Clinical manifestations

Presentation and course

According to the International Classification of Sleep Disorders (ICSD-3) 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 enuresis, parasomnia unspecified, parasomnia due to drug or substance, and parasomnia due to medical conditions; and (4) isolated symptoms and normal variants including sleep talking (01).

Nightmares are common sleep-related parasomnias arising from REM sleep, associated with a frightening dream of 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 consist in the occurrence of extended, extremely dysphoric, and well-remembered dreams that usually involve threats to survival, security, or physical integrity. Nightmares 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) 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”) (61). 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 the diaphragm, external eye muscles, and stapedius (61). 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). 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) (13). The episodes last from a few seconds to several minutes disappearing spontaneously or upon 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) the diagnostic criteria for recurrent isolated sleep paralysis, all of which must be met, include: (1) recurrent inability to move the trunk and all of the limbs at sleep onset or upon 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 sleep disorder (especially narcolepsy), mental disorder, medical condition, 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 (54). 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 (48; 19).

During the episodes, patients can be accidentally violent and bed partners are frequently unintentionally injured (54; 01). REM sleep behavior disorder is more common in the second half of the sleep period, when REM sleep episodes tend to last longer. Almost half of the patients are not aware of their dream-enactment behaviors, with 70% of them reporting good sleep quality. In most of these cases bed partners are essential to convince patients to seek medical help (19). REM sleep behavior disorder can be isolated or associated with neurologic disorders, mostly a-synucleinopathies (28).

Sleep talking may occur during REM or NREM sleep and can be idiopathic or associated with other parasomnias.

Prognosis and complications

Parasomnias may be associated with serious complications or predicate the potential of other neurologic impairment, such as REM sleep behavior disorder, which may precede the symptoms of parkinsonian syndromes such as multiple system atrophy or Lewy body dementia by years (50; 52; 28; 41). In a large multicenter cohort of idiopathic REM sleep behavior disorder the overall conversion rate from idiopathic REM sleep behavior disorder to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after a 12-year follow-up (53). The rate of phenoconversion was significantly increased with abnormal quantitative motor testing, objective motor examination, olfactory deficit, mild cognitive impairment, erectile dysfunction, an abnormal DAT scan, color vision abnormalities, constipation, and age. Parkinson disease patients with REM sleep behavior disorder are likely to have more severe neuropsychological deficits, 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 cerebellum and visual-motor relevant cortex) than Parkinson disease patients without REM sleep behavior disorder (04; 18; 49; 17; 36).

As a complication of REM sleep behavior disorder, the patient or bed partner may be unintentionally injured (39).

In addition to being a well-known symptom of posttraumatic stress disorder, having nightmares before a trauma has been shown to increase one’s risk of developing posttraumatic stress disorder (46; 02). Moreover, as dream enactment behavior of nightmares is a phenomenon demonstrated in patients with posttraumatic stress disorder, the definition of a trauma-associated sleep disorder, which shares diagnostic criteria with REM sleep behavior disorder, has been proposed (07). Nightmares are also of special importance in a clinical context because nightmares are an independent predictor of suicidal ideation and suicide (56).

Sleep paralysis may be part of a dissociative symptomatology (14).

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 contents, 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 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

Frequent nightmares in children are associated with child-, sleep-, and family-related factors such as insomnia and parental predisposition (35). Nightmares can occur as a primary complaint or in the context of other sleep (eg, insomnia), psychiatric (anxiety, depression, schizophrenia), or neurologic diseases (eg, epilepsy) or medication/substances 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 (34). 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).

The causes of sleep paralysis are likely to be multifactorial (12). No significant effects of age and sex have been found (13). Exploring genetic associations between sleep paralysis and a number of circadian-expressed single nucleotide polymorphisms, the authors found a moderate genetic influence on sleep paralysis (53%) in 862 monozygotic and dizygotic twins and siblings (12). Many experiences of threatening/traumatic events also appear to be related to sleep paralysis. 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. It does appear, however, that episodes are linked with sleep disruption and are particularly associated with SOREMPs (13). 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 the inhibition of motor neurons during REM sleep, thus, contributing to the 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 (13).

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 the generation of this REM attribute.

This disorder can be produced in animals by selective brainstem lesions. Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus mimics human REM sleep behavior disorder (63). A substantial proportion of patients with REM sleep behavior disorder have CNS disorders such as Parkinson disease, multiple system atrophy, or Lewy body disease. Some patients who are neurologically normal at the time of diagnosis of REM sleep behavior disorder could later develop parkinsonism (50; 52; 53; 27). Relatives of patients with idiopathic REM sleep behavior disorder carry a higher risk of alpha-synucleinopathy, suggesting a possible familial aggregation and staging pathology of alpha-synucleinopathy (37). Although no association between rare heterozygous genetic variants of parkinsonism were found in rapid eye movement sleep behavior disorder patients (44), polygenic disease burden may play a role (62). A rigorous in-depth proteomic analysis to identify circulating biomarker signatures for idiopathic REM sleep behavior disorder revealed a significant reduction in serum levels of dopamine β-hydroxylase and vitamin D binding protein, consistent with alterations in the norepinephrinergic and dopaminergic systems, respectively. Additional altered protein profiles indicated that immunity, inflammation, complement, and coagulation also play a role in REM sleep behavior disorder pathophysiology (42). REM sleep behavior disorder can also be associated with autoimmune diseases (eg, anti-IgLON5 disease) or with other neurologic disorders such as narcolepsy (61). REM sleep behavior disorder linked to narcolepsy has been insufficiently characterized, leaving a number of 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 inhibitor, nonoccupational exposure to pesticides, and benzodiazepine use were associated with higher likelihood of having probable REM sleep behavior disorder (38; 64).

Epidemiology

The incidence of parasomnias is highly variable, depending on the particular disorder (08). Nightmares are frequent, occurring in an estimated 6.6% of the general population (47) and in 16% of a 700-patient cohort with sleep disorders (32). 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 (57). In a study, nightmares were reported by nurses working rotational shift work schedules compared to nurses working daytime only. This suggests that circadian rhythm misalignment and sleep deprivation caused by such shift schedules could play a role in the nightmares’ origin (09).

Lifetime prevalence rate of sleep paralysis in the general population is approximately 8%, though individual study estimates greatly vary from 2% to 60% with a slightly higher lifetime prevalence in non-Caucasian compared to Caucasian groups (58; 01).

REM sleep behavior disorder is more prevalent in males after the age of 50: a 0.5% prevalence is estimated in the elderly population (01; 11). 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 (25). REM sleep behavior disorder remains relatively infrequent during childhood (31).

Prevention

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 (61). In individuals who have 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 (45).

REM sleep behavior disorder observed in patients on antidepressant treatment was initially classified as “medication-induced secondary REM sleep behavior disorder” (55). However, later studies showed that cessation of antidepressant treatments did not resolve the REM sleep behavior disorder. The development of REM sleep behavior disorder with antidepressants is now seen as an early sign of an underlying neurodegenerative disease (52).

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

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 patients such as infants or retarded individuals, who cannot describe their symptoms. Main differential features can be found in Table 1.

Table 1. Differences Between REM Sleep Parasomnias Features

Nightmares and nightmare disorder need to be distinguished from REM sleep behavior disorder, sleep terrors, hypnagogic hallucinations with or without sleep paralysis, and nocturnal panic attacks. Differently from REM sleep behavior disorder, patients may vocalize or move minimally during their nightmares but complex motor behaviors paralleling dream content usually are 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 treatment of apnea (05).

Sleep paralysis needs to be differentiated from epilepsy and this can be achieved by performing vPSG or video-EEG during the attack (23; 61). Concerning the possibly related hallucinations, their content can be distinguished from other sleep disorders as consisting of an emotionally loaded imaginary 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 (05). 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 (61; 06).

Diagnostic workup

The diagnostic workup is highly contingent on the type and frequency of symptoms. Many parasomnias can be diagnosed on the basis of 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 needs to 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 (33; 20). Prompting the patient to make audio-video recordings at home may facilitate the diagnosis, often adding details that are missed in verbal descriptions given by relatives. Patients should be considered for video-EEG monitoring if the events are stereotyped or repetitive, occur frequently (minimum of one event per week), or have not responded to medication trials, and the history is suggestive of potentially epileptic events (43).

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 symptoms of insomnia (13). 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 (13).

Video-polysomnography is essential for diagnosing REM sleep behavior disorder. 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 (10). Actigraphy has also been proposed as a reliable screening instrument for REM sleep behavior disorder and is potentially useful in the general population (60). Automatic methods based on artificial intelligence may also significantly contribute to advancements in the field of REM sleep behavior disorder in the future.

Management

Behavioral and cognitive-behavioral treatments and mindfulness-based stress reduction have been employed successfully in parasomnias (22; 15). Stress management, counseling, and avoidance of cognitively impairing medications may improve the frequency of the events. Patients with the potential for injuring themselves or their families need to be counseled in methods to reduce risk of injury (protective material across windows, lack of access to potential weapons, etc.) (30). 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. Some patients require medication therapy for their nocturnal events.

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 (05). 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 the treatment of posttraumatic stress disorder-associated nightmares whereas clonidine’s benefit is less clear (65). 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 trial (05).

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 (59). 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 effectiveness of sodium oxybate in treating sleep paralysis was mixed and based on lower quality evidence (13).

In REM sleep behavior disorder patients, the primary management goal is to prevent sleep-related injuries to self and bed partner. The first step is to propose environmental modifications by controlling bedroom safety and avoid drugs that may potentially cause or precipitate REM sleep behavior disorder, such as most classes of antidepressants (29). Clonazepam is considered the treatment of choice for REM sleep behavior disorder, with reported success rates up to 90% (21). Melatonin (3 to 9 mg) has been proposed as an additional or alternative therapy (40). However, large placebo-controlled trials are lacking (24).

Special considerations

Pregnancy

Parasomnia events appear to decrease during pregnancy. The events had the greatest decrease in primipara women. Compared to the prepregnant period, sleepwalking decreased by over 40% in the second trimester.

Sleep paralysis could increase in the later part of pregnancy (26).