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Update On Non-Pharmacological Interventions in Parasomnias: Postgraduate Medicine
Update On Non-Pharmacological Interventions in Parasomnias: Postgraduate Medicine
To cite this article: Maria Ntafouli, Andrea Galbiati, Mary Gazea, Claudio LA Bassetti & Panagiotis
Bargiotas (2019): Update on non-pharmacological interventions in parasomnias, Postgraduate
Medicine, DOI: 10.1080/00325481.2019.1697119
Article views: 7
Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group
DOI: 10.1080/00325481.2019.1697119
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Bargiotas1,5
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Sleep Wake Epilepsy Center and Dept. of Neurology, Inselspital University Hospital,
University of Bern, Bern, Switzerland
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"Vita-Salute" San Raffaele University, Faculty of Psychology, Milan, Italy; IRCCS San
Raffaele Scientific Institute, Department of Clinical Neurosciences, Neurology - Sleep
Disorders Center, Milan, Italy.
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3
Centre for experimental Neurology, Dept. of Neurology, Inselspital University Hospital,
University of Bern, Bern, Switzerland
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4
Department of Biomedical Research (DBMR), Inselspital University Hospital, University of
Bern, Bern, Switzerland
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Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
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Corresponding Author:
Dr. med. Panagiotis Bargiotas
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Department of Neurology
Medical School, University of Cyprus
Nicosia, Cyprus
Email: bargiotas.panagiotis@ucy.ac.cy
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Abstract
Parasomnias are abnormal behaviors that occur during the sleep and can be associated, in
particular during adulthood, with impaired sleep quality, daytime dysfunction and
occasionally with violent and harmful nocturnal behaviors. In these cases, therapies are often
considered. Pharmacological treatments are invasive and often have limited efficacy.
Therefore, behavioral approaches remain an important treatment option for several types of
parasomnias. However, the evidence-based approaches are limited. In the current review, we
highlight results from various non-pharmacological techniques on different types of
parasomnias and provide a glimpse into the future of non-pharmacological treatments in this
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field.
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Introduction
The term parasomnia originates from the Greek word “para” (meaning “alongside of”) and
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the Latin word “somnus” (meaning “sleep”).
Parasomnias are defined as abnormal behaviors that occur during the sleep period, during
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specific sleep stages or during sleep-wake transitions [1, 2]. They are usually classified by the
sleep stage during which they occur [2] into rapid eye movements (REM) parasomnias, non-
REM (NREM) parasomnias and other parasomnias [3]. NREM parasomnias include disorders
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nightmare disorder, recurrent isolated sleep paralysis, and REM sleep behavior disorder
(RBD) [4]. Sleep-related hallucinations, and exploding head syndrome are grouped to other
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parasomnias and their association to specific sleep stage remains unclear [5]. While
parasomnias are more common in childhood, they can persist or even occur de novo during
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adulthood [6]. The neurobiological mechanisms that underlie parasomnias are not fully
understood but parasomnias are believed to be the consequence of a dissociation between
wakefulness, NREM or REM sleep with behaviors characteristic of one state succeeding the
other [7].
Although current research focuses mainly on the nighttime symptoms, impaired daytime
functioning is often reported in subjects with parasomnias. Commonly, fatigue, sleepiness and
neuropsychiatric symptoms such as anxiety, depression, obsessive compulsive symptoms,
phobic complaints and cognitive deficits have been reported [6, 8, 9].
Pharmacological agents have been reported for the treatment of parasomnias. Their efficacy is
related to the type of parasomnia being treated. Antidepressants, especially those that affect
the body's level of serotonin, have some efficacy in the treatment of sleep terrors, considering
the serotonergic model that has been suggested for this parasomnia. In addition,
benzodiazepines (mainly clonazepam and diazepam), anticholinergic and dopaminergic (such
as pramipexole) agents, calcium blockers and stimulants (such as gamma-Hydroxybutyric
acid) yielded positive responses in some types of parasomnias [2, 10-12].
Pharmacotherapy is not always effective in NREM parasomnias (no improvement in one third
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of patients), while medications (i.e. antidepressants) can sometimes cause or worsen
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parasomnia symptoms[13].
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Due to these limitations of pharmacotherapies, behavioral therapies are often considered to be
the first-line treatment for parasomnias, whenever treatment is needed. Psychotherapy has
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been reported to be beneficial for parasomnias, mainly by reducing classical trigger factors of
parasomnias such as stress and anxiety. In addition, psychotherapy aims to increase the
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awareness for emotional conflicts over the individuals’ own behaviors and judgments, which
often provokes important dysfunctional behavior reinforcement patterns that are possibly
related to parasomnias episodes. However, the literature on cognitive–behavioral
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interventions for parasomnias consists mainly from case reports and only few controlled
trials, with a statistically relevant sample size. In the current review, we highlight results from
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NREM Parasomnias
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Sleepwalking (SW)
Sleepwalking or somnambulism is defined by the American Academy of Sleep Medicine as a
series of complex behaviors that are usually initiated during arousals from sleep and
culminate in walking around with an altered state of consciousness and impaired judgment
[4]. The sleepwalking episode typically starts during slow-wave sleep (SWS) and thus these
episodes are most often seen during the first third of the night when SWS is more abundant
[14]. According to the third edition of the International Classification of Sleep Disorders
(ICSD 3), the diagnosis of SW is based only on clinical criteria, however, several
neurophysiological biomarkers might have supportive role in the diagnosis [15].
Data from controlled studies on behavioral treatments for sleepwalkers is limited. Standard
management strategies include scheduled awaking, safety measures, reassurance and
education of sleep hygiene [16-18].
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children assessed the use of scheduled awaking in different age groups and reported a relevant
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decrease in the frequency of sleepwalking episodes over time [17]. Despite some questions
raised, the short application of the technique does not seem to be associated with the
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development of insomnia in treated subjects with Arousal Disorders [19].
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A wide range of interventions is currently used to prevent sleepwalkers from putting
themselves or others in danger, a set of behavioral techniques referred to as safety measures.
Safety measures are important for protection of the sleepwalkers and their bed partners and
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include, among others, the removal of potential dangerous and sharp objects from the room
(i.e. mirrors), locking windows and protection from fallings [20].
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CBT and MBSR effectively reduced the parasomnia symptoms (mainly the frequency of
episodes) in 80% of the treated subjects [23].
In summary, CBT might represent a promising avenue for the treatment of SW parasomnia
and further large, controlled studies are required to fully elucidate its efficacy in this field.
Sleep terrors
Sleep terrors (ST) occur mainly during SWS. ST episodes last from 30 sec to 5 min, and the
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individual is amnesic for the events during the episode [3, 24, 25]. The individuals typically
feel confused and stressed. Interestingly, there is an association between sleep terrors and
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psychiatric disorders. Patients tend to manifest anxiety and depressive symptoms [26]. The
etiopathogenesis of ST remains unclear. However, similarly to SW, disrupted and fractioned
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SWS is a common feature in ST as well [15].
Several behavioral techniques have been reported in individuals with ST. One important step
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for the management of ST is the reassurance, which is a behavioral method that counteracts
fears. The technique has been reported to be efficacious especially among children and
adolescents with ST [18, 27].
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Confirming anecdotal evidence, Attarian et al., [27] suggested behavioral techniques that
focus on creating a safe sleep environment could be very helpful in the management of ST.
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Measures may include, among others, minimizing the risk of injury, by sleeping on the
ground floor and removing obstructions in the bedroom.
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Scheduled awakening has been reported in patients with ST as well and seems to be
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efficacious. It is important for the parents to keep firstly a sleep log typically for two weeks,
in order to note accurately the time of the ST events [19]. Subjects with ST should be then
awakened 15 minutes prior to the expected ST event [14, 28].
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Relaxation techniques have been also applied, mainly in children with ST. More recently, a
case study reported the beneficial effect of relaxation techniques in a 3 years old girl with co-
exist acute leukemia and ST by reducing anxiety related to maternal separation and medical
procedures [29]. In addition, regular control and advice on sleep hygiene was associated with
improved ST severity in 15% of patients [13].
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the first third up to the first half of the sleep period [31]. Typically, CA are brief events that,
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apart from confusion, may include disorientation, sleeptalking, and simple motor behaviors.
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CA is often associated with SW and ST and other parasomnias (i.e. sleep-related sexual
behaviors).
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To the best of our knowledge, there are no controlled studies on behavioral/non-
pharmacological treatment on CA. In children, reassurance is often suggested as the first-line
approach in CA [18].
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Furthermore, an additional behavioral technique is safety measures, where parents or family
are instructed to overtake important precautions, i.e., placing mattresses on the floor, securing
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windows and outside doors, covering windows with heavy curtains, and using alarm systems
and bells to alert parents should the child leave the room [18]. Furthermore, improving the
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sleep environment is important, in order to feel safe. Adult subjects with CA are counselled
not to co-sleep with children, because even a single event might expose children to significant
danger with serious consequences.
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Anecdotal evidence suggests that scheduled awakening can be effective in the management
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and possibly in the prevention of CA as well [14, 31]. Scheduled awakenings may be
ineffective in children or adults who do not present arousal parasomnias frequently or in a
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In many cases, CA co-occur with other sleep-related disorder, such as sleep-related breathing
disorders, circadian rhythm sleep disorders (i.e. shift work), narcolepsy, and encephalopathies
[31]. Treating co-morbid sleep disorders may effectively decrease CA episodes as well [33].
In addition, avoiding centrally acting medications, stress management, taking appropriate
precautions and applying measures to maximize sleep stability, together with sleep education
(sleep hygiene, preventing sleep deprivation), are often considered in the management of CA
[13].
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the recent years an increasing number of studies and case reports reported efficacious
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behavioral strategies, often in combinations, to manage sleep enuresis. Several studies and
case reports highlighted the efficacy of behavioral treatments against bedwetting in children
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and young people. Simple and complex interventions have been reported. Simple
interventions included rewarding for dry nights, “lifting” (the caregiver lift the subject/child
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from their bed while they sleep and walking the child to the bathroom to pass urine, without
necessarily waking the child) and bladder training (which is based on retention control
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training and fluid restriction). Even, the use of a diary, in which the patients note dry and wet
nights has shown to be useful in reducing frequency of SE in 15%-20% of children with SE
[35].
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More complex interventions, such as enuresis alarm therapy and psychotherapy, have been
also suggested for SE and reported by few studies. Enuresis alarm (EA) therapy consist of an
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alarm system which is triggered by micturition [37] and focuses on improving arousal in
response to a sensation of a full bladder. Mowrer et al. [38] reported the use of enuresis
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alarms in bed-based condition in children. There are several types of enuresis alarms
available: pad-and-bell alarms where the sensor pad is positioned under a draw sheet beneath
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the child in bed [35]. Cognitive therapy also appeared to be more effective than rewards in a
small trial [39].
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In a recent meta-analysis, it appears that simple behavioral interventions are less effective
compared to more complex interventions, such as enuresis alarm therapy, and
pharmacotherapy[40]. Apart from this, EA seems to be an effective long-term intervention
[35].
Sleep-Related Eating Disorder (SRED) is defined by the partial arousals from sleep time to
consume food and occurs usually within the first 3 hours of falling asleep [4]. The episodes
are characterized by rapid ingestion of food, specifically food high in calories [41]. The level
of consciousness during the episodes, the time of nocturnal eating and the presence of eating
disorders as comorbidities are crucial for the discrimination between SRED and night eating
syndrome (NES), a syndrome that is characterized by conscious eating during the night and it
is not a parasomnia [41]. Data on pharmacotherapy [42] and behavioral treatment for SRED
are very limited. Hypnotherapy, psychotherapy and various behavioral techniques (safe sleep
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environment) did not show constant efficacy against SRED [43]. Recent data suggest that
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bright light therapy can be beneficial for disordered-eating behavior [44]. However, placebo-
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controlled studies, assessing symptom change frequently and the longer-term efficacy of
bright light therapy against SRED, are needed.
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REM Parasomnias
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Nightmare Disorder
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The essential feature of a nightmare disorder is the repeated occurrence of frightening dreams
that lead to awakening [45]. Nightmares can be idiopathic or associated with other disorders
including posttraumatic stress disorder (PTSD), substance abuse, anxiety disorder, borderline
personality and schizophrenia spectrum disorders [46].
Various psychological treatments for nightmare disorder or chronic nightmares in adults have
been suggested, including the imaginal confrontation with nightmare contents (ICNC),
relaxation, imagery rescripting and rehearsal (IRR), or awakening while having a nightmare.
For chronic nightmares, Imagery Rehearsal Therapy (IRT), Exposure Relaxation and
Rescription Therapy (ERRT), Imagery Rescripting and Exposure Therapy (IRET), self-
exposure, lucid dreaming treatment (LDT) and Eye Movement Desensitization Reprocessing
therapy have been reported [45, 46].
Image Rehearsal Therapy (IRT) is CBT technique aiming to transform a nightmare into a
positive scenario. This technique helps the patient to displace the previous content as soon as
the same dream happens again [47]. Patients are suggested to repeat the technique every day
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for 10-20’. IRT had positive impact in 168 women with moderate to severe PTSD by
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improving sleep quality and reducing the levels of post-traumatic stress 3 and 6 months after
screening.
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Another study proposed IRT as part of CBT treatment in patients with chronic nightmares and
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found that at 3-month and 30-month follow-up, the IRT group had a 72% reduction in
nightmare frequency (7.2/month to 2.0/month) compared to a 42% reduction in frequency
(9.4/month to 5.0/month) noted in the recording-only group [48]. It is noted that only the
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rehearsal group had less total distress compared to other groups.
behavioral and cognitive aspects related to nightmares and includes psychoeducation, such as
sleep hygiene training, progressive muscle relaxation therapy, exposure and re-scripting
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techniques [46]. It differs with IRT only in the exposure part of therapy [46]. Kunze et al. [49]
performed imagery IRT and ERRT in two patients with nightmare disorder and reported
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al. [50] found that 84% of 27 participants treated by manualized CBT reported an absence of
nightmares. Lancee et al. [51] found that IRT and exposure appeared equally effective in
ameliorating nightmare complaints.
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Self-exposure Therapy is a successful CBT technique aiming to help the patient to confront
fears stressful events. Patients are asked to create a list of events/dreams that are associated
with anxiety and stress. The therapy involves exposing the patient gradually to the anxiety
source, which might be a daytime event or a nightmare, without exposing the patient to
danger [46].
In 170 adults with primary nightmares, the application of self-exposure therapy was
significantly more effective against nightmares compared to placebo or no intervention [52].
Grandi et al. [53] reported a significant improvement in 10 adults with Nightmare disorder
who followed a self-exposure manual and were asked to follow its instructions for 4 weeks in
addition to the continuous therapeutic session with the therapist.
Lucid dreaming treatment (LDT) teaches nightmare sufferers to become lucid in their
nightmare through homework during the day. This technique indicated effectiveness in
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decreasing frequency of chronic nightmares [54]. Spoormaker and van den Bout [54], found
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that in 23 nightmare sufferers that received LDT, the frequency of nightmares markedly
decreased after 12 months follow up.
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Eye Movement Desensitization Reprocessing (EMDR) therapy involves alternated bilateral
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sensorial stimulation at the same time that the traumatic event is being processed [55].
Recently, Raboni et al. showed that EMDR therapy improved depression, anxiety and sleep
disturbances which are often associated with recurrent nightmares, in 13 patients with
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posttraumatic stress disorder (PTSD) [56, 57].
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behavior arising from REM sleep which is accompanied by (oft frightening) vivid dreaming
[58-60]. REM sleep phase is typically characterized by random, rapid movement of the eyes,
REM atonia (low/missing muscle tone in the skeletal muscles), and the propensity of the
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sleeper to dream vividly. In RBD, REM atonia is disturbed, which in combination with vivid
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dreaming might lead the patient to “act out his/her dreams” or dream enactment behaviour
(DEB), exhibiting a variety of motor activities. RBD affects less than 1% of the general adult
population and 2-8% of the older adult population [61, 62]. However, it can be commonly
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found in the context of neurodegenerative disorders such as Parkinson’s disease and dementia
with Lewy body [63-66], predating their presentation by many years [67], but also in
narcolepsy [68, 69] and rarely also in the context of a parasomnia overlap disorder and its
extreme form of a wake-sleep state breakdown (status dissociatus) [70-72]. Dreams can be
violent in subjects with RBD and therefore, RBD represents a complex and potentially
dangerous condition with increased risk of experiencing self-injurious behavior [73, 74].
Types of injury ranged from light to severe, such as lacerations to fractures and subdural
hematomas [75-79].
To our knowledge, there are no controlled studies on behavioral treatment for RBD. Non-
pharmacological treatments focus mainly on:
1) avoiding and treating trigger factors such sleep deprivation and sleep disorders including
insomnia and sleep-disordered breathing and 2) securing patients’ and bed partner’s safety by
removing potentially harmful objects out of the bedroom, placing the bed far from windows
and separating bed partners [2]. Sometimes drugs can be exacerbating the problem, such as
antidepressants, monoamine oxidase inhibitors, and beta-blocker [80].
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The controlled environmental safety consists of prevention measures that aim to decrease
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RBD frequency and to educate subjects with RBD and their bed-partners to create a safe
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environment by removing potentially dangerous objectives from the room [1, 2, 73]. Howell
et al., suggested alarm therapy as an effective tool to prevent sleep-related injury (SRI) during
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DEB [81]. In this single case, authors reported that the use of a recorded voice message
during DEB, such as “Peter, you are having a dream, lay back down” could reduce the risk of
SRI [2, 81]. In another report, the use of a recorded message has been the most effective
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intervention in patients who failed to tolerate pharmacological medication [82].
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perseverates into wakefulness [4], resulting in the inability of the affected person to move or
speak during wakefulness. It is often accompanied by terrified hallucinations [4]. Some
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studies have pinpointed a genetic component of the disorder [83]. Epidemiological studies
and a recent meta-analysis have elucidated further risk factors for the development of ISP,
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such as insomnia symptoms, trauma, stress, anxiety and psychiatric disorders [84-86].
There are no published controlled studies for the treatment of ISP. Jalal et al. suggested a
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combination of cognitive behavioral techniques for the treatment of ISP [87]. This
combination consists of a focused-attention meditation and a muscle relaxation technique.
The model contains four components: a) reappraisal of the content of the ISP episode; b)
neuropsychological distancing; c) train to focused-attention meditation; d) muscle relaxation
techniques. This model aims mainly in identify the source of ISP [87]. A different case study
indicates that ISP occurrence can be decreased by reassurance and explanation of the
physiological basis of the patient`s experience [88]. Recent studies suggested that even simple
measures such as the change of sleeping positions (e.g., sleeping on the side instead of their
backs) and sleeping patterns (e.g., amount of time spent asleep), can prevent future ISP
episodes [85].
Sharpless et al. presented the first psychotherapeutic manual for ISP [89]. The manual
“Cognitive–Behavioral Therapy for Isolated Sleep Paralysisˮ is based on earlier experiences
of the authors with the treatment of ISP, validated insomnia treatments and an empirical
investigation into the ways how ISP sufferers attempt to both prevent and disrupt episodes.
This treatment includes specific sleep hygiene, relaxation techniques to be used during RISP
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episodes, in vivo episode disruption techniques, several strategies to cope with frightening
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hallucinations, cognitive techniques to cope with thoughts and imaginary rehearsal to deal
with RISP episodes. A CBT for isolated sleep paralysis manual now exists as a promising
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therapy, however systematic evidence for its magnitude of effectiveness is still missing from
literature [85].
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Other Parasomnias
behavioral treatment in patients with EHS is available. Education and reassurance could be
helpful in patients with EHS [91, 92], however further research is needed.
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Sleep-Related Hallucinations
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Sleep-related hallucinations are hallucinatory experiences, are vivid, often intense visual or
sensory experiences that happen during sleep or often during transition states [93]. The
sensory experiences would be auditory stimuli or a sense of movement. It is estimated that
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about 25-37% of people have reported hypnagogic hallucinations [94]. Occasionally sleep-
related hallucinations may be associated with episodes of sleep paralysis [94].
Data on behavioral treatment of hallucinations during sleep are very limited. The use of
sedative hypnotics or certain antidepressant and sleep deprivation can be hallucinogen and
therefore should be avoided in patients with recurrent sleep-related hallucinations. Hypnosis
has been applied for the treatment of hallucination in two patients with limited success [95].
Discussion
Treatment of parasomnias is not always necessary. However, it should be considered if
episodes of parasomnias are very frequent and include violent and harmful behaviors that
impose danger and/or psychological distress to the patients and the bed partners, or if they are
associated with undesirable consequences such as daytime dysfunction and neuropsychiatric
symptoms. Current treatment practice is typically based no “doctor’s choice” and depends on
the parasomnia type.
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Pharmacotherapy has shown moderate evidence for efficacy in this regard considering also
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potential side effects. Often long-term pharmacological treatments might be necessary since
parasomnias are considered to be chronic conditions, especially those occurring in adulthood.
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Even in cases where pharmacological treatments are effective, parasomnias might re-appear
after the termination of the pharmacological treatment, if triggers factors remain. Therefore,
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the use of cognitive and behavioral treatments for parasomnias represents an expanding
clinical practice, which, apart from being less invasive, it is often well accepted by patients
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and might probably offer a better solution towards long-term management of parasomnias. In
addition, this type of treatment implies that the patient has an active part in his own treatment.
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This can lead to a long-term benefit for the patient by learning how to recognize the signs of
the disorder and how to cope with it, ultimately improving quality of life.
The literature on cognitive and behavioral treatment of parasomnias is limited and includes
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mainly case reports or uncontrolled trials with a small sample size, usually addressing only
one type of parasomnia. Behavioral measures such as advice on improving sleep hygiene,
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safety measures and reassurance often represent an effective first line behavioral treatment
option regardless of the parasomnia type. Other techniques seem to be more applicable for
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specific types of parasomnias. The new stress reduction approach MBSR, a behavioral
program that has been used in several sleep disturbances, showed promising results in
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reducing the severity and frequency of episodes in patients with stress-associated parasomnias
such as sleepwalking, sleep terrors and confusional arousals but also in patients with REM
parasomnias, such as recurrent sleep paralysis. Similarly, enuresis alarm therapy seems to be
effective for sleep enuresis. For nightmare disorder, behavioral techniques such as Imagery
Rehearsal Therapy (IRT), Exposure Relaxation and Rescription Therapy (ERRT), Imagery
Rescripting and Exposure Therapy (IRET), and self-exposure, can be effective by reducing
the frequency of nightmares or by changing dream scenarios into more positive and
productive dramas. Furthermore, cognitive behavioral treatment (CBT) for insomnia (CBTi)
and cognitive behavioral treatment for stress and anxiety (CBTs-a) have been reported to be
an effective treatment options for several parasomnias, including sleepwalking, sleep terror,
nightmare disorders, recurrent sleep paralysis and others. CBT-i is already an established
therapy for insomnia, targeting its perpetuating factors and leading to decline of predisposing
and precipitating factors. Parasomnias manifest frequently in association with precipitating
and perpetuating factors such as stress, alcohol consumption, poor sleep hygiene or sleep loss.
However, to our knowledge, structured CBT protocols tailored to parasomnia disorders are
lacking.
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It should be mentioned that this review focused mainly on recent reports on non-
pharmacological therapies in parasomnias and a detailed systematic presentation of the
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literature was out of the review’s scope. Therefore, important studies on the field might be
missing.
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Conclusions
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In summary, a wide range of cognitive and behavioral therapies are available, and overall,
data indicate promising results of these therapies towards the improvement of parasomnias,
especially when precipitating and perpetuating factors are psychologically driven. However,
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reliable evidence for their efficacy is still missing. Therefore, well-designed randomized
controlled trials applying cognitive and behavioral techniques and appropriate control
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may help to recruit a large pool of patients with a wide variety of parasomnia types.
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Authors Disclosures
Maria Ntafouli, Andrea Galbiati, Claudio L. Bassetti and Panagiotis Bargiotas have nothing to
disclose
Mary Gazea has received a funding by the German Research Foundation (DFG, GA 2410/1-1
to M. G.)
The contents of the paper and the opinions expressed within are those of the authors, and it
was the decision of the authors to submit the manuscript for publication.
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Conflicts of Interest
The authors declare no conflict of interest regarding the publication of this paper
Acknowledgements
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We thank Dr. med. Pinelopi Anagnostopoulou for critical reading the manuscript
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education of sleep hygiene
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Psychological approach focused on Conway et al., 2011
emotional triggers
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CBTi, CBTs and MBSR Drakatos et al., 2018
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Sleep hygiene advice Drakatos et al., 2018
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Alarm Therapy Howell et al., 2011
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Isolated sleep Behavioral technique Jalal, 2016
paralysis Muscle-Relaxation (MR) Therapy
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Cognitive–Behavioral Therapy for Isolated Sharpless, B.A, 2016
Sleep Paralysis
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Reassurance Gangdev, 2004
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Conflicts of Interest
Authors Disclosures
Maria Ntafouli, Andrea Galbiati, Claudio L. Bassetti and Panagiotis Bargiotas have nothing to
disclose
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Mary Gazea has received a funding by the German Research Foundation (DFG, GA 2410/1-1
to M. G.)
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Acknowledgements
We thank Dr. med. Pinelopi Anagnostopoulou for critical reading the manuscript
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