Clinical manifestations

Presentation and course

Parasomnias are defined as abnormal behaviors, emotions, and autonomic nervous system activity emerging during NREM or REM sleep or emerging during wake-sleep or sleep-wake transitions (03). Parasomnias are classified by the sleep state in which they arise. Confusional arousals, sleep terrors, sleepwalking, sexual behaviors, and eating behaviors emerge as disordered arousals from deep NREM sleep (slow-wave sleep; N3 sleep) and, at times, from N2 sleep. Conversely, REM sleep behavior disorder is a parasomnia that occurs during REM sleep. NREM parasomnias are typified by amnestic, inappropriate behavior, typically without violence or dream enactment in children but with more variable and complex manifestations in adults, including dream enactment and aggressive or violent behaviors. REM sleep behavior disorder is characterized by dream enactment due to a lack of REM sleep atonia manifested by an elevation of EMG tone (ie, REM sleep without atonia) or increased phasic EMG twitching in REM sleep during polysomnographic recording (03).

Not uncommonly, patients with parasomnia may have an overlap of symptoms and report a combination of confusional arousals, sleep terrors, or sleepwalking behavior (presumably from NREM sleep) along with dream-enactment behavior (presumably from REM sleep). Polysomnographic evaluation may demonstrate that sleepwalking patients also have REM sleep without atonia and enhanced phasic EMG activity during REM sleep. Conversely, patients with RBD may report confusional arousals or sleepwalking behaviors in addition to violent dream-enactment behavior. Parasomnia overlap disorder and status dissociatus are considered clinical subtypes of RBD in the International Classification of Sleep Disorders, third edition (03). Parasomnia overlap disorder diagnosis requires that criteria for both RBD and a NREM parasomnia (a disorder of arousal [typically sleepwalking] or an appetitive parasomnia involving eating and sex) be met (see Tables 1, 2, and 3).

In contrast to middle-aged or elderly patients with isolated dream enactment of RBD, patients with parasomnia overlap disorderare more likely to present prior to the end of the third decade of life (54; 34). The disorder of arousal is typically the presenting parasomnia (04; 41). Because of these and other distinguishing features, some investigators have suggested that parasomnia overlap disorderis not a subtype of RBD but instead either a chance comorbidity or maybe a distinct pathophysiological parasomnia (20). However, an underlying generalized motor dyscontrol during sleep involving both NREM and REM sleep should also be considered with parasomnia overlap disorder(16).

Status dissociatus manifests as a breakdown in sleep state (wake/NREM sleep/REM) based on both behavioral observation and polysomnography (40; 03; 42). It commonly presents in the setting of other neurologic conditions, such as narcolepsy-cataplexy, and conditions with GABAergic thalamic pathology. In acute cases, the etiology is usually toxic, such as in ethanol withdrawal. Subacutely, autoimmune encephalopathies, such as those due to anti-potassium channel or anti-NMDA antibodies, can cause status dissociatus. Chronic cases are often related to synuclein neurodegeneration in multiple system atrophy or dementia with Lewy Bodies (04). In these cases the signs and symptoms evolve over decades, from the dream-enactment behavior of RBD to the parkinsonism and autonomic instability of multiple system atrophy and then, finally, to status dissociatus (40; 61; 14; 58). A new classification scheme was proposed defining status dissociatus as either classic or intermediate (see Table 4).

Patients with status dissociatus often report vivid dreams with observed dream-enactment, with episodes at times being quite lengthy. In other cases, patients are encephalopathic and unable to report symptoms. During behavioral wakefulness, the patients appear either delirious in the setting of ethanol withdrawal and anti-NMDA encephalitis or demented in the setting of terminal neurodegeneration (40; 61; 58).

Table 1. REM Sleep Behavior Disorder Criteria (03)

Table 2. Sleepwalking Criteria (ICSD-2)

Table 3. General Diagnostic Criteria for Disorders of Arousal from Non-Rapid Eye Movement Sleep

Table 4. Status Dissociatus 2015 Classification

Admittedly, our knowledge of these conditions is limited and stems from single case reports and small case series. These reports are summarized below, with some tentative conclusions drawn.

The largest series of patients with parasomnia overlap disorder(n=33) reported that, like RBD, violent behavior was common, with 91% of patients reporting injuries to self or bed partner (54). Extensive psychological testing did not reveal significantly elevated psychopathology in patients with parasomnia overlap disorder, indicating that underlying mental illness is not a root cause for the behavior (54). Accordingly, treatment for presumed psychiatric disease, either pharmacological or behavioral, is not warranted when parasomnia overlap disorderoccurs in the absence of symptomatic psychopathology (54).

Autonomic activation such as tachycardia, diaphoresis, and tachypnea are frequently noted during arousals from NREM sleep in parasomnia overlap disorder, very typical of sleep terrors, an NREM parasomnia.

In status dissociatus, motor activity that emanates out of behavioral sleep is usually characterized by bilateral upper extremity gestures with perioral movements. These behaviors are often referred to as an "oneiric stupor" (04). Although status dissociatus behaviors can intermittently recur, they are not strikingly repetitive and stereotyped, distinguishing them from frontal lobe epilepsy (58). Polysomnography demonstrates the simultaneous occurrence or rapid oscillation between wake, NREM, and REM sleep. After (apparent) sleep behaviors, the patient will often report dream mentation; EMG demonstrates a loss of chin and limb atonia, with complex motor activity suggestive of RBD. Often simultaneously, the EEG reveals cortical slowing consistent with deep NREM sleep. These polysomnography findings of sleep state boundary dysfunction often improve with behavioral wakefulness.

Status dissociatus can resemble the period of transition between sleep states, which is incompletely defined by polysomnography. Even in healthy subjects, sleep state transitions do not occur simultaneously but are instead a process with significant variability. Further, the complexity of sleep state transition is not adequately represented by the three biophysiological measures used to score sleep state (scalp EEG, electrooculography, and chin electromyography). For example, prior to the transition into REM sleep, there is often a drop in chin tone that precedes the EEG transition by several minutes. This finding is consistent with research indicating that REM sleep brainstem neuronal activity precedes REM sleep changes in cortical activity (23).

Agrypnia excitata (rousing sleeplessness) is a severe form of status dissociatus and is seen in three conditions: severe ethanol withdrawal, Morvan syndrome, and fatal familial insomnia (29; 04).

Agrypnia excitata is referred to as classic status dissociatus in more recent criteria (see Table 4). Additionally, the delirium and cognitive deterioration seen at the end of life is suggestive of classic status dissociatus. However, terminally ill patients are rarely investigated by polysomnography.

Prognosis and complications

The prognosis of parasomnia overlap disorderand status dissociatus depends predominantly on the presence of associated conditions. As RBD is a prodromal neurodegenerative syndrome, it is reasonable to question whether parasomnia overlap disordersubjects are also at increased risk for neurodegenerative disorders. A series of studies by the Bassetti group in Bern identified de novo sleepwalking in middle-aged and older adults (often associated with RBD, ie, parasomnia overlap disorder) that was found in a series of patients with Parkinson disease (16). Furthermore, these patients were more disabled from Parkinson disease, with higher depression and anxiety scores, higher Hoehn and Yahr scores, and lower Activities of Daily Living scores. The authors concluded that the simultaneous occurrence of sleepwalking or RBD (parasomnia overlap disorder) in most patients with Parkinson disease in their study suggested a common underlying disturbance of motor control during sleep in Parkinson disease--with variable manifestations in different sleep stages. Additionally, a cross-sectional study involving 25,694 men from the Health Professionals Follow-up Study, a population-based cohort of male health professionals in the United States, which utilized the Mayo Sleep Questionnaire, found that 0.9% had probable sleepwalking (pSW), 10.6% had probable RBD (pRBD), and 1.0% had Parkinson disease (66). After adjusting for potential confounders, the pSW, pRBD, and combined pSW/pRBD groups had higher odds of Parkinson disease, with the odds ratio being 4.80 for pSW, 6.36 for pRBD, and 8.44 for combined pSW/pRBD. The conclusion was the same as just discussed (16), that is, Parkinson disease-related neurodegeneration may impair arousal regulation during sleep, expressed as motor dysregulation in both NREM and REM sleep.

Although the exact conversion rate of patients with parasomnia overlap disorderis unknown, it appears to be less common than in RBD alone. One case demonstrated conversion to Parkinson disease after 48 years of symptoms suggestive of parasomnia overlap disorder(64). The course of prion diseases is tragically relentless and progressive. However, in cases of ethanol withdrawal or autoimmune encephalitis, parasomnia overlap disorderand status dissociatus are potentially reversible.

Sleep-related injury is a potential complication of parasomnia overlap disorderas RBD and NREM parasomnias can result in serious traumatic injury to oneself or a bed partner.

Clinical vignette

A 62-year-old male presented with an 8-month history of abnormal nocturnal behavior following a left pontine stroke. The patient described violent dream-enactment behaviors that coincided with frightening dream mentation. These events occurred nightly and, on one occasion, resulted in an arm laceration. Furthermore, in the several weeks after he returned home from the hospital, he had multiple episodes of amnestic nocturnal ambulation. These behaviors were not associated with sedative hypnotic medication; however, the patient was noted to snore and had episodes suggestive of airway collapse during sleep. According to the patient's spouse, his snoring and labored breathing had decreased in severity since his stroke but had not resolved. The sleepwalking events continued to occur on a weekly basis. Following acute rehabilitation, the patient was functioning well, with near complete resolution of wakeful clinical deficits. Two months following his stroke, he returned to his place of employment.

At presentation, the patient described modest daytime dysfunction due to somnolence, with an Epworth Sleepiness Scale score of 11 out of 24. At night he had difficulty falling asleep related to intrinsic motor restlessness. His past medical history included systemic hypertension, and he was taking hydrochlorothiazide along with aspirin.

Pertinent findings on neurologic examination demonstrated slight pronator drift on the right and mild dysmetria on the left. There was no evidence of early parkinsonian findings, and the patient still had adequate olfactory function. MRI of his head revealed a chronic lesion in the left pontine tegmentum suggestive of a lacunar infarct. Polysomnography demonstrated moderate sleep-disordered breathing (apnea-hypopnea index of 19 events an hour) during both NREM and REM sleep. After controlling sleep-disordered breathing with nasal auto-continuous positive airway pressure (AutoCPAP), more than 80% of REM sleep epochs still revealed elevated EMG tone.

The patient was able to tolerate AutoCPAP, and download data at 3-month follow-up revealed resolution of airway obstruction along with excellent AutoCPAP compliance. In addition, the patient was started on 0.5 mg of clonazepam, which eliminated the dream-enactment behavior. Sleepwalking events persisted until the patient was treated with 0.25 mg of pramipexole, which also resolved his evening motor restlessness.

Biological basis

Etiology and pathogenesis

Parasomnia overlap disorder occurs when a patient presents with both NREM parasomnias and REM sleep behavior disorder (03). At this time, it is uncertain whether a single pathology can result in both conditions or whether parallel pathologies occur simultaneously (see Pathogenesis and pathophysiology).

NREM parasomnias, such as confusional arousals and sleepwalking, arise when there is incomplete arousal from deep slow-wave sleep, manifesting as a dissociated state of motor (and emotional) activation in the motor and cingulate cortices with the persistence of sleep in other brain regions, resulting in inappropriate, amnestic, complex motor activity (10). High-density EEG studies (utilizing 256 electrodes) are providing deeper insights into the underlying neurophysiological substrates of NREM parasomnias, particularly the disorders of arousal (11). Conditions that lead to NREM parasomnias include disorders that fragment sleep, such as environmental sleep disruption, or phenomena that inhibit cortical arousal, such as sedative medications (17; 49). Very high-risk pathologies include those that lead to both sleep fragmentation and an increased sleep drive, such as obstructive sleep apnea (21; 25). The presence or absence of underlying motor restlessness, such as that seen in restless legs syndrome, may explain why some patients, after incomplete arousal from sleep, ambulate (sleepwalking) and others do not (confusional arousal alone) (32; 30).

Normally, REM sleep is characterized by skeletal muscle paralysis, preventing dream enactment. In REM sleep behavior disorder, brainstem pathology, typically pontine, results in a loss of REM sleep atonia with emergent dream-enactment behavior (08).

There is evidence to suggest that increased motor activity exists on a spectrum among parasomnias. In a study, patients with sleepwalking or night terrors demonstrated increased phasic motor activity during REM sleep, whereas patients with RBD had elevated scores on the Paris Arousal Disorders Severity Scale (28).

Although many experimental and clinical lesions lead to parasomnia overlap disorder and state dissociation, it is uncertain whether a unifying pathophysiological mechanism exists. One intriguing investigation suggested that glycine dysfunction could explain parasomnia overlap disorder pathology. In this report, two sisters with a homozygous variant of the GLRA1 gene, which causes hereditary hyperekplexia, also demonstrated both REM sleep behavior disorder and NREM parasomnias during a polysomnography investigation (39). In status dissociatus, GABA dysfunction, which can release the hypothalamus and brainstem from corticolimbic control, appears to be a pathway leading to a breakdown in wake-sleep states (51; 29; 58).

Case reports with pathological findings are reported herein.

A case of parasomnia overlap disorder that emerged in parallel with discrete brainstem lesions provides some insight into the biophysiological mechanisms of sleep-related motor dyscontrol (36). A 40-year-old female was described with a combination of symptoms suggestive of sleepwalking and RBD, in addition to ataxia, eye movement abnormalities, and multiple cranial nerve abnormalities. PSG revealed sudden arousals from slow-wave sleep as well as increased tonic and phasic chin muscle tone during REM sleep, with dream-enactment behavior. The findings were correlated with a unilateral lesion of the pontine tegmentum close to the subcoeruleus nuclei, a region noted to induce RBD (63).

Parasomnia overlap disorder may be due, at least in part, to psychotropic medications (20). In one report, two individuals presented with an NREM parasomnia, sleepwalking in one case and sleep terrors in the other. Later, both manifested dream-enactment behavior and REM sleep without atonia on polysomnography after starting an antidepressant agent known to induce RBD (quetiapine and venlafaxine).

Sexual behaviors during sleep, or "sexsomnias," have been considered a variant of NREM parasomnias; however, four cases with dream-enactment behavior have also been reported (12). In all of these cases, the sexual behaviors during sleep were either noted to occur during NREM sleep on polysomnography or they responded to nCPAP therapy for comorbid obstructive sleep apnea. Resolution of parasomnia behaviors with treatment of obstructive sleep apnea is a feature common among disorders of arousal (NREM parasomnias) (50; 25; 12). Further, no sexual behavior was noted during REM sleep during these studies. These findings, thus, suggest that sexual behaviors during sleep are a NREM phenomenon, even when occurring in the setting of parasomnia overlap disorder. A case series on a novel variant of sexsomnia (sleep masturbation using the non-dominant hand) included one patient with the parasomnia overlap disorder (05). This 59-year-old right-handed female with multiple system atrophy and worsening dysautonomia was documented by polysomnography to have RBD and who also engaged in sleep masturbation using her left hand, as observed by her bedpartner. In contrast, dream enacting RBD behaviors occurred bilaterally.

Gender differences in parasomnia overlap disorder were reported in a study of 130 women and 130 men with polysomnography confirmed isolated RBD, with 13.8% of women versus 9.8% of men having parasomnia overlap disorder (p=0.06) (02).

In conclusion, parasomnia overlap disorder suggests that the primary underlying feature of all parasomnias is motor and behavioral disinhibition during sleep. When it predominantly occurs during NREM sleep, it manifests as a disorder of arousal; when it predominantly occurs during REM sleep, it manifests as RBD, with the parasomnia overlap disorder occupying an intermediate position, with features of both.

Status dissociatus. Pathology in advanced clinical cases of status dissociatus often localizes to the thalamus or its brainstem connections. The thalamus is important in promoting the slow-wave activity and spindles of NREM sleep. Fatal familial insomnia is a prion disease that can ultimately manifest as status dissociatus and is characterized by extensive thalamic pathology. Lesioning the dorsal medial nucleus of the thalamus, a GABAergic region that normally provides cortical and brainstem inhibition, results in effects similar to the hyperadrenergic state of fatal familial insomnia and ethanol withdrawal (59). Lesions in the pons, a location high in acetylcholine activity and correlated with RBD cases, have been associated with status dissociatus (08). In one report, a 36-year-old male developed status dissociatus after a pontomesencephalic cavernoma was surgically removed (52). In another, status dissociatus was described in a 62-year-old male with lesions in both the diencephalon and median pons (13). Finally, the evolution of RBD into status dissociatus “may result from a disarray of (brainstem) structures that orchestrate the whole brain wake-sleep conditions” (62).

Voltage-gated potassium channel antibody syndromes. These disorders, despite an underlying similar mechanism of antibodies against neuronal voltage-gated potassium channels (VGKC), have various manifestations depending on the specific antigen target of the antibodies. There is a diverse spectrum of sleep disorders among patients with antibodies to voltage-gated potassium channels ranging from insomnia to status dissociatus. These findings suggest that voltage-gated potassium channels are important for the maintenance of normal sleep and are implicated in some status dissociatus cases. The most pertinent known syndromes for status dissociatus include Morvan syndrome (due to Caspr2-antibodies) and LGI1 encephalitis (14; 01; 37).

Morvan syndrome is characterized by a combination of neuromyokymia (muscle twitching), autonomic instability, and sleep disorders (01; 04). In Morvan syndrome, the voltage-gated potassium channels target is the contactin-associated protein-2 (Caspr2). The sleep symptoms often start innocuously enough with insomnia but then relentlessly progress to status dissociatus.

Dipeptidyl-peptidase-like protein-6 (DPPX) autoimmunity syndrome (anti-DPPX encephalitis), first identified in 2013, affects patients who have autoantibodies directed against DPPX, which is a subunit of voltage-gated potassium channels that are found on gut and brain neurons. These channels comprise one of the key components in the generation and propagation of electrical impulses in the gut and nervous system. In a case series of anti-FPPX autoimmune syndrome involving patients with severe sleep disturbances, polysomnography documented REM-without-atonia in four patients, and status dissociatus in one patient (with mixed features of wakefulness, NREM sleep, and REM sleep) (24).

LGI1 encephalitis. Voltage-gated potassium channel antibodies can also target leucine-rich glioma-inactivated protein 1 (LGI1), manifesting in faciobrachial dystonic seizures and limbic encephalitis. Early sleep symptoms of patients with LGI1 encephalitis include hypersomnia, REM sleep behavior disorder, periodic leg movements, and obstructive sleep apnea (37).

Among patients with VCKC antibody syndromes, status dissociatus has been noted in 24% of individuals with LGI1 antibody encephalitis and 40% with Caspr2 antibody encephalitis (Morvan). The two antibody syndromes differed in the nature and complexity of their movements. Among those with CASPR2 encephalitis, complex movements were noted and consistent with dream enactment, whereas more simple limb movements were noted in LGI1 encephalitis (37). Importantly, if identified early (see the management section below), many cases are reversible with plasma exchange or intravenous immunoglobulin. Otherwise, if left untreated, the syndrome ultimately progresses to delirium and death (04).

Multiple system atrophy. Two cases of multiple system atrophy suggest that status dissociatus may be a final manifestation of alpha-synuclein degeneration (61). Both cases initially presented with dream-enactment behavior, later confirmed by polysomnography to be RBD. Subsequently, parkinsonism and autonomic instability developed in both patients, consistent with a diagnosis of multiple system atrophy. Ultimately, the patient's sleep became disrupted by nearly continuous motor activity and vocalizations, along with prolonged confusional arousals. Follow-up polysomnography demonstrated severe disruption in sleep structure without recognizable features of NREM sleep (absence of spindles, K complexes, slow-wave activity). Further, the rapid eye movements of REM sleep were intermixed with slow eye movements, and EMG tone fluctuated between atonia and phasic activity (61).

Cruetzfeldt-Jacob disease. A case of prion disease presented initially as parasomnia overlap disorder but then progressed to status dissociatus. This 44-year-old male with rapidly progressing cognitive and motor dysfunction was later confirmed to have Cruetzfeldt-Jacob disease, the most common human prion disease. This history is consistent with the extensive corticothalamic degeneration seen among patients with Cruetzfeldt-Jacob disease (53).

Harlequin syndrome. Interestingly, two cases of Harlequin syndrome (asymmetric sweating and flushing of the upper chest and face) presented with parasomnia overlap disorder symptoms but were later noted to have status dissociatus (38). Both cases were women (ages 52 and 66) who, approximately one year after onset of autonomic symptoms, developed abnormal nocturnal behaviors. The parasomnias were characterized by confusional arousals and motor activity during frightening dreams. Polysomnography studies in both cases confirmed multiple arousals from NREM sleep with behavioral activation and REM sleep without atonia. Mixed patterns of wakefulness (desynchronized and alpha EEG activity) and REM sleep (saw-tooth waves and chin muscle atonia) were documented to intrude into NREM sleep. Mixed sleep phenomena occupied 20% to 34% of the total sleep time.

Autonomic testing of ocular function in Harlequin syndrome suggests a lesion of the first sympathetic neuron. The course of the first sympathetic neuron runs from the ipsilateral hypothalamus inferior through the brainstem and cervical cord, traversing the pons near, as noted above, areas previously associated with parasomnia overlap disorder pathology (38; 52; 13; 36). However, MRI studies on status dissociatus in Harlequin syndrome have thus far been unable to localize a potential lesion.

Mulvihill-Smith syndrome. Three cases of status dissociatus in another rare condition, Mulvihill-Smith syndrome, have been reported (22; 65). Delayed growth, cutaneous lesions, respiratory infections, squamous cell carcinoma, and sensorineural hearing loss characterize Mulvihill-Smith syndrome. Status dissociatus features include a near-complete lack of subjective sleep; an absence of NREM sleep phenomena, such as K complexes, spindles, and slow-wave activity; and REM sleep without atonia. The pathophysiological mechanism underlying Mulvihill-Smith syndrome is unknown, although thalamo-limbic pathology is suspected.

Epidemiology

Although the prevalence of parasomnia overlap disorder is unknown, the clinical phenomena of NREM parasomnias and RBD are not uncommon; thus, it would be expected that a substantial number of patients would have both disorders. NREM parasomnias usually peak in childhood with a prevalence of approximately 15% (33; 48) and then decrease to a prevalence range between 1% to 4% during adulthood (33; 45; 03; 47). Previous reports of RBD prevalence varied depending on whether measurement of REM sleep chin tone by polysomnography was included in the diagnosis. The prevalence of clinical RBD is approximately 1% (27), with higher frequencies among patients with narcolepsy or cataplexy (15; 27) and neurodegenerative diseases, particularly synucleinopathies (Parkinson disease, multiple system atrophy, and dementia with Lewy bodies) (08).

A substantial number of patients with either RBD or sleepwalking, when asked, report symptoms of a reciprocal parasomnia. In a series, approximately 21% of all RBD cases and 28% of all sleepwalking or sleep terror cases were later determined to have parasomnia overlap disorder (54). In another report of 93 patients with RBD, 10 patients also had a history of sleepwalking or nocturnal wandering behavior (46). A report described a population of sleepwalkers who were carefully evaluated for the presence of REM motor activity and dream enactment. This study demonstrated that only about 6% of these sleepwalkers had evidence of parasomnia overlap disorder (06).

Parasomnia overlap disorder is more common among men (04). The age of onset is typically younger than in idiopathic RBD. In a series of 33 patients with polysomnography confirmation of both NREM parasomnias and RBD, the mean age of reported onset was 15 years old (54). Confusional arousals or sleepwalking more commonly present first and dream enactment later (04; 41). One illustrative case reported sleepwalking that started during childhood. These parasomnias persisted into adulthood, were then supplanted by more aggressive behaviors and dream enactment, and then ultimately diagnosed 50 years later with RBD (67). The age of onset of parasomnia overlap disorder varies depending on whether the behaviors are idiopathic or are symptomatic of some other process. In two case series, the idiopathic subgroup typically presented during childhood, whereas the symptomatic subgroup was more likely to present in young adulthood. Conditions in the symptomatic subgroup included medication effect, Mobius syndrome, narcolepsy, multiple sclerosis, CNS neoplasm tumor, traumatic brain injury, posttraumatic stress disorder or major depression, chronic ethanol or amphetamine abuse and withdrawal, and schizophrenia (54; 20). Parkinson disease has been found to be a prominent member of the symptomatic parasomnia overlap disorder subgroup (16; 66).

Prevention

Parasomnia overlap disorder now appears to be a neurodegenerative prodrome in Parkinson disease, and it is not known whether it is amenable to disease-modifying therapies, which is similar to the situation with isolated RBD. However, NREM parasomnias are often associated with sleep fragmenting conditions such as sleep-disordered breathing, periodic limb movements, narcolepsy, and environmental sleep disruption, which are amenable to therapeutic interventions. Further, NREM parasomnias are also frequently associated with conditions that lead to increased sleep drive, such as sleep deprivation and sedative-hypnotic agents. Addressing these phenomena along with discontinuing serotonergic agents in the setting of antidepressant medication-induced RBD often resolves parasomnia behavior and would be expected to assist with parasomnia overlap disorder management.

Differential diagnosis

The differential diagnosis of parasomnia overlap disorder includes either a NREM parasomnia (confusional arousals, sleepwalking, sleep terrors) or isolated RBD. Less likely etiologies include sleep-related dissociative disorder or nocturnal epilepsy. The behavior in sleep-related dissociative disorder is often prolonged, and polysomnography demonstrates wakefulness throughout the episode during wake-sleep transitions or after a variable period of N1 or N2 sleep. Nocturnal epilepsy is characterized by stereotyped, recurrent, abnormal behaviors, and the EEG may, but not universally, demonstrate epileptic activity. Frequently following traumatic experiences patients will describe a sleep disorder characterized by nightmares and hyperarousal. This disorder has superficial features resembling RBD and parasomnia overlap disorder. Also, a proposed a novel sleep disorder, trauma-associated sleep disorder, may partly overlap with parasomnia overlap disorder, with abnormal behavioral arousals from sleep related to CNS hyperarousal from previous trauma (44).

The differential diagnosis for status dissociatus includes various deliriums. Potential pathological processes include infectious, metabolic, and toxic etiologies, most commonly alcohol withdrawal. In the setting of status dissociatus with limbic encephalitis, paraneoplastic etiologies should be considered. Importantly, non-convulsive or minimally convulsive seizures could resemble status dissociatus and are reversible with antiepileptic treatment.

Diagnostic workup

A careful clinical evaluation is needed to identify the NREM and REM parasomnias of parasomnia overlap disorder.

Bed partner reports are important to characterize the timing, frequency, and nature of parasomnia behaviors. Sleepwalking is typically assumed if there is a history of complex, nonviolent behavior emanating from the first half of the night. RBD, conversely, is characterized by short, repetitive, dream-enactment behavior, often violent and emerging in the second half of the night.

However, reports alone are inadequate for the diagnosis of parasomnia overlap disorder. Unlike typical sleepwalking cases where video polysomnography is not usually indicated, this procedure is indicated among cases of presumed parasomnia overlap disorder. Polysomnography is needed to identify the REM sleep without atonia of RBD and is helpful in recognizing biophysiological markers associated with disorders of arousal, such as NREM sleep fragmentation, as well as identifying reversible precipitating disorders such as sleep-disordered breathing (60). One series indicated that in contrast to NREM parasomnia, where only 64% of cases were supported with polysomnography, 98% of parasomnia overlap disorder cases were confirmed with polysomnography (19).

A protocol of 25 hours of prior sleep deprivation leading up to polysomnography, with forced awakenings, increases the likelihood of inducing simple and complex behaviors from slow-wave sleep in patients with sleepwalking (49).

In addition to polysomnographic evaluation, the workup for status dissociatus should focus on excluding the causes of delirium noted in the differential diagnosis section. This is particularly true in acute or subacute cases without a previous history of parasomnia, as they are more likely to be caused by autoimmunity and are potentially reversible. In these cases, screening for anti-VGKC and anti-NMDA antibodies is recommended, and, in particular, among cases with additional symptoms and signs, such as insomnia, hypersomnia, obstructive sleep apnea, myokymia, and limbic encephalitis (37).

Management

The first steps in parasomnia management include severity assessment, elimination of presumed aggravating agents, optimizing the duration and circadian timing of sleep, maximization of environmental safety, and identification and treatment of any comorbid sleep disorder (60). This strategy of first addressing sleep hygiene, followed by the management of possible precipitating disorders and subsequently by pharmacotherapy, has been demonstrated to be an effective therapy 97% of the time in the management of NREM parasomnias and in cases of parasomnia overlap disorder (18).

Pharmacotherapy is appropriate in patients when nocturnal behaviors persist despite these interventions or in situations with a high probability of injury. However, the evidence for pharmacotherapy in parasomnia overlap disorder alone is sparse.

Clonazepam is the most commonly cited therapy for parasomnia overlap disorder and status dissociatus. In one case series, treatment outcome data were available for 20 patients. Clonazepam was effective in eliminating or nearly eliminating injurious nocturnal behaviors in 13 patients, whereas alprazolam or carbamazepine successfully resolved four others (54). In a large series, 69% of subjects responded well to pharmacotherapy (predominantly benzodiazepines), which is a better treatment response than is typically seen in sleepwalking and about the expected treatment response to RBD. Other successful pharmacotherapies include zopiclone, fluoxetine, ropinirole, and pregabalin.

Several other case reports have described initial treatment efficacy with clonazepam; however, continued resolution of behaviors has not been consistently demonstrated (36; 12; 41; 57).

Patients with parasomnia overlap disorder have been treated with deep brain stimulation of the subthalamic nucleus. This deep brain stimulation therapy was employed to assist in managing these patients' comorbid Parkinson disease. The results have been mixed, and it is uncertain if deep brain stimulation therapy is efficacious in the management of parasomnias (07). Further investigations are necessary.

Admittedly, sleep-related injury may intermittently occur, even among patients who are otherwise treatment-responsive, and sedating agents are contraindicated in the setting of neurodegenerative diseases. Some treatment-refractory cases of parasomnia overlap disorder may respond to a customized bed alarm that delivers a calming message from a familiar voice (31). Bed alarm therapy appears to be most effective during episodes arising from REM sleep, when arousal thresholds are low and complex auditory processing is similar to wakefulness.

Hypnosis was reported to be effective in one 16-year-old male patient with parasomnia overlap disorder. In this case, three sessions of hypnotic suggestion provided sustained improvement in symptoms over five years (35).

Reversible status dissociatus. Reversible status dissociatus has been described in patients with antibodies against voltage-gated potassium channels, including those targeting Caspr2 and LGI1 (37).

An initial case report of voltage-gated potassium channels limbic encephalitis described a patient complaining of severe insomnia, whereas polysomnography evaluation demonstrated an absence of REM sleep (43). Both the encephalitis and sleep disturbance resolved with intravenous immunoglobulin followed by methylprednisolone. In one series, all 10 cases who received immunotherapy demonstrated clinical improvement, with eight of 10 patients reporting resolution or near-complete resolution of both sleep and other neurologic symptoms (14). Finally, in the largest known series of 27 patients with voltage-gated potassium channels syndromes, all 27 demonstrated a good response to immunomodulating therapy: corticosteroids, intravenous immunoglobulin, or immunosuppressants (37). We conclude that all cases of unexplained status dissociatus should be evaluated for anti-voltage-gated potassium channel antibodies and, if diagnosed, given immunosuppressive therapy.

In summary, although clonazepam appears to be effective in some parasomnia overlap disorder cases, more methodologically rigorous studies are needed to convincingly prove efficacy. Importantly, agencies that regulate drug approval do not recognize these treatments, so their use represents off-label use of pharmacotherapy, which should be discussed with patients and their families. For treatment-refractory cases, a customized bed alarm appears to help prevent sleep-related injury. Reversible causes of status dissociatus, such as ethanol withdrawal or autoimmunity, should be considered and treated.