinically significant distress including bedtime anxiety or fear of sleep; and (4) the disturbance is not better explained by another current sleep disorder (especially narcolepsy), mental disorder, medical disorder, or medication or substance use.

In REM sleep behavior disorder, the normal muscle atonia of REM sleep is disrupted, and patients are able to “act out” their dreams (38). REM sleep behavior disorder is characterized by more or less purposeful gestures enacting attack or defense reactions, sometimes associated with emotional expressions of joy, laughter, or sorrow (14).

During the episodes, patients can be accidentally violent, and bed partners are frequently unintentionally injured (38; 01). Usually, the main themes collected in the dream recall were violent and aggressive attacks by people or animals, not matching with personality features during wakefulness (43; 13). REM sleep behavior disorder is more common in the second half of the night, when REM sleep episodes tend to last longer. Almost half of the patients are unaware of their dream-enactment behaviors, with 70% of themreporting good sleep quality. In most cases, bed partners are essential to convince patients to seek medical help (14). REM sleep behavior disorder can be isolated or associated with a heterogeneous group of conditions, including neurologic disorders, mostly a-synucleinopathies (46; 20).

According to the International Classification of Sleep Disorders (ICSD-3-TR), the diagnostic criteria for REM sleep behavior disorder, all of which must be met, include: (1) repeated episodes of sleep-related vocalization or complex motor behaviors; (2) these behaviors are documented by video-polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep; (3) polysomnographic recording demonstrates REM sleep without atonia; (4) the disturbance is not better explained by another current sleep disorder or mental disorder.

Prognosis and complications

As a complication of REM sleep behavior disorder, the patient or bed partner may be unintentionally injured (27).

Isolated REM sleep behavior disorder can occur many years before the onset of motor or other non-motor symptoms of parkinsonian syndromes, such as multiple system atrophy or Lewy body dementia (20; 29; 52). In a large multicenter study of 1280 patients from 24 different centers, the overall conversion rate from isolated REM sleep behavior disorder to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after a 12-year follow-up. The rate of phenoconversion was significantly increased if motor symptoms, olfactory deficit, mild cognitive impairment, erectile dysfunction, an abnormal DAT scan, color vision abnormalities, and constipation were present (21).

Twenty-four-hour blood pressure control was impaired in patients with isolated REM sleep behavior disorder as well as in de novo Parkinson disease, consisting of reduced amplitude of nocturnal dipping and increased frequency of nondipping status, with possible implications for cardiovascular morbidity and mortality in isolated REM sleep behavior disorder (48).

REM sleep behavior disorder also could be present in patients with Parkinson disease, defining a more severe phenotype. In these cases, REM sleep behavior disorder is associated with a faster cognitive decline and motor progression, impulse control disorders, and functional and structural brain-imaging phenotype (more severe nigrostriatal dopaminergic impairment, altered regional homogeneity, and connectivity in the cerebellum and visual-motor relevant cortex) (12; 34; 11; 25; 53). Also, a greater severity of REM sleep without atonia at polysomnography is associated with an increased risk for poor cognitive performance and depressive mood in patients with REM sleep behavior disorder (15).

Nightmares and sleep paralysis, when occurring frequently or involving intense negative emotional components, can induce intense fear and anxiety associated with poor sleep, impairing well-being and social functioning (44).

Recurrent nightmares are the most defining symptom of post-traumatic stress disorder (02). The association between nightmares and suicide has yielded different results, but the incidence of depression seems higher among those who suffer from nightmares.

Clinical vignette

A 72-year-old woman presented with a 4-year history of nocturnal injuries and terrifying dreams. The woman’s history comprised well-controlled diabetes type 2 and left mammary carcinoma at 61, surgically treated. Family history was unremarkable apart from reported essential tremor in the sister and in the grandmother.

Almost every night the patient experienced vivid dreams full of violent content, frequently involving threatening situations where she was being attacked or had to flee from danger. The patient’s daughter who slept in the contiguous room reported movements and vocalizations mimicking the contents of those dreams, including punching, kicking, hitting the nightstand, and throwing herself out of bed. These episodes were more frequent in the latter part of the night. Serious traumatisms also happened. “On one night I dreamt to be chased by a flock of rampaging bulls, I tried to jump behind a rock to protect myself…I suddenly woke up with intense pain and blood covering my face, I threw myself out of the bed, broking my nose by cracking the glass nightstand,” the patient reported. Neurologic examination was negative apart from a slight postural tremor in both hands. Video-polysomnography documented persistent muscular tone on mylohyoideus muscle and increment of phasic muscular activity in limbs during REM sleep. Moreover, during REM sleep, the patient started to abruptly move the left hand and shouted as she was arguing with someone. Based on the characteristic history, on polygraphic findings, and in the absence of any previous neurologic condition, she was diagnosed with isolated REM sleep behavior disorder. Pharmacologic treatment was suggested. The patient started clonazepam 1 mg taken 20 minutes before going to bed. At a follow-up visit 4 months later, the patient reported improvement of the symptoms, in particular, intense dream-enacting disappeared, and no more traumas occurred; unpleasant dreams also reduced to two to three per month.

Biological basis

Etiology and pathogenesis

REM sleep behavior disorder can manifest as isolated or can be associated with a heterogeneous group of conditions, including alpha-synuclein neurodegenerative disorders, narcolepsy, paraneoplastic or autoimmune disorders, central nervous system lesions (eg, tumors or stroke), antidepressants or other medications, drug withdrawal states, and toxic metabolic states (44).

In REM sleep behavior disorder, the patients have lost the ability to maintain the skeletal muscle atonia due to a primary or secondary effect on generating this REM attribute.

REM sleep behavior disorder can be produced in animals by selective inactivation of the sublateral dorsal nucleus in the pontine tegmentum and GABAergic/glycinergic in ventromedial medullary inhibitory neurons (50). Neuropathological and pharmacological damage to the same nuclei in humans can lead to REM sleep behavior disorder manifestation. Beyond the brainstem, neuroimaging documented structural and functional changes involving the nigrostriatal system, limbic system, and cortex-suggesting that REM sleep behavior disorder is a multi-systemic neurodegenerative process (51).

Although no association between rare heterozygous genetic variants of parkinsonism was found in patients with REM sleep behavior disorder (32), polygenic disease burden may play a role (49). Altered protein profiles indicated that immunity, inflammation, complement, and coagulation also play a role in REM sleep behavior disorder pathophysiology (30). Measuring biological aging using DNA methylation-based epigenetic clocks, patients with isolated REM sleep behavior disorder tended to be epigenetically older than controls, suggesting that accelerated aging characterizes prodromal neurodegeneration (05).

REM sleep behavior disorder linked to narcolepsy has been insufficiently characterized, leaving several issues unsolved. In particular, it is still debated whether REM sleep behavior disorder is an intrinsic feature of narcolepsy or an associated feature with a still unclear pathophysiology (03).

In community-based studies of older adults, lower education, presence of head injury, atrial fibrillation, hyperlipidemia, constipation, olfactory disturbance, imbalance, use of alcoholic beverages, selective serotonin reuptake inhibitors, nonoccupational exposure to pesticides, and benzodiazepine use were associated with a higher likelihood of having probable REM sleep behavior disorder (26; 54).

Nightmares can occur as a primary complaint or in the context of other sleep (eg, insomnia), psychiatric (eg, anxiety, depression, schizophrenia), neurologic diseases (eg, epilepsy), or medication or substance intake. The etiology of nightmares is best explained by a disposition-stress model hypothesizing that both nightmare frequency and neuroticism are significantly related to nightmare distress. Other research groups have underlined that the etiology of nightmare disorder may be influenced by increased hyperarousal that accumulates during the day and is maintained at night, associated with an impaired fear extinction (06). Frequent nightmares in children are associated with child-, sleep-, and family-related factors, such as insomnia and parental predisposition (24).

The causes of sleep paralysis are likely to be multifactorial, including a moderate genetic influence and recurrent experience of threatening or traumatic events (10). Studies suggested an increased prevalence of sleep paralysis in patients with obstructive sleep apnea, nocturnal leg cramps, and psychiatric disorders, especially posttraumatic stress disorder, anxiety, and panic disorder. Very little experimental work into the underlying neurophysiology of sleep paralysis has been performed. However, it appears that episodes are linked with sleep disruption and are particularly associated with SOREMPs (10). At a neurobiological level, the paralysis associated with REM sleep is believed to be regulated by the GABA and glycine neurotransmitter systems, which are important in inhibiting motor neurons during REM sleep, thus, contributing to muscle atonia. What is currently unknown is why some people regain waking levels of consciousness during REM sleep, resulting in an episode of sleep paralysis (10).

Epidemiology

REM sleep behavior disorder is more prevalent in males after the age of 50 years: a 0.5% prevalence is estimated in the elderly population (09; 01). In a population-based study (HypnoLaus, Lausanne, Switzerland), the prevalence of REM sleep behavior disorder was 1.06%, with no difference between men and women (16).

Nightmares are frequent, occurring in an estimated 6.6% of the general population. Even though sleep histories of nightmare sufferers indicate that nightmares often begin in childhood and are stable over time, longitudinal studies, especially in adults, are scarce (40). Nightmares were often reported by nurses working rotational shift work schedules compared to nurses working daytime only, suggesting a role of circadian rhythm misalignment and sleep deprivation in the nightmares’ origin (07).

The lifetime prevalence rate of sleep paralysis in the general population is approximately 8%, 28% among students, and 32% among psychiatric patients (44).

Sleep paralysis occurs more in women than men and in the supine position when sleeping.

Some authors report a slightly higher lifetime prevalence in non-Caucasians compared to Caucasian groups (41; 01) and in those who had at least one alcoholic drink the previous month (44).

Prevention

Withdrawal from therapy with REM suppressant medications (eg, clonidine, antidepressants, or anxiolytic agents) can result in REM sleep rebound, vivid dreaming, and nightmares.

REM sleep behavior disorder observed in patients on antidepressant treatment was initially classified as “medication-induced secondary REM sleep behavior disorder” (39). However, later studies showed that cessation of antidepressant treatments did not resolve the REM sleep behavior disorder, considering the development of the disorder with antidepressants as an early sign of an underlying neurodegenerative disease.

The genetic backgrounds of REM sleep behavior disorder, Parkinson disease, and Lewy body dementia only partially overlap, and larger REM sleep behavior disorder studies will be required to better elucidate the genetic background of the disorder. The lysosomal pathway, and more specifically the GBA pathway, could be a crucial target for therapeutic development targeting REM sleep behavior disorder (22).

The primary prevention of nightmares and sleep paralysis is based on reducing stress, improving sleep hygiene, ensuring regular and adequate sleep routines, and avoiding sleep loss or deprivation and cognitive-impairing substances (46). In individuals with events as a symptom of another sleep disorder, such as obstructive sleep apnea, parasomnia disappears after treatment of the primary sleep disorder.

Studies documented that more than 60% of nightmare sufferers had never discussed nightmares with a clinician; therefore, it may be assumed that they are going without adequate nightmare treatment. Given the clinical relevance of nightmares, it is necessary to improve the identification and treatment of nightmare disorder, recommending that questions about nightmares should be included in taking a sleep history and that patients should be offered an effective treatment (33).

Differential diagnosis

Confusing conditions

The differential diagnosis of parasomnias depends largely on the symptoms and signs associated with the particular disorder. Evaluation requires special emphasis on a detailed description of the nocturnal events, including age at onset, the frequency of the episodes during the night, the timing, the presence of stereotypic movements, the response to intervention, and the recall of the event. Conditions associated with nocturnal pain may be a factor, particularly in infants or developmentally disabled individuals who cannot describe their symptoms. The primary differential features can be found in Table 1.

Table 1. Differences Between REM Sleep Parasomnias Features

Nightmares and nightmare disorder must be distinguished from REM sleep behavior disorder, sleep terrors, hypnagogic hallucinations with or without sleep paralysis, and nocturnal panic attacks. Unlike patients with REM sleep behavior disorder, patients with nightmare disorder may vocalize or move minimally during their nightmares, but complex motor behaviors paralleling dream content are usually lacking. In addition, patients with nightmare disorder exhibit physiological REM sleep muscle atonia during polysomnography. Sleep terrors emerge from stage 3 NREM sleep with shouting and high autonomic changes. In contrast to sleep terror, in nightmares, no confusion or disorientation is present, and the highly disturbing dream content frequently contrasts strikingly with relatively minor autonomic activation (except for the increase of autonomic tone before the awakenings) and no acting out of the nightmare (06). Hallucinations and sleep paralysis may be described as “nightmares,” but they specifically occur at sleep onset and offset, and the paralysis affects the whole body. Nocturnal panic attacks are not associated with detailed mental imagery. Severe sleep apnea may be associated with disagreeable sleep-associated perceptions or images that resolve with the apnea treatment (04).

Sleep paralysis should be differentiated from epilepsy, and this can be achieved by performing vPSG or video-EEG during the attack (46). Concerning the possibly related hallucinations, their content can be distinguished from other sleep disorders as consisting of an emotionally loaded imagination set against an existing background as one part of a perceived scene (06).

REM sleep behavior disorder needs to be distinguished from disorders of arousal. In contrast to REM sleep behavior disorder, sleepwalking and night terrors are more frequent in children and rarely appear de novo in middle-aged or elderly subjects. Confusion and amnesia for the episodes, which are common features of NREM parasomnias, are not seen in patients with REM sleep behavior disorder (04). Dream-enacting behaviors could also appear in severe obstructive sleep apnea, and nocturnal epileptic seizures may also mimic REM sleep behavior disorder. In both cases, polysomnography will be mandatory to make the diagnosis (46; 06).

Diagnostic workup

The diagnostic workup is highly contingent on the type and frequency of symptoms. Many parasomnias can be diagnosed based on the history, including a clear description of the events from witness and physical examination. In general, one can differentiate parasomnias by looking for key distinguishing features. Yet the clinician should distinguish between a “benign” parasomnia and a nocturnal event that requires further investigation. Patients should be considered for polysomnographic evaluation if the presentation is atypical for a parasomnia or if:

Sleep laboratory evaluations may include one or two nights of recording in a laboratory with personnel experienced in studying patients with parasomnias or nocturnal epileptic seizures. Simultaneous polysomnographic-audio-video monitoring is essential for such recordings, often with additional physiological measures beyond the minimum required for standard polysomnography (31). Prompting the patient to make audio-video recordings at home may facilitate the diagnosis, often adding details missed in verbal descriptions given by relatives. Patients should be considered for video-EEG monitoring if the events are stereotyped or repetitive, frequently occur (minimum of one event per week), or have not responded to medication trials, and the history is suggestive of potentially epileptic events (31). Obstructive sleep apnea that requires CPAP may reduce the diagnostic accuracy for REM sleep behavior disorder by a video polysomnogram. False-negative results were probably due to frequent electromyographic artifacts or severe sleep disruption from apneic events during REM sleep (23).

Overnight polysomnography is not routinely used to assess nightmare disorder but may be appropriately performed to exclude other parasomnias or sleep-disordered breathing. Sleep recordings during nightmares occasionally show abrupt awakenings from REM sleep preceded by accelerated heart and respiratory rates.

Sleep paralysis should be considered by clinicians when diagnosing sleep disorders, especially in narcolepsy and those exhibiting insomnia symptoms (10). Sleep paralysis should be assessed more frequently in psychiatric patients, particularly those presenting with posttraumatic stress disorder and anxiety disorders. In patients who experience severe episodes of sleep paralysis, it is necessary to consider the patient's mental and physical health and the quality of sleep as possible sleep-paralysis-related factors (10).

Video-polysomnography is essential for diagnosing REM sleep behavior disorder (01; 47). Prodromal REM sleep behavior disorder is a stage in which symptoms and signs of evolving REM sleep behavior disorder are present but do not yet meet the established diagnostic criteria for REM sleep behavior disorder. However, the boundary between prodromal and definite REM sleep behavior disorder is still unclear, as pointed out by Cesari and colleagues (08). Actigraphy has also been proposed as a reliable screening instrument for REM sleep behavior disorder and is potentially useful in the general population (45). Automatic methods based on artificial intelligence may also significantly contribute to future advancements in the field of REM sleep behavior disorder.

Management

In REM sleep behavior disorder, the primary management goal is to prevent sleep-related injuries to patients and their bed partners. The first step is to propose environmental modifications by controlling bedroom safety and avoiding drugs that may potentially cause or precipitate REM sleep behavior disorder, such as most classes of antidepressants (44). The AASM suggests that clinicians use clonazepam or immediate-release melatonin to treat isolated or secondary REM sleep behavior disorder due to medical conditions in adults (19). Clonazepam and melatonin are clinically assumed to majorly modify or eliminate REM sleep behavior disorder in nearly all patients, although there is an urgent need to test the magnitude of this treatment effect. Finally, pharmacological treatment with clonazepam must always be personalized according to the type of patient, the risk of addiction, and the concomitant presence of respiratory disorders (37).

The AASM suggests that clinicians use transdermal rivastigmine for treating isolated REM sleep behavior disorder in adults with mild cognitive impairment and for the treatment of secondary REM sleep behavior disorder due to medical condition (Parkinson disease) and not use deep brain stimulation for the treatment of secondary REM sleep behavior disorder due to medical condition in adults (19).

In a single-center, randomized, double-blind placebo-controlled crossover trial in a selected population of 18 patients with Parkinson disease and REM sleep behavior disorder, 50 mg of 5-HTP daily improved sleep stability and contributed to ameliorating patients' global sleep quality (28).

Currently, no treatment is available that can modify the disease course of REM sleep behavior disorder or, at least, slow down the neurodegenerative process underlying phenoconversion (36).

Patients with other underlying sleep disorders, such as obstructive sleep apnea or periodic limb movements, should have these disorders appropriately treated to decrease the potential for sleep disruption (19).

Recurrent nightmares may also be a deleterious effect of various drugs such as antidepressants, antihypertensives (beta blockers, α-adrenergic receptor agonists, enalapril, losartan, verapamil), dopamine receptor agonists, cholinesterase blockers (donepezil, rivastigmine, tacrine), varenicline (a nicotinic acetylcholine blocker), and ganciclovir. The abrupt withdrawal of REM sleep-suppressive agents (antidepressants, benzodiazepine, barbiturate, ethanol) or the end-of-night REM sleep rebound after using short-acting hypnotics such as zolpidem can promote nightmares (04). The best-established treatment of idiopathic nightmare disorder is image rehearsal therapy, whereas systematic desensitization and progressive deep muscle relaxation training are suggested. There is lower-grade evidence for using lucid dreaming therapy and self-exposure therapy. Prazosin is useful for treating posttraumatic stress disorder-associated nightmares, whereas clonidine’s benefit is less clear (55). Several drugs (trazodone, atypical antipsychotic medications, topiramate, low-dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants) and behavioral therapies (relaxation, hypnosis, eye movement desensitization) lack documented efficacy in controlled trials (04).

Sleep paralysis should be considered a disorder only if it results in clinically significant distress, including bedtime anxiety or difficulty initiating sleep. Explanation and reassurance usually are sufficient to address the patient’s concerns. Sleep hygiene, instructions on various sleep hygiene techniques (eg, going to sleep and waking up at the same time each day and no use of alcohol or caffeine before bedtime), and specific instructions (eg, avoiding sleeping in a supine or prone position) may serve as preventative measures. Cognitive behavioral therapy could be helpful (42). Tricyclic antidepressants and selective serotonin reuptake inhibitors are commonly used to treat sleep paralysis, often in the context of narcolepsy, but no adequately reported studies of pharmacologic interventions are available. The evidence of the effectiveness of sodium oxybate in treating sleep paralysis was mixed and based on lower-quality evidence (10).

Special considerations

Pregnancy

Sleep paralysis could increase later in pregnancy (17).