Central sleep apnea
Apr. 03, 2022
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In this article, the author reviews parasomnia overlap disorder and status dissociatus. Clinicians are occasionally faced with patients who have clinical features of both nonrapid eye movement (NREM) parasomnias and REM sleep behavior disorder (RBD), making management difficult. The epidemiology, etiology, investigation, and management of this condition are summarized. In addition there is a detailed review of status dissociatus, a severe motor parasomnia in which features of wake and sleep states coexist. Importantly, status dissociatus is occasionally caused by voltage-gated potassium channel antibody syndromes and treatable with immunomodulating therapy.
• Parasomnia overlap disorder occurs when patients demonstrate features of both nonrapid eye movement (NREM) parasomnias (sleepwalking, confusional arousals) and REM sleep behavior disorder (RBD); it is relatively common in the parasomnia population.
• Patients with parasomnia overlap disorder are predominantly male and present younger than most idiopathic cases of REM sleep behavior disorder.
• Clinical history alone is insufficient to properly diagnose parasomnia overlap disorder as cryptic confusional arousals and sleepwalking can occur together with RBD. Conversely, subtle dream-enactment behavior is common among adult patients with NREM parasomnias as well as in the general population.
• Polysomnography in parasomnia overlap disorder typically demonstrates NREM sleep instability in combination with a lack of REM sleep atonia (at times with dream-enactment behaviors).
• Treatment of parasomnia overlap disorder should be focused on resolving comorbid conditions that fragment sleep, such as sleep-disordered breathing, and the elimination of suspected precipitating pharmacology. Clonazepam is often effective, particularly for patients with violent dream-enactment behavior. For medication-resistant patients, a customized bed alarm may help prevent sleep-related injury.
• Status dissociatus is an extreme form of parasomnia overlap wherein features of NREM sleep, REM sleep, and wakefulness coexist. This breakdown in wake-sleep state boundaries appears to be caused by pathologies involving GABAergic circuits in the thalamus, including fatal familial insomnia, delirium tremens, Morvan syndrome (and other related antipotassium channel antibody disorders), and anti-NMDA receptor encephalitis. Status dissociatus may also represent the final, fulminant manifestation of multiple system atrophy and dementia with Lewy Bodies (03).
Early reports of sleepwalking date to the writings of Hippocrates and Galen. In 1968, sleepwalking was identified as a disorder of arousal emanating from deep nonrapid eye movement (NREM) sleep (07). In 1986, a series of patients with violent dream-enactment behavior with a paucity of REM sleep atonia was reported, and the condition was named “REM sleep behavior disorder” (RBD) (48). Subsequently, in 1997 a series of 33 cases with combined NREM parasomnias and RBD was reported, with the condition named “parasomnia overlap disorder” (49).
In 1991, status dissociatus was reported in 6 patients with neurodegeneration, anoxic injury, or severe ethanol withdrawal (34). Later, etiologies included prion, neurodegeneration, autoimmune disease, and various toxic etiologies (03).
Parasomnias are defined by the sleep state in which they arise. In particular, confusional arousals and sleepwalking are associated with deep NREM sleep (N3). Conversely, RBD is a parasomnia that occurs during REM sleep. NREM parasomnias are typified by amnestic inappropriate behavior, but typically without violence or dream enactment. RBD 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) and/or increased phasic EMG twitching in REM sleep during polysomnographic recording (02).
Not uncommonly, parasomnia patients may have an overlap of symptoms and report a combination of confusional arousals and/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 (02). Parasomnia overlap disorder diagnosis requires that criteria for both RBD and a disorder of arousal (typically sleepwalking) be met (see Tables 1, 2, and 3).
In contrast to the middle aged or elderly patients with isolated dream enactment of RBD, patients with parasomnia overlap disorder are more likely to present prior to the end of the third decade of life (49; 28). The disorder of arousal is typically the presenting parasomnia (03; 35). Because of these and other distinguishing features (patients with parasomnia overlap disorder are less likely to manifest parkinsonism), some investigators have suggested that parasomnia overlap disorder is not a subtype of RBD but instead either a chance comorbidity or maybe a distinct pathophysiological parasomnia (15).
Status dissociatus manifests as a breakdown in state (wake/NREM sleep/REM) sleep based on both behavioral observation and polysomnography (34; 02; 36). It commonly presents in the setting of other neurologic conditions, most notably those 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 (MSA) or dementia with Lewy Bodies (03). In these cases the signs and symptoms evolve over decades, from the dream-enactment behavior of RBD to the parkinsonism and autonomic instability of MSA and then, finally, to status dissociatus (34; 54; 10; 51). A new classification scheme was proposed defining status dissociatus as either classic or intermediate (see Table 4).
Patients with status dissociatus are frequently 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 (34; 54; 51).
A. Repeated episodes of sleep-related vocalization and/or complex behaviors.
B. These behaviors are documented by polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep.
C. Polysomnographic recording demonstrates REM sleep without atonia (RSWA).
D. The sleep disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use.
A. The disorder meets general criteria for NREM disorders of arousal (see below).
B. The arousals are associated with ambulation and other complex behaviors out of bed.
A. Recurrent episodes of incomplete awakening from sleep.
B. Inappropriate or absent responsiveness to efforts of others to intervene or redirect the person during the episode.
C. Limited or no associated cognition or dream imagery.
D. Partial or complete amnesia.
E. The disturbance not better explained by another sleep disorder, mental disorder, medical condition, or medication/substance.
A. Classic. Most severe form of status dissociatus. Complete loss of sleep and circadian pattern. Autonomic imbalance and oneiric stupor. No conventional sleep state identifiable on polysomnography. Pathology is localized to thalamic circuits.
B. Intermediate. Intermittent form of status dissociatus. Behavioral wake and sleep states are still recognizable intermittently. Admixture of motor activity such as myoclonus and dream enactment during sleep. Sleep stages still intermittently recognized on polysomnography. Pathology is localized to forebrain.
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 parasomnia overlap disorder patients (n=33) reported that like RBD, violent behavior was common, with 91% of patients reporting injuries to self and/or bed partner (49). Typical polysomnography findings in NREM parasomnias, such as periodic limb movements or obstructive sleep apnea, were not more common than in the general population. 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 (49). Accordingly, treatment for presumed psychiatric disease, either pharmacological or behavioral, is not warranted when parasomnia overlap disorder occurs in the absence of symptomatic psychopathology (49).
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, a 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” (03). Although status dissociatus behaviors can intermittently recur, they are not strikingly repetitive and stereotyped, distinguishing them from frontal lobe epilepsy (51). 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 3 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 (18).
Agrypnia excitata (rousing sleeplessness) is a severe form of status dissociatus and is seen in 3 conditions: severe ethanol withdrawal, Morvan syndrome, and fatal familial insomnia (23; 03).
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.
The prognosis of parasomnia overlap disorder and 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 disorder subjects are also at increased risk for dementing disorders. Although the exact conversion rate of patients with parasomnia overlap disorder is 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 (56). The course of prion diseases is tragically relentless and progressive. However, in cases of ethanol withdrawal or autoimmune encephalitis, parasomnia overlap disorder and status dissociatus are potentially reversible.
Sleep-related injury is a potential complication of parasomnia overlap disorder as RBD and NREM parasomnias can result in serious traumatic injury to oneself and/or a bed partner.
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 1 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 autocontinuous 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.
Parasomnia overlap disorder occurs when a patient presents with both NREM parasomnias and REM sleep behavior disorder (02). At this time, it is uncertain whether 1 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 an incomplete arousal from deep slow-wave sleep, resulting in inappropriate, amnestic, complex motor activity (19). 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 (12; 43). Very high-risk pathologies include those that lead to both sleep fragmentation and increased sleep drive, such as obstructive sleep apnea (16; 19). The presence, or absence, of underlying motor restlessness, such as that seen in restless legs syndrome, may explain why some patients, after an incomplete arousal from sleep, ambulate (sleepwalking) and others do not (confusional arousal alone) (26; 24).
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 (06).
There is evidence to suggest that increased motor activity exists upon a spectrum among parasomnias. In a study, sleepwalking/night terrors patients demonstrated increased phasic motor activity during REM sleep whereas RBD patients had elevated scores on the Paris Arousal Disorders Severity Scale (22).
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, 2 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 (33). 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 (45; 23; 51).
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 (30). 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 (55).
Parasomnia overlap disorder may be due, at least in part, to psychotropic medications (15). In 1 report 2 individuals presented with an NREM parasomnia, sleepwalking in 1 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 (SBS), or “sexsomnias,” have been considered a variant of NREM parasomnias; however, 4 cases with dream-enactment behavior have also been reported (08). In all of these cases the SBS were either noted to occur during NREM sleep on polysomnography and/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) (44; 19; 08). Further, no sexual behavior was noted during REM sleep during these studies. These findings thus suggest that SBS is a NREM phenomenon, even when occurring in the setting of parasomnia overlap disorder.
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 localize 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 (52). Lesions in the pons, a location high in acetylcholine activity and correlated with RBD cases, have been associated with status dissociatus (06). In 1 report, a 36-year-old male developed status dissociatus after a pontomesencephalic cavernoma was surgically removed (46). In another, status dissociatus was described in a 62-year-old male with lesions in both the diencephalon and median pons (09).
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 (10; 01; 31).
Morvan syndrome is characterized by a combination of neuromyokymia (muscle twitching), autonomic instability, and sleep disorders (01; 03). 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.
LGI1 encephalitis. Voltage-gated potassium channels 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 (31).
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 2 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 (31). Importantly, if identified early (see management below), many cases are reversible with plasma exchange or intravenous immunoglobulin (IVIG). Otherwise, if left untreated, the syndrome ultimately progresses to delirium and death (03).
Multiple system atrophy (MSA). Two cases of MSA suggest that status dissociatus may be a final manifestation of alpha-synuclein degeneration (54). 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 MSA. 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 (54).
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 disfunction 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 (47).
Harlequin syndrome. Interestingly, 2 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 (32). Both cases were women (ages 52 and 66) who, approximately 1 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 (32; 46; 09; 30). 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 (17; 57). 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.
Although the prevalence of parasomnia overlap disorder is unknown, the clinical phenomena of NREM parasomnias and RBD are not uncommon, and, 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% (27; 42) then decrease to a prevalence range between 1% to 4% during adulthood (27; 39; 02; 41). Previous reports of RBD prevalence varied depending on whether a measurement of REM sleep chin tone by polysomnography was included in the diagnosis. The prevalence of clinical RBD is approximately 1% (21), with higher frequencies among patients with narcolepsy/cataplexy (11; 21) and neurodegenerative diseases, particularly synucleinopathies (Parkinson disease, multiple system atrophy, and dementia with Lewy bodies) (06).
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/sleep terror cases were later determined to have parasomnia overlap disorder (49). In another report of 93 patients with RBD, 10 patients also had a history of sleepwalking or nocturnal wandering behavior (40). 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 (04).
Parasomnia overlap disorder is more common among men (03). 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 (49). Confusional arousals and/or sleepwalking more commonly present first and dream enactment later (03; 35). 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 (58). The age of onset of parasomnia overlap disorder varies depending on whether the behaviors are idiopathic or are symptomatic of some other process. In 2 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/major depression, chronic ethanol/amphetamine abuse and withdrawal, and schizophrenia (49; 15).
It is unknown whether parasomnia overlap disorder is a neurodegenerative prodrome or whether it is amenable to disease modifying therapies. However, NREM parasomnias are often associated with sleep fragmenting conditions such as sleep-disordered breathing, periodic limb movements, narcolepsy, and environmental sleep disruption. 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.
The differential diagnosis of parasomnia overlap disorder includes either a NREM parasomnia (confusional arousals, sleepwalking, night terrors) or RBD in isolation. 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. 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 had superficial features of RBD and parasomnia overlap disorder. Investigators have suggested that these cases represent a novel sleep disorder, trauma-associated sleep disorder (TSD), and suggested that brain hyperarousal from the trauma overrides REM sleep and contributes the frequently associated symptom of insomnia (38).
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.
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 (53). 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 (14).
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 (43).
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 (31).
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 (53). 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 (13).
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 1 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 and/or carbamazepine successfully resolved 4 others (49). 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 (30; 08; 35; 50).
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 at this point it is uncertain if deep brain stimulation therapy is efficacious in the management of parasomnias (05). 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 (25). 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, 3 sessions of hypnotic suggestion provided sustained improvement in symptoms over 5 years (29).
Reversible status dissociatus. Reversible status dissociatus has been described in patients with antibodies against voltage-gated potassium channels, including those targeting Caspr2 and LGI1 (31).
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 (37). Both the encephalitis and sleep disturbance resolved with intravenous immunoglobulin followed by methylprednisolone. In 1 series, all 10 cases who received immunotherapy demonstrated clinical improvement, with 8 out of 10 patients reporting resolution or near-complete resolution of both sleep and other neurologic symptoms (10). 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 (31). We conclude that all cases of unexplained status dissociatus should be evaluated for anti- voltage-gated potassium channels 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.
Michael J Howell MD
Dr. Howell of the University of Minnesota has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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