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Sleep Medicine Reviews 28 (2016) 5e17

Contents lists available at ScienceDirect

Sleep Medicine Reviews


journal homepage: www.elsevier.com/locate/smrv

CLINICAL REVIEW

From state dissociation to status dissociatus


Elena Antelmi a, b, Raffaele Ferri c, Alex Iranzo d, Isabelle Arnulf e, Yves Dauvilliers f,
Kailash P. Bhatia b, Rocco Liguori a, g, Carlos H. Schenck h, Giuseppe Plazzi a, g, *
a
Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
b
Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, UK
c
Sleep Research Centre, Department of Neurology, I.C., Oasi Institute (IRCCS), Troina, Italy
d
Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain
e
Sleep Disorder Unit, Piti
e-Salp^
etri
ere University Hospital, APHP, Paris, France
f
Centre de Ref ^pital Gui-de-Chauliac, INSERM U1061,
erence Nationale Maladies Rares, Narcolepsie et Hypersomnie Idiopathique, Service Neurologie, Ho
Montpellier, France
g
IRCCS Institute of Neurological Sciences, Bologna, Italy
h
Minnesota Regional Sleep Disorders Center, Department of Psychiatry, Hennepin County Medical Center, University of Minnesota Medical School,
Minneapolis, MN, USA

a r t i c l e i n f o s u m m a r y

Article history: The states of being are conventionally defined by the simultaneous occurrence of behavioral, neuro-
Received 27 January 2015 physiological and autonomic descriptors. State dissociation disorders are due to the intrusion of features
Received in revised form typical of a different state into an ongoing state. Disorders related to these conditions are classified
11 July 2015
according to the ongoing main state and comprise: 1) Dissociation from prevailing wakefulness as seen
Accepted 18 July 2015
in hypnagogic or hypnopompic hallucinations, automatic behaviors, sleep drunkenness, cataplexy and
Available online 6 August 2015
sleep paralysis 2) Dissociation from rapid eye movement (REM) sleep as seen in REM sleep behavior
disorder and lucid dreaming and 3) Dissociation from NREM sleep as seen in the disorders of arousal.
Keywords:
State dissociation
The extreme expression of states dissociation is characterized by the asynchronous occurrence of the
Status dissociatus various components of the different states that prevents the recognition of any state of being. This
REM sleep behavior disorder condition has been named status dissociatus. According to the underlying disorders/diseases and to their
Parasomnia severity, among status dissociatus we may recognize disorders in which such an extreme dissociation
Agrypnia Excitata occurs only at night time or intermittently (i.e., autoimmune encephalopathies, narcolepsy type 1 and
Narcolepsy IgLON5 parasomnia), and others in which it occurs nearly continuously with complete loss of any
conventionally defined state of being, and of the circadian pattern (agrypnia excitata).
Here, we render a comprehensive review of all diseases/disorders associated with state dissociation
and status dissociatus and propose a critical classification of this complex scenario.
© 2015 Elsevier Ltd. All rights reserved.

Introduction wave activity, eye closure, immobility/activity, etc., and short-


lasting transient phenomena such as eye movements, short mus-
The states of being are characterized by an identifiable and cle contractions, sleep spindles, K-complexes, etc. The combination
stable cluster of behavioral, neurophysiological and autonomic of these parameters has empirically allowed finding clusters
descriptors, observed over a period of time. In the classical sleep defining each state (namely wakefulness, rapid eye movement
stage scoring system [1], this period has an arbitrary fixed length of (REM) sleep and NREM sleep) (Supplemental materials: Table 1).
30 s, allowing the identification of both long-lasting phenomena, These clusters are typically preserved in most of the sleep dis-
such as muscle tone changes, subcontinuous EEG alpha or slow- orders (e.g., insomnia, sleep-related breathing disorders, circadian
disorders) and eventual changes involve their quantity, rather than
their basic features. However, a particular group of other conditions
* Corresponding author. Department of Biomedical and Neuromotor Sciences, is characterized by the disintegration of these clusters, with the
Alma Mater Studiorum, University of Bologna, Via Altura 3, Bologna, Italy. Tel.: þ39
asynchronous occurrence of the various components of the
051 4966924; fax: þ39 051 4966098.
E-mail address: giuseppe.plazzi@unibo.it (G. Plazzi). different states that prevent the recognition of a well-defined

http://dx.doi.org/10.1016/j.smrv.2015.07.003
1087-0792/© 2015 Elsevier Ltd. All rights reserved.
6 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17

Abbreviations N type 1 narcolepsy type 1


OSAS obstructive sleep apneas during sleep
AMBEs arousal-related motor-behavioral episodes PD Parkinson disease
caspr2 contactin-associated protein 2 PLMs periodic leg movements
CSF cerebro-spinal fluid POD parasomnia overlap disorder
DLB dementia with levy bodies PSG polysomnography
EEG electroencephalography RBD REM sleep behavior disorder
EMG electromyography REM rapid eyes movement
FFI Fatal familial insomnia RWA REM-sleep without atonia
GBS Guillain Barre syndrome SD status dissociatus
Hcrt hypocretin SOREMP REM sleep onset periods
Lgi1 leucine-rich glioma inactivated 1 VGKC-Ab voltage-gated potassium channel complex antibodies
MSA multiple system atrophy W wake
NMDA N-methyl-D-aspartate

cluster defining a single state over the established epoch length - Dissociation from prevailing wakefulness, due to intrusion of
[2,3]. This group of conditions will be the focus of this review. features of other stages into ongoing wakefulness;
It is important to pinpoint that also in normal subjects an - Dissociation from NREM sleep, due to intrusion of features of
admixture of features of different stages may occur, mainly at state other stages into ongoing NREM sleep and;
transition. Usually, this dissociation is brief and emerges only at a - Dissociation from REM sleep, due to intrusion of features of
neurophysiological level; however, if it lasts longer, it may result in other stages into ongoing REM sleep.
behaviors such as hypnagogic hallucinations, lucid dreams or sleep
paralysis. For the sake of simplicity, we will use the labels reported above
For the sake of clarity, it should also be mentioned here that the to classify the spectrum of state dissociation disorders. The number
type of sleep abnormalities that will be discussed in this review of diseases, which can be associated with an abnormal dissociation
does not always refer to the recently introduced concept of “local of states is extensive (Supplemental materials: Table 2). However,
sleep” [4]. This concept refers to the possibility to identify discrete one should acknowledge that the above-mentioned classification is
neuronal aggregates that show features of one state while others not always thorough as there are more complex conditions (i.e.,
are exhibiting features of a different state also in physiological sleep parasomnia overlap disorder) that would not fit in any of these
of healthy controls. However, the sleep/wake dynamics are still boxes. Moreover, as for all the classifications, which try to underpin
recognizable as a “global” phenomenon during which “local” the complexity of human brain, this categorization may at times
neuronal aggregates might disentangle temporarily from the global sound artificial as in particular conditions more than one type of
state and engage a different state, obtaining a sort of state disso- dissociation may occur simultaneously. Examples are conditions
ciation. On the contrary, the conditions that will be mainly treated classified among the “within-mind” dissociation that may present
here can be characterized by a much more stable and profound also with features of the “mind-body” dissociation (as seen in
dissociation during which no feature clusters nor states can be automatic behaviors or in NREM parasomnia) or vice-versa as seen
distinguished. However, in order to give a comprehensive analysis in sleep paralysis (see later).
of the topic, on some occasion we will present also milder condi-
tions that might be explained by an extension to pathology of the
concept of “local sleep” mechanisms. Dissociation from wakefulness

There are several examples of behaviors/disorders emerging


Literature search criteria
from the intrusion of other states into wakefulness.
We searched the Medline database (via PubMed: http://www.
ncbi.nlm.nih.gov) for publication between 1986 to January 2015, Within-mind dissociation
using the search terms: status dissociatus (SD), state dissociation,
dissociation of states, dissociated states, narcolepsy, narcolepsy In this subtype of dissociation from wakefulness, the mind
with cataplexy, narcolepsy type 1, REM sleep behavior disorders, simultaneously contains elements of wake as subjects may retrieve
parasomnia, parasomnia-overlap syndrome, lucid dreaming, hal- quite a good recollection of the mental experience and of the
lucinations, sleep inertia, sleep paralysis, agrypnia excitata, poly- environmental stimuli and a wake motor aspect (eyes open, motor
somnography* and encephalopathies, drug intoxications, alcohol tone present with at times even complex motor behaviors) and
withdrawal, neurodegenerative diseases. Only papers in English elements of REM sleep (vivid dreams) or of NREM sleep (dream-like
were selected and reference lists of the articles retrieved by the mentation).
electronic searches were checked for other relevant reports not They include hypnagogic or hypnopompic hallucinations, and
indexed in the electronic database. In addition, original articles complex nocturnal hallucinations in which dream mentation oc-
focusing on pathophysiology, or single case reports of particular curs during the transition from sleep to wakefulness and vice versa.
interest were eventually included even if published before 1986. Hallucinations at the wakeesleep transition are typical of narco-
lepsy [5,6], although they can also be the consequence of alcohol/
From dissociation of states to “status dissociatus” drug intoxication or withdrawal, of brainstem or thalamic lesions,
severe visual loss (Charles Bonnet syndrome) and of other neuro-
In 1991, Mahowald and Schenck [2] proposed a classification of logical conditions (autoimmune encephalitis) [5].
the dissociation of states based on the parent (or main) state; by Yet, visual hallucinations are common in neurodegenerative
using this model, the following dissociations can be recognized: diseases, such as Parkinson disease (PD) and dementia with Levy
E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17 7

bodies (DLB) [7] and reputedly related to the occurrence of REM Subjects typically present with eyes open, showing an empty
sleep mentation [8,9]. gaze and with retained muscle tone, preserving the ability to move
Moreover, even normal subjects may experience somatosensory and to interact with the environment while performing inappro-
illusions or hallucinations at wakeesleep transitions, especially priate behaviors. Scalp EEG shows admixed features of NREM sleep.
during childhood or in the setting of sleep deprivation or stressful The intracerebral EEG recording of a patient with confusional
events [10] underlining the fact that switch errors may frequently arousals, as part of a presurgical study [12], demonstrated different
occur also in the normal population in the “pre-dormitum”. The local activations with wake EEG on the motor and cingulate cortices
latter, indeed, represents the natural setting for the onset of and increased delta activity on the fronto-parietal associative
physiological states of dissociation [4]. cortices. Furthermore, activation of thalamo-cingulate pathways and
The intrusion of sleep elements into wakefulness would pro- persistent deactivation of other thalamo-cortical arousal systems
mote also the emergence of automatic behaviors. Automatic be- have been shown by means of single photon emission computed
haviors are difficult to capture in the laboratory setting and there tomography while capturing an episode of sleepwalking [13].
are no conclusive polysomnographic documentations of this con- NREM parasomnias often show a familial predisposition,
dition, therefore it is still unclear if they are due to NREM or REM although no genes have been identified as yet. They are generally
sleep intrusions. They are typically seen in pathological conditions, more frequent during childhood, but may persist or even arise during
such as idiopathic hypersomnia, and in narcolepsy, but may be adulthood (even without any underlying psychopathology) [14e16].
experienced also by healthy individuals [5]. During such dissocia- Genetic factors, external triggers (sleep deprivation, sleeping in
tion, it may be seen that the subjects during a conversation pro- novel or other particular settings, noise, etc.) or internal triggers
nounce some out-of-context sentence or perform an inappropriate (anxiety, stress) may act by modifying the arousal threshold and
action that are reputedly related to a brief dream mentation. At precipitating the persistence of such dissociation [15e17].
times subjects may perform complex behaviors, for example
driving long distances. Dissociation from REM sleep
Other examples are sleep drunkenness or sleep inertia, during
which an impairment of cognition and attention occurs, in the Mind-body dissociation: REM sleep behavior disorder
transition between sleep and wake, with EEG features of wake and
light NREM sleep. Also this type of dissociation is common in REM sleep behavior disorder (RBD), i.e., dream enacting be-
idiopathic hypersomnia [5]. haviors, due to incomplete declaration of REM sleep because of the
intermittent lack of REM-sleep muscle atonia (RWA), is probably
the best known example of state admixture. In this condition the
Mind-body dissociation
mind is asleep (REM dream mentation) while the body is awake
(spinal motor neurons are still excitable). RBD seems to be due to a
In this subtype of dissociation from wakefulness the body is
dysfunction of the brainstem structures regulating REM sleep ato-
“asleep” (paralyzed) while the mind is awake. Cataplexy and sleep
nia, i.e., subceruleus and magnocellularis nuclei and their anatomic
paralysis are examples of such dissociation.
connections, including those with the amygdala [5].
Cataplexy is thought to be due to REM sleep muscle atonia
RBD may present as an acute phenomenon or as a chronic dis-
surfacing during wakefulness and triggered by strong, mainly
order. Acute/subacute RBD cases are rare and mainly seen during
positive, emotions [5]. Cataplexy is the typical motor feature of
intense REM sleep rebound states [5], such as during withdrawal
narcolepsy type 1.
from alcohol abuse and from sedative-hypnotic agents, or in asso-
Sleep paralysis is a conscious state of involuntary immobility
ciation with certain medications or drug intoxication mainly
typically arising on awakening from REM sleep or at the beginning
involving antidepressants [18].
of a REM sleep onset period (SOREMP) and due to persistence/
Transient RBD has also been reported in the context of auto-
anticipation of REM sleep atonia, freezing voluntary movements in
immune diseases. In the anti-voltage-gated potassium channel
an otherwise normally awake brain [5]. It is frequently reported in
complex antibodies (VGKC-Ab) encephalitis, it has been argued that
narcolepsy or idiopathic hypersomnia but, less frequently, it may be
RBD could be linked to the impairment of limbic structures [19,20].
reported in the general population with similar triggers as for
In the Guillain Barre  syndrome (GBS), patients with RBD and SD
hypnagogic hallucinations [5].
showed decreased cerebro-spinal fluid (CSF) levels of hypocretin-1
There is very scarce EEG documentation of sleep paralysis, but a
(Hcrt-1), leading to the hypothesis that the autoimmune process
recent report highlighted that the EEG traces presented two main
can somehow involve also the central nervous system [21]. More-
frequency components, one in the wake state range with eyes
over, a more complex dissociation of states, with clinical and
closed (9 Hz) and one in the REM sleep range (19 Hz) [11]. Hence,
pathophysiological features of both RBD and narcolepsy, has been
this is suggestive of a dissociated state of mind as well.
reported in anti Ma 2 encephalitis [22e24].
The chronic idiopathic form is mainly seen as an early marker of
Dissociation from NREM sleep an impending neurodegenerative disease and recently identified as
a promising candidate for testing disease-modifying agents [25e30].
Within-mind dissociation Even if RBD is most commonly a precursor of the a-synuclei-
nopathies, i.e., of PD, DLB and multiple system atrophy (MSA)
Examples of this subtype of dissociation are the disorders of [28,30,31], it has sometimes been reported in tauopathies, as well
arousal. They include a spectrum of widely overlapping conditions, as in other neurological disorders as spino-cerebellar ataxia type 3,
ranging from confusional arousals, to somnambulism and to sleep brainstem lesions and myotonic dystrophy disease [5,32e34]. RBD
terrors, which are named NREM parasomnias, as a group. Some- is also common in narcolepsy [35].
times, they may also present with peculiar behaviors, namely Sometimes full-blown RBD does not occur even if the physio-
“sleep-related eating disorder” and “sleep-related sexual activity”. logical atonia of REM sleep is lacking in the chin muscle (but not in
They result from an admixture of wakefulness and NREM sleep and the limbs where atonia is preserved). Hence, RWA may be defined
may present with different degrees of behavioral and autonomic as a neurophysiological dissociation (muscle tone is dissociated
features [5]. from the parent state).
8 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17

Within-mind dissociation: lucid dreaming onset (childhood or adolescence) than patients with RBD alone, and
in most of them the disorder of arousal precedes RBD [5]. Both
Lucid dreaming is the experience of being aware of dreaming idiopathic and symptomatic forms have been reported [5]. The list
while asleep and continuing to dream. Lucid dreaming has been of symptomatic forms is large even if coming essentially from single
documented by polysomnography (PSG) to occur during REM sleep, case reports and it includes narcolepsy, multiple sclerosis, brain
indicating that lucid dreaming is a dissociated REM sleepewakeful tumor, rhombencephalitis, brain trauma, congenital Moebius syn-
state. Lucid dreamers may recognize that they are dreaming, but drome, Machado-Joseph disease, various psychiatric disorders and
may also develop some control of the dreaming activity (changing their pharmacotherapies, substance abuse disorders, and with-
the setting, the characters or the scenario) as well as some control of drawal states. However, only few studies report details on neuro-
the eye movements (by displaying specific eye signals to be recog- physiological investigations [43].
nized by the researcher when they are aware of dreaming). POD pathophysiology is unknown. Similarly to RBD and SD, in
Over a sample of nearly one thousand adults, 51% subjects re- POD there is a motor/behavioral disorder occurring during sleep
ported experiencing a lucid dream at least once in life, while the along with the presence of excessive phasic EMG twitching.
monthly frequency of lucid dreams is higher in children than in Currently, POD is classified as a variant of RBD [5]. However in
teenagers and adults. Of note, up to 78% of patients with narcolepsy the idiopathic forms, a correlation with neurodegeneration is still
are lucid dreamers [36]. doubtful [44].
Intriguingly, it has been reported that healthy subjects during Still, pertinent to this category are also the arousal-related
REM sleep may generate some “conscious” experience (reflexive motor-behavioral episodes (AMBEs) occurring from either REM or
consciousness), showing that the brain still keeps the capacity to NREM sleep in PD, DLB patients [41] and subjects with severe OSAS
detect and categorize internal states of mind [36]. Moreover, [45]. They may represent confusional states arising from sleep.
recently Mazza et al. [37] reported the observation of a patient who, Interestingly, in neurodegenerative diseases, it appears that
while being recorded with intra-cerebral electrodes for refractory sometimes progressive thalamo-cortical network/neocortical
epilepsy, was able to reproduce during REM sleep a motor behavior degeneration may lead from RBD to AMBEs and, in some cases, to
performed during wakefulness with EEG activity comparable to the full-blown SD [40,41].
that of wakefulness over the prefrontal and parietal areas and over
the anterior cingulate cortex.
Status dissociatus
Intrusion of NREM in REM sleep and vice versa
SD represents the extreme expression of state dissociation, due
This type of dissociation includes conditions/disorders, which to the complete breakdown of state-determining boundaries.
can be better recognizable by polysomnographic recording rather Classically defined SD consists of nearly continuous motor and
than clinically. verbal behavior, with experience of dreaming, in the absence of PSG
Examples are: defined conventional REM and NREM sleep stages [2,3,5]. Indeed,
in the severe form of SD the brain is not able to orchestrate the
- “spindling” REM sleep (i.e., the presence of spindles during REM behavioral, neurophysiological, and autonomic patterns typical of
sleep), as seen in patients taking benzodiazepines [5]. any state of being [2,3], and thus it is unable to produce a fully
- muscle twitches, periodic leg movements (PLMs), and whole blown state of being. Currently, SD is classified among the subtypes
body jerks during stage 3 NREM sleep, as seen in some PD, MSA of RBD [5].
or DLB patients [38,39]. Dissociated sleep was previously reported as a polysomno-
- REM sleep polygraphic features during NREM sleep, as seen in graphic trait in tricyclic-medicated narcoleptic patients [46], while
some patients with PD or with DLB [39], or REMs during NREM the concept of SD was first introduced by Mahowald and Schenck in
sleep in subjects taking antidepressants (“Prozac eyes”) [5]. 1991 [2], when they reported six patients, with different causal
triggers, of extreme state dissociation. The original paper reported
Finally, as already mentioned, among the spectrum of state on six different conditions (chronic alcohol abuse and acute with-
dissociation disorders and SD there are borderline disorders, in drawal; olivopontocerebellar atrophy; cardiac surgery-related
which different subtypes of state dissociation disorders may occur. central nervous system anoxic injury; OSA/narcolepsy-cataplexy
Indeed, in these conditions, elements of wake may occur either with methylphenidate/imipramine therapy; and narcolepsy-
during an ongoing NREM sleep or REM sleep and occasionally cataplexy with methylphenidate/imipramine therapy) all charac-
features of these two latters as well may be merged together. We terized by “ambiguous, multiple or rapid oscillation of state-
report here some examples: determining variables with simultaneous appearance of elements
of all three states, and with the only full-declared state being
- conditions with admixture of features of stage 2 of NREM sleep wakefulness”. After this report, the literature on diseases/disorders
(spindles) with REM sleep features (electro-oculogram with causing SD has expanded. SD has been recognized in a wide range
REMs, EMG phasic twitches) and complex behaviors as of clinical settings:
described in neurodegenerative diseases or transiently before
the development of the full-blown SD [40,41]. 1) rapidly progressive neurodegenerative diseases, i.e., fatal fa-
- parasomnia overlap disorder (POD) [5,42,43]. milial insomnia (FFI) and other prion diseases;
2) autoimmune diseases, i.e., autoimmune encephalitis (anti VGKC
and Ma2 encephalitis), narcolepsy, GBS, alcohol or drug abuse
Parasomnia overlap disorder withdrawal;
3) brain lesions, i.e., hypothalamic, thalamic and brainstem lesions;
In the rare POD patients have both clinical and PSG evidence of 4) neurodegenerative diseases (i.e., PD and DLB);
RBD and of a disorder of arousal from NREM sleep [5,42,43]. This 5) rare congenital malformative, possibly genetic, conditions such
condition is male predominant. POD patients have an earlier age at as the Mulvihill-Smith syndrome.
E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17 9

The hallmarks of “classically defined” SD are: Morvan's syndrome is a rare autoimmune disease due to anti-
bodies targeting the contactin-associated protein-2 (caspr2) of
 lack of the conventional (PSG) features of NREM sleep, with potassium channels. It is characterized by acute or sub-acute onset
disappearance of spindle and delta activities. Neurophysiolog- of insomnia, nearly continuous muscle activities (myokimias and
ical features of REM sleep, instead, persist but occur mainly in cramps), autonomic imbalance and pain in the extremities [51,52].
the form of “covert” EEG REM sleep or RWA. Moreover, REM In most cases, the disease favorably responds to plasma exchange
sleep fails to stabilize, appearing in short recurrent episodes, or intravenous immunoglobulins within a few months, but some
isolated, or mixed with stage 1 NREM potentials. cases do not recover, showing progressive worsening of symptoms,
 motor agitation with enacted dreams, oneirism, continuous or followed by death [51,52].
semi-continuous movements. Finally, alcohol withdrawal syndrome (delirium tremens) arises
 impaired level of vigilance, with fluctuations in attention and, after sudden alcohol withdrawal in alcohol abusers [53]. Usually
sometimes, confabulation and mental confusion. these patients present with tremors, nausea, anxiety, insomnia,
motor and autonomic activation with agitation, hallucinations and
There are some reports on SD in the literature that do not render violent dream enactment. An eventual pattern with calmer ges-
the original concept. This is quite understandable because of the tures mimicking daily life activities similar to those described in
complexity of the human brain engendering a wide spectrum of agrypnia excitata has been reported [2,53]. A similar condition may
state dissociations, which may not always fit into a “box”. In this occur after withdrawal from meprobamate, barbiturates, and ben-
review, for the sake of simplicity, we will categorize the reported zodiazepines [5].
cases of SD into two subtypes, based on severity, underlying dis- The term “agrypnia excitata” aims to depict the common
eases, and the peculiar clinical and neurophysiological features framework of the above disorders. Indeed, all these three condi-
(Supplemental materials: Table 3): tions combine organic insomnia (i.e., the inability to initiate and
sustain sleep) with a confuso-oneiric state (dreaming behaviors
1) classically defined SD with no recognizable neurophysiological due to complex hallucinations/dreams), together with motor hy-
features of sleep, nearly continuous motor activity/hyperactivi- peractivity, autonomic hyperactivity (with tachycardia, tachypnea,
ty, impaired vigilance and loss of circadian rhythm. Indeed, this hypertension, fever, hyperhidrosis etc.) and increased blood cortisol
category includes the most severe form of SD, i.e., agrypnia and plasma catecholamines [47,54,55]. Both the cyclic structure of
excitata. sleep and the circadian rhythmicity are lost. Motor activity is
2) the intermittent/intermediate SD, in which proper sleep may be increased throughout the 24 h without any circadian pattern [54].
still recognizable, even if it sometimes clearly lacks of conven- Before reaching the state of agrypnia excitata, patients often present
tional state PSG features for the simultaneous occurrence of with reduced sleep time, hypnagogic hallucinations and RBD, pin-
different states of being, but on occasions preserved circadian pointing the fact that agrypnia excitata may represent a continuum
pattern. Abnormal behaviors will be seen in both NREM and with state dissociation disorders. With the progression of the dis-
REM sleep. ease, the patients become more and more confused, alternating
between wakefulness and oneiric confusional states, until they
A borderline condition, which would not fit in any of the pre- reach the final state of akinetic mutism in FFI.
vious definitions is the “Indeterminate sleep” status as seen in A state of sub-wakefulness, polygraphically characterized by
advanced PD and DLB patients, characterized by continuous slow stage 1 NREM with interspersed short REM sleep episodes, be-
waves or continuous alpha rhythm (with absence of the markers comes the dominant diurnal and nocturnal behavioral and neuro-
typical of other stages, namely theta, delta, spindles, k complex) physiological pattern (Fig. 1). Clustered REM sleep episodes
and frequently association with hallucinations, confusions and frequently coincide with gestures mimicking task-oriented daily-
delusions. Also in this case, circadian pattern may still be recog- life activities, such as dressing, combing the hair, washing, or
nizable. However, categorizing this entity as a different subtype of manipulating an imaginary object. These episodes may also occur
SD is still premature because of the lack of PSG documentation in with open eyes. If questioned at the end of these behaviors, patients
this regard. often do not admit that they were asleep, although they link these
gestures to an oneiric/hallucinatory scene, and the motor activity
appears to be clearly related to the oneiric content. This peculiar
Classically defined/severe SD behavior, named “oneiric stupor”, represents in fact the behavioral
marker of agrypnia excitata. [55].
This type of SD represents the most severe form of SD and has The full-blown picture of agrypnia excitata with the typical
been labeled as agrypnia excitata. The term put forth in 2001 by Elio neurophysiological and clinical features, leading to death, has also
Lugaresi and coworkers [47], who first used it to lump together the been described in two unrelated cases affected by a very rare and
extreme sleep disorganization found in three different diseases, complex congenital neurodegenerative disease, the Mulvihill-
namely FFI, alcohol withdrawal syndrome and Morvan's syndrome, Smith syndrome, a rare condition characterized by progeria-like
which share strikingly similar clinical and neurophysiological fea- aspect, peculiar multiple pigmented nevi, low stature, and cogni-
tures. FFI is as an autosomal dominant prion disease with selective tive impairment (Fig. 2) [56,57].
thalamic and inferior olivary degeneration at the pathologic ex- Features of SD have been observed also in the sporadic and in
amination [48]. It is caused by a missense mutation at codon 178 of the variant forms of the CreutzfeldteJakob disease (CJD). However,
the prion protein gene co-segregating with methionine (met) at except for the form in which a prominent thalamic involvement has
methionineevaline (Val) polymorphic codon 129 in the mutated been reported [58,59], the full-blown spectrum of Agrypnia Excitata
allele [49]. Sporadic cases are rare. FFI starts at a mean age of 50 y. cannot be recognized [60,61].
There is a phenotype variability related mainly to the poly- SD has been reported also in chronic bilateral vascular para-
morphism at codon 129 of the prion protein-gene [50]. Patients median thalamic lesions [62e64], and in a diencephalon and
may have a short (from eight months) or a prolonged (up to 72 mo) medial pons lesion, after surgery for a tegmental ponto-
clinical course according to whether they are homozygote met/met mesencephalic cavernoma [65]. These cases however lack auto-
or heterozygote met/val at codon 129 [50]. nomic imbalance.
10 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17

The intermittent/intermediate SD

This form is characterized by abnormal NREM and REM sleep


architecture, RWA, RBD and vivid dreams, with extremely frag-
mented and unstable sleep and frequent shifts between W, REM
sleep, and NREM sleep. The circadian pattern is generally, but not
always, impaired and anyway less severely than what is seen in
agrypnia ecitata. This subtype of SD has been mainly reported in
autoimmune encephalitis.
In the past, specific relationships between the immunologic
pattern e namely the specific subtypes of VGKC, such as leucine-
rich glioma inactivated 1 (Lgi1) and caspr2 - and the clinical
phenotype have been suggested [19,20,66e69]. Thus, sleep ab-
normalities have mainly been associated with caspr2 antibodies,
namely Morvan's syndrome [51,52,68,69] whereas patients with
Lgi1 antibodies typically demonstrate limbic encephalitis without
sleep disturbances. However, this idea has been overtaken by the
recent report of insomnia associated with partial loss of recogniz-
able sleep and enacted dreams even in limbic encephalitis due to
Lg1 antibodies [66,67].
Cases of this subtype of SD have been reported also in the
context of anti Ma1 and Ma2 antibody-positive encephalitis char-
acterized by RBD, narcolepsy with cataplexy, and progressive
supranuclear gaze palsy-like features [23,24,70]. Yet, features sug-
gestive of SD have been reported in nearly one third of patients
affected by GBS [21]. In the latter, sleep studies revealed frag-
mented and unstable sleep with frequent shifts between stages.
Vivid dreaming, RBD and hallucinations associated with specific
wakefulness/NREM/REM sleep state dissociation were frequently
reported. In the majority of patients the state resolved with syn-
drome improvement, suggesting that GBS autoantibodies could
also target certain structures of the CNS, in particular the lateral
hypothalamus, where hypocretinergic neurons are located. Indeed,
in most of these patients, CSF Hcrt-1 levels were reported to be
transiently reduced [21]. However, one must acknowledge that PSG
studies in these disorders are scarce and therefore conclusive re-
marks are still ventured.
The recently described NREM and REM sleep IgLON5 para-
somnia could fit in this category [71]. Patients have been reported
presenting (subacutely or cronically) with abnormal sleep along
with various neurological problems (such as gait instability,
dysarthria, mild dysautonomia, chorea, and dysphagia). Patients
complained of non-restorative sleep but were unaware of their
abnormal sleep behaviors that were only noticed by the bed part-
ners. Video-PSG showed a very complex distinct sleep pattern
(Fig. 3) characterized by 1) normal occipital alpha rhythm during
wakefulness; 2) sleep-onset characterized by prolonged periods of
theta activity with motor activation and rapid repetitive leg
movements; 3) poorly structured stage 2 NREM sleep with frequent
vocalizations and goal directed behaviors, like manipulating objects
and eating and sucking the thumbs; 4) RBD characterized by very
frequent limb and body jerks but no violent behaviors; 5) periods of
Fig. 1. Sleep histogram and polygraphic recordings from a 68 y-old man with Morvan's diffuse delta activity, typical of normal stage 3 NREM sleep, mixed
syndrome. From top to bottom: sleep histogram showing sustained wakefulness (W) with spindles; 6) periods of normal stage 2 NREM and normal stage
interrupted by recurrent lapses into non-REM stage 1 sleep (N1) and into REM sleep 3 NREM sleep, and 7) OSAS mainly during normal stage 3 NREM
without atonia (REM*); polygraphic recordings showing continuous muscle-fiber ac-
sleep and inspiratory stridor secondary to vocal cord palsy. Longi-
tivity during sustained wakefulness (W), during N1 and during REM*. Abbreviations
(from top to bottom): EOG-R, right electro-oculogram; EOG-L, left electro-oculogram; tudinal follow-up by PSG showed no deterioration of these features
F3-A2, C3-A2, O1-A2, EEG channels; chin, mylohyoideus muscle; ECG, electrocardio- with time. Therefore, in these patients even if NREM sleep stages 2
gram; Airflow, oral respirogram; Thorax, thoracic respirogram; Abdomen, abdominal and 3 are still recognizable, sleep architecture is unstable with
respirogram; FDS-R, right wrist extensor muscle; FDS-L, left wrist extensor muscle; frequent stage transitions and with features of different states of
Tib-R, right tibialis anterior muscle; Tib-L, left tibialis anterior muscle. Abdomen,
being that merge together generating behavioral manifestations,
abdominal respirogram; Airflow, oral respirogram; chin, mylohyoideus muscle; ECG,
electrocardiogram; EOG-R, right electro-oculogram; EOG-L, left electro-oculogram; F3- such as undifferentiated NREM movements, RBD and even “pur-
A2, C3-A2, O1-A2, EEG channels; FDS-L, left wrist extensor muscle; FDS-R, right wrist poseful-mimicking” behavior resembling somehow those typical of
extensor muscle; Thorax, thoracic respirogram; Tib-L, left tibialis anterior muscle; Tib- the oneiric stupor. Autoantibodies against IgLON5, a neuronal cell
R, right tibialis anterior muscle.
adhesion protein, were identified in all the patients and the
E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17 11

Fig. 2. Aspect of the face and trunk of a 25 y-old female with Mulvihill-Smith syndrome showing multiple pigmented skin lesions. (II) T2-weighed cerebral MRI imaging of the same
patient showing mild enlargement of the cortical sulci. Stage A: polysomnographic recording showing desynchronized EEG activity, presence of eye movements similar to those
recorded during wakefulness, irregular breathing, and heart arrhythmia, accompanied by purposeless movements of the upper limbs and hands. Stage B: desynchronized EEG
activity with mixed slow waves, low chin muscle tone, presence of slow eye movements, heart arrhythmia, regular breathing and absence of motor activity. Stage C: presence of a
periodic respiratory pattern characterized by the regular occurrence of central apnea episodes, heart arrhythmia, desynchronized EEG activity, high chin muscle tone and presence
of rapid eye movements. Left bottom panels: Sleep hypnogram and nocturnal time course of the EEG delta band (0.5e4.5 Hz) power of the same patient. Abbreviations (from top to
bottom): EOG-R, right electro-oculogram; EOG-L left electro-oculogram; F3-A2, C3-A2, O1 A2, EEG channels; chin, mylohyoideus muscle; ECG, electrocardiogram; Airflow, oral
respirogram; Thorax, thoracic respirogram; Abdomen, abdominal respirogram; Delt-R, right deltoideus muscle; Delt-L, left deltoideus muscle; Tib-R, right tibialis anterior muscle;
Tib-L, left tibialis anterior muscle.

haplotypes DQB1*0501 and DRB1*1001 were detected. Patients did underlying nature of SD in this disorder is unknown, and authors
not respond to immunotherapy and most died suddenly during speculated on a possible implication of a pontine dysfunction [73].
either wakefulness or sleep. Whether or not those antibodies are Also SD in narcolepsy pertains to this subtype (see below).
the “primum movens” is still unclear, as the neuropathology per- Indeed, we have here reported a number of examples of state
formed in two patients showed a previously not described neuronal dissociation disorders, which typically occur in this disease.
tauopathy, mainly involving the tegmentum of the brainstem and However, narcolepsy as a whole configures a status dissociatus
the hypothalamus. for the continuous shifts from a state dissociation to another,
Moreover, a form of SD may eventually be recognized in meta- which at times may even occur simultaneously (see below).
bolic encephalopathies [72] or in critical illness due to metabolic
and functional disturbances of neurotransmitters or of brain SD in narcolepsy
structures orchestrating sleep and the environmental entrainment.
However, sleep studies in such cohorts have been hampered by Narcolepsy is one of the most striking examples of state disso-
cumbersome and time-consuming methods, thus we do not have ciation. It is a hypersomnia of central origin due to loss of
conclusive findings on this topic. hypocretin producing neurons in the hypothalamus and with a
Finally, a milder form of this subtype of SD has been reported strong genetic association with the human leukocyte antigen
in two middle-aged ladies affected from Harlequin syndrome [73], DQB1*0602 haplotype, supporting the hypothesis of an autoim-
which is a rare condition due to sympathetic nervous system le- mune etiology [5]. Hence, narcolepsy (and in particular the type 1)
sions and characterized by asymmetric sweating and flushing on is not generally characterized by an increased amount of sleep but,
the upper thoracic region of the chest, the neck, and the face. The instead, by the inability to maintain the normal boundaries of
12 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17

Fig. 3. A 30-s epoch of poor structured non-REM stage 2 sleep (N2) with K complexes and spindles and increased phasic EMG activity in all the four limbs associated with
purposeless motor behaviors and vocalizations in a 53 y-old man with anti IgLON5 associated parasomnia. Abbreviations (from top to bottom): EOG, electrooculogram; Chin,
electromyography of mentalis muscle; EEG, electroencephalogram; EMG, electromyogram; ECG, electrocardiogram; Flexor, flexor digitorum superficialis muscle; Tib, anterior
tibialis muscle; EDB, extensor digitorum brevis muscle; Flow, nasal air flow; Thorx, thoracic respiratory movement; Abdomen, abdominal respiratory movement.

wakefulness, NREM and REM sleep, resulting in a number of etc.) may eventually lead to a condition in which conventional
dissociated behaviors [5], as originally pointed out by Broughton in states of being are difficult to recognize, with EEG activity con-
1986 [74]. Thus, patients with narcolepsy type 1 experience a sisting essentially of continuous theta or alpha activity (Fig. 4).
number of state dissociation disorders, ranging from wakefulness This EEG pattern is mainly associated with confusion, somno-
dissociation (cataplexy, sleep paralysis, hallucinations and auto- lence, hallucinations and sometimes delusions. One should
matic behaviors) to REM sleep dissociation (lucid dreaming, RBD). acknowledge that these conditions still need a full clinical and
Such dissociated states may sometimes merge together, generating neurophysiological characterization as PSG studies are currently
complex admixtures such as cataplectic attacks occurring during lacking and therefore we will not include this subtype in our
RBD episodes [75], or hallucinations or impaired consciousness classification. However, we suggest that the term “indeterminate
occurring during sleep paralysis [11,76]. sleep SD type” may be used to render this condition as it may
Thus, all three types of dissociation may exist but patients are somehow recall what has been formerly labeled “indeterminate
still able to orchestrate the proper states of being, even if the sleep” in newborns [79,80].
system is so unstable that dissociation occurs very frequently, Indeed, these conditions may represent a type of reversal of
leading to the sudden occurrence of hallucinations or cataplectic sleep ontogenesis. In fact, NREM sleep stages, as defined in adult-
attacks. hood, do not fully develop until late infancy. Physiologically, during
The condition of “status cataplecticus” deserves a particular the first months of life only two stages of sleep may be recognized,
mention in narcolepsy type 1. In fact, at times, the boundary i.e., the active (REM) sleep and the quiet (NREM) sleep. Yet, seldom
instability may be even more severe and cataplexy, in children at neither REM nor NREM sleep may be recognized configuring what
disease onset, may present with an almost continuous or semi- has been named “indeterminate” sleep [79]. Moreover, sleep or-
continuous state (status cataplecticus) during which fragments of ganization represents one of the pivotal biomarkers of neuro-
REM sleep may abruptly intrude into wakefulness. All through this developmental maturation in premature newborn [80], and
abnormal boundary state, children present with fluctuating preborn infants have a greater proportion of indeterminate states
remarkable facial atonia along with stereotyped dyskinesia mainly and poor sleepewake alternation [80].
involving the face and the arms [77]. In adults, instead, status cat-
aplecticus is usually precipitated by anticataplectic drug with- Pathophysiology
drawal and may consist in a prolonged period (up to several days),
with repetitive cataplexy episodes, hallucinations, automatic be- So far, SD presenting as agrypnia excitata has been mainly linked
haviors, sleep attacks, but no stereotyped dyskinesia [78]. to a thalamo-limbic GABAergic dysfunction that releases the hy-
pothalamus and brainstem from the cortico-limbic control [55].
The indeterminate sleep SD type GABAergic impairment may be due to different causes, i.e., direct
degeneration of the thalamus in prion disease [47e50], autoanti-
In clinical practice it is frequent to observe patients with bodies targeting the thalamo-limbic structures in autoimmune
neurodegenerative diseases, such as PD and DLB, in whom the encephalitis [51,52], and sudden change in GABAergic synapses in
progression of neurodegeneration and associated external trig- the limbic system from a down-regulation induced by alcohol or
gers (i.e., fever, metabolic abnormalities, hospitalization, drugs, drugs [53]. Therefore, the thalamic involvement may be considered
E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17 13

hypothalamus and the limbic area in GBS [21] and narcolepsy Type
1 [81].
Thus, structural or functional (autoimmune or metabolic)
impairment of thalamus or of structures that interact with the
thalamus (mainly frontal and cingulate cortices) may account for
SD in this wide spectrum of diseases. In fact, impairment of the
circuits orchestrating the states of being may occur at different
nodes/levels. However, when the thalamus is the principal target of
the pathological process, it results in agrypnia excitata [48,55].
Beside the neuronal structures involved in sleepewake regula-
tion, a direct role of potassium channels impairment has been
advocated to explain sleep abnormalities in Lg1 antibody mediated
encephalitis. Hence, recent experimental data have shown that
sub-families of VGKCs are involved in wake-sleep cycle regulation
[82] and mutation of the Shaker gene, which encodes for a VGKC
(Kv1), has been associated with a short-sleeping phenotype in
drosophila [83]. In narcolepsy, instead, the lack of Hcrt-producing
cells, resulting in undetectable Hcrt-1 levels in the CSF [84],
seems to have a pivotal role in promoting SD. Indeed, there are
many studies supporting the importance of Hcrt-1 for arousal/
states stability [85] and REM-sleep modulation [86], and animal
models have shown that Hcrt knockout or Hcrt-R2 deficient mice
have normal amounts of sleep and wakefulness but exhibit an
increased instability of behavioral states [87].
Interestingly, one of the most striking features of SD is its as-
sociation with motor hyperactivity characterized by nearly constant
body movements, ranging from simple twitching, jerks and distal
limb movements to enacted dreams and to behaviors of the oneiric
stupor.
Based on the reported cases, we may distinguish mainly three
categories of abnormal movements associated to SD:

1) the purposeless and simple movements (excessive twitching,


jerks of the limbs or trunk or whole body movements);
2) the “dream-enactment” behaviors (e.g., punching, kicking,
gesturing, raising the hand), and
3) the stereotyped, repetitive, routine behaviors, mimicking ges-
tures of daily life such as buttoning a shirt or manipulating a
fictive object, typical of oneiric stupor.

The first type has been reported in almost all forms of SD and
Fig. 4. Polysomnographic features of a 63 y-old female with a 13 y history of idiopathic represents the loss of the inhibition of motor activity and of muscle
PD referred for nocturnal agitation. Over a time span of 8 h of night sleep, no sleep tone that physiologically occurs during sleep. To some extent, this
figures can be recognizable on her PSG. In the upper panel (W) she is awake with eye
motor hyperactivity may resemble that of the sleepewake transi-
closed; in the middle panel (sleep), she has the eyes closed and does not move (this
represent 2% of the epochs), in the lower panel (98% of the recorded epochs) the pa- tion and, thus represents the motor counterpart of sleep instability
tient stays with her eyes closed, quiet, displaying movements and behaviors. Abbre- or, alternatively, it may resemble the usual motor activity of a REM
viations (from top to bottom): EOG-R, right electro-oculogram; EOG-L, left electro- sleep episode that would be rich in phasic events: body jerks, head
oculogram; F3-A2, C3-A2, O1-A2, EEG channels; chin, mylohyoideus muscle; ECG,
jerks, frequent twitching of the extremities.
electrocardiogram; Tib-R, right tibialis anterior muscle; Tib-L, left tibialis anterior
muscle; Airflow, oral respirogram; Thorax, thoracic respirogram; Abdomen, abdominal
Dream-enacting episodes are mainly reported in subtle forms of
respirogram. SD, indicating that the neurophysiological substrate is that of RWA
and not of mixed W/stage 1 NREM REM/RWA. Such movements are
to be the anatomical biomarker of agrypnia excitata [48,55]. mainly reported in SD associated with autoimmune encephalopa-
Accordingly, in the case-reports describing the variant forms of CJD, thy or in prion diseases other than FFI, as well as in MSA [40].
without prominent thalamic involvement, the full-blown spectrum In the stereotyped and “purposeful-resembling” behaviors of
of agrypnia excitata cannot be recognized [60e65], and functional oneiric stupor, gestures are different from the vigorous and
or anatomical abnormalities of different parts of the brain have animated behaviors of the “typical” RBD. Studies on mental recall
been reported in the “intermittent/intermediate” subtype of SD. In after RBD episodes [88] report that mentation is mainly, but not
fact, in the autoimmune encephalitis other than Morvan's syn- always, that of a dream, often brief, in which emotions and mem-
drome, different structures apart from the thalamus, seem to be ories are transformed into a fantastic movie-like plot. Conversely, in
targeted by the neuropathological process, such as the dorsolateral oneiric stupor a single oneiric scene is usually reported [89].
midbrain, the amygdala [23], the hypothalamus, and the Moreover, oneiric stupor is an almost sub-continuous state, and
mammillary bodies [24] in anti Ma encephalitis, the neocortex and this is very visible if the patient is left alone and not stimulated [89],
the limbic area in anti Lgi1 antibodies encephalitis [67,68], the whereas RBD is a dynamic process [88,90]. Accordingly, acting-out
14 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17

behaviors of oneiric stupor have been reported to last longer 1) classically defined SD [47e57], which includes diseases grouped
(52 ± 47 s, mean ± SD), when compared to RBD episodes (16 ± 17 s) under the name of agrypnia excitata, and which represents the
[89]. most severe form of SD. Peculiar features are: complete loss of
Finally, while PSG displays the RWA pattern in RBD, it discloses sleep (agrypnia), loss of circadian pattern, autonomic imbalance
an admixture of stage 1NREM/REM sleep in oneiric stupor. Thus, and oneiric stupor. No conventional state of being can be iden-
the different motor patterns may be the expression of the asso- tified anymore. This condition is related to functional (autoim-
ciated sleep mentation, which in oneiric stupor is much more mune or toxic) or structural (neurodegeneration) impairment of
similar to that reported in NREM sleep than in REM sleep. Indeed, the thalamus;
mentation during REM sleep seems to be more vivid, bizarre, 2) intermittent/Intermediate SD [21e24,66e72,74e78] in which
emotionally charged, hallucinatory and story-like (with a more at times proper sleep may still be recognizable but features of
developed plot) [88,90] than that of NREM sleep, which is more different states of being sub-continuously merge generating a
thought-like and linked to current concerns [91]. Recently, anti-N- poorly structured and unstable sleep, along with motor
methyl-D-aspartate- (NMDA) receptor encephalitis has been pro- manifestations coming into the forms of excessive twitching
posed to be to some extent a form of SD [92]. Hence, together with and jerks, dream enactment behaviors, or cataplexy. This
impaired consciousness, autonomic instability and hypo- subtype is mainly linked to autoimmune diseases and narco-
ventilation, nearly 90% of these patients present complex bilateral lepsy Type 1. In this subtype, apart from the thalamus,
antigravity stereotyped movements of the arms, perioral and eye different brain structures (mainly of the forebrain) may be
movements and, less frequently, leg movements [93]. These involved.
movements occur when patients enter in a state of subcon-
sciousness [94]. Moreover, severe organic insomnia has been re- Finally, there is some suggestion that in neurodegenerative
ported in these patients [95] and NMDA R antibodies may mediate disorders, such as in parkinsonian conditions, there may be a pro-
GABAergic dysfunction [94,95]. However, conclusive findings are gression from state dissociation disorders (namely RBD or AMBEs)
not available since PSG studies are lacking and the EEG during to SD [40,41]; and SD has been recently reported in the late stages
these episodes has been reported to be characterized mainly by of congenital neurodegenerative diseases [56,57]. Thus, it seems
generalized slowing [95]. that progressive degeneration of brain structures and altered
Overall, two theories have been proposed to explain these neurochemistry with aging or pathological processes, in association
types of movements in SD. The first is that they represent the with internal or external triggers, may result in the dissociation of
expression of the related neurophysiological states [92]. Indeed, states. In some way, this closes the cycle, as the reverse of sleep
patients are not able to reach any full-blown state of being, thus ontogeny. In fact, during embryogenesis, there are no clear-cut
the movements may reflect this “undefined” status, merging states, but rather a simultaneous admixture of all stages occurs.
mentation of NREM and REM sleep [55]. The second theory refers Gradually, the currently unknown central networks responsible for
to neuroethological models based on the possible release of the synchronization of the state-specific variables develop. Func-
central pattern generators: species-specific innate stereotyped tional or structural damage or degeneration of these networks, at
motor patterns generated by neuronal networks located at the different levels, will result in loss of this complex orchestrated
subcortical level (brainstem and spinal cord) and under the in- process. Indeed, even if sleep is a property of small groups of
fluence of the phylogenetically recent neocortical structures [96]. neurons [4], usually in humans it manifests as a global phenome-
Central pattern generators are under tonic supratentorial non with conventionally defined clinical and neurophysiological
GABAergic inhibitory control [97] and therefore the GABAergic descriptors of each different stage. However, if the central neural
impairment may reduce corticostriatal input and pallidal- network orchestrating the synchronization characterizing the
mesencephalic tonic inhibition, releasing brainstem pattern states of being fails (episodically or chronically), it will result in
generators from inhibitory control. In this respect, the patterns of admixed states, which would not fit anymore in any of the
facial and jaw movements are reminiscent of the oral and conventionally defined states of being. There is evidence that the
masticatory automatisms observed in complex partial seizures structures most frequently involved/impaired in generating
[96]. However, a part from this the movement pattern of SD is extreme dissociation are located in the forebrain or brainstem,
quite different from that of other parasomnias or that of frontal which are known to orchestrate sleepewake regulation [98].
lobe epilepsy in which the release of central pattern generators However, the impairment may arise at different nodes/levels, giv-
has also been invoked [96]. ing rise to an imbalance in communication and synchronization
between neuronal structures because of uncoupling of brain func-
tioning networks. The complete loss of sleep and oneiric stupor
Discussion characterizing agrypnia excitata seem to be brought mainly by
thalamic involvement.
With this review, we aimed to render a comprehensive By reviewing the literature dealing with state dissociation dis-
overview of conditions related to an impairment of state- orders and SD, it becomes evident how it is difficult to classify these
determining boundaries. Firstly, we divided these conditions in conditions according to the conventional/classical sleep classifica-
state dissociation disorders and SD. Conditions characterized by tion and to score sleep stages with the current scoring system.
the intermittent/episodic occurrence of features of one state of Therefore, it emerges that new sleep stages need to be defined and
being into an ongoing main state belong to the first category. identified taking into account the results of the latest evidence
Conditions in which the state-determining boundaries are coming from studies using more precise techniques (such as
further compromised with inability to generate any convention- spectral EEG analysis, functional brain imaging), but also in light of
ally defined state of being or frequent state transitions and new knowledge advances by means of integrated study approaches
synchronous occurrence of features of different states of being, (as for example simultaneous high-density EEG recordings and
belong to the second category. SD may be further divided, on the functional neuroimaging). The current sleep classification [5] as
basis of peculiar clinical, anatomical and neurophysiological well needs to be reviewed because conditions such as SD or POD
features, into two subtypes: cannot be merged with RBD.
E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17 15

Moreover, most of the state dissociations disorders/SD reported


in the autoimmune encephalitis have been poorly investigated with Research agenda
PSG studies and, therefore, conclusive remarks are not available
and additional researches/cohort-studies are needed in order to 1) Conventional/classical sleep classification and scoring
better characterize the sleep pattern of these patients and to pro- system are no longer able to define the complex nature of
pose an evidence-based new classification. the basic states of being. New (dissociated) sleep stages
There is some suggestion that SD may be the ending point of a need to be defined and identified taking into account the
progressive degenerative process [40,41,56,57] and, accordingly, it recent findings but also by means of further studies using
would be worthwhile in the future to characterize sleep pattern in multiple approaches (such as simultaneous high-density
the advanced/final stages of neurodegenerative disorders. EEG analysis and functional brain imaging). This prob-
Finally, as already prompted by Tononi and Cirelli [99], an ably would give more clues in order to understand the
additional question emerges. Considering that one of the still mechanisms and networks underlying SD.
controversial function of sleep seems to be that of maintaining 2) Additional research is warranted in order to better char-
synaptic homeostasis and to facilitate memory consolidation, how acterize sleepewakefulness states macro and micro-
is it possible that patients with SD present an impairment of vig- structural changes and in order to set up an original and
ilance with preserved intellectual functions? [40] Is it then valid classification of state dissociation disorders and SD.
possible that this function of sleep may be dissociated from the 3) Are conditions such as “delirium/hallucinatory state” as
polysomnographic and behavioral manifestation of sleep? If so, it seen in critical illness or in some elderly inpatients, sub-
might be hypothesized that SD may represent a type of “mosaic types of SD? PSG studies are lacking in these conditions.
sleep”, so that some neurons still preserve sleep even if this is not 4) May conditions such as hallucinatory states, seen in in-
recognizable on the scalp EEG. Thus, focusing only on sleep patients with neurodegenerative disease or autoimmune
physiology to investigate such states of dissociation is no longer encephalopaties, be considered a form SD? These con-
sufficient and most likely in the near future new approaches, such ditions too need to be captured by means of extensive
as high-density PSG/EEG, spectral EEG, functional brain imaging, video-PSG recordings.
and molecular studies may facilitate the development of a deeper 5) Considering the pivotal role of Hcrt-1 in maintaining
and more refined understanding of this important area of sleep arousal/states stability and in modulating REM sleep, it
science. should be worthwhile to check for its CSF levels in all the
conditions that present with SD, especially those pre-
senting with the “intermittent/intermediate” subtype.
6) May the new concepts of “state dissociation” and
“mosaic sleep” also be a key to the study of other states
of being (i.e., vegetative state)?
Practice points
7) May conditions such as daytime hallucinations or auto-
matic behaviors, often observed in schizophrenia be
1) State dissociation disorders may rarely occur physio-
linked somehow to a state boundary control impairment?
logically, mainly at sleepewake transition, or be a “para-
8) Do state dissociations occur, even if transiently, in the
physiological” phenomenon as seen in parasomnias or
very elderly shortly before death e i.e., in the “agonal
in sleep inertia.
state?”
2) State dissociation disorders are more frequent in
particular diseases and may be a clue toward their
diagnosis, such as cataplexy in narcolepsy type 1, or a Conflicts of interest
biomarker for impending neurodegeneration, such as
REM sleep behavior disorder in parkinsonian conditions. The authors do not have any conflicts of interest to disclose.
3) Status dissociatus (SD) is the extreme expression of state
dissociation as the brain is no longer able to produce a Appendix A. Supplementary data
full-blown state of being or presents with frequent state
transitions and synchronous and aberrant occurrence of Supplementary data related to this article can be found at http://
features of different states of being. dx.doi.org/10.1016/j.smrv.2015.07.003.
4) The most severe type of SD is that seen in agrypnia
excitata in which there are no recognizable neurophysi-
ological features of sleep, along with a nearly continuous References
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