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 R
ef
^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-

The states of being are characterized by an identifiable and
stable cluster of behavioral, neurophysiological and autonomic
descriptors, observed over a period of time. In the classical sleep
stage scoring system [1], this period has an arbitrary fixed length of
30 s, allowing the identification of both long-lasting phenomena,
such as muscle tone changes, subcontinuous EEG alpha or slow-
* Corresponding author. Department of Biomedical and Neuromotor Sciences,
Alma Mater Studiorum, University of Bologna, Via Altura 3, Bologna, Italy. Tel.: þ39
051 4966924; fax: þ39 051 4966098.
E-mail address: giuseppe.plazzi@unibo.it (G. Plazzi).
lasting transient phenomena such as eye movements, short mus-
cle contractions, sleep spindles, K-complexes, etc. The combination
of these parameters has empirically allowed finding clusters
defining each state (namely wakefulness, rapid eye movement
(REM) sleep and NREM sleep) (Supplemental materials: Table 1).
These clusters are typically preserved in most of the sleep dis-
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
is characterized by the disintegration of these clusters, with the
asynchronous occurrence of the various components of the
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
AMBEs arousal-related motor-behavioral episodes
caspr2 contactin-associated protein 2
CSF cerebro-spinal fluid
DLB dementia with levy bodies
EEG electroencephalography
EMG electromyography
FFI Fatal familial insomnia
GBS Guillain Barre
syndrome
Hcrt hypocretin
Lgi1 leucine-rich glioma inactivated 1
MSA multiple system atrophy
NMDA N-methyl-D-aspartate
cluster defining a single state over the established epoch length
[2,3]. This group of conditions will be the focus of this review.
It is important to pinpoint that also in normal subjects an
admixture of features of different stages may occur, mainly at state
transition. Usually, this dissociation is brief and emerges only at a
neurophysiological level; however, if it lasts longer, it may result in
behaviors such as hypnagogic hallucinations, lucid dreams or sleep
paralysis.
For the sake of clarity, it should also be mentioned here that the
type of sleep abnormalities that will be discussed in this review
does not always refer to the recently introduced concept of “local
sleep” [4]. This concept refers to the possibility to identify discrete
neuronal aggregates that show features of one state while others
are exhibiting features of a different state also in physiological sleep
of healthy controls. However, the sleep/wake dynamics are still
recognizable as a “global” phenomenon during which “local”
neuronal aggregates might disentangle temporarily from the global
state and engage a different state, obtaining a sort of state disso-
ciation. On the contrary, the conditions that will be mainly treated
here can be characterized by a much more stable and profound
dissociation during which no feature clusters nor states can be
distinguished. However, in order to give a comprehensive analysis
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.
Literature search criteria
We searched the Medline database (via PubMed: http://www.
ncbi.nlm.nih.gov) for publication between 1986 to January 2015,
using the search terms: status dissociatus (SD), state dissociation,
dissociation of states, dissociated states, narcolepsy, narcolepsy
with cataplexy, narcolepsy type 1, REM sleep behavior disorders,
parasomnia, parasomnia-overlap syndrome, lucid dreaming, hal-
lucinations, sleep inertia, sleep paralysis, agrypnia excitata, poly-
somnography* and encephalopathies, drug intoxications, alcohol
withdrawal, neurodegenerative diseases. Only papers in English
were selected and reference lists of the articles retrieved by the
electronic searches were checked for other relevant reports not
indexed in the electronic database. In addition, original articles
focusing on pathophysiology, or single case reports of particular
interest were eventually included even if published before 1986.
From dissociation of states to “status dissociatus”
In 1991, Mahowald and Schenck [2] proposed a classification of
the dissociation of states based on the parent (or main) state; by
using this model, the following dissociations can be recognized:
N type 1 narcolepsy type 1
OSAS obstructive sleep apneas during sleep
PD Parkinson disease
PLMs periodic leg movements
POD parasomnia overlap disorder
PSG polysomnography
RBD REM sleep behavior disorder
REM rapid eyes movement
RWA REM-sleep without atonia
SD status dissociatus
SOREMP REM sleep onset periods
VGKC-Ab voltage-gated potassium channel complex antibodies
W wake
- Dissociation from prevailing wakefulness, due to intrusion of
features of other stages into ongoing wakefulness;
- Dissociation from NREM sleep, due to intrusion of features of
other stages into ongoing NREM sleep and;
- Dissociation from REM sleep, due to intrusion of features of
other stages into ongoing REM sleep.
For the sake of simplicity, we will use the labels reported above
to classify the spectrum of state dissociation disorders. The number
of diseases, which can be associated with an abnormal dissociation
of states is extensive (Supplemental materials: Table 2). However,
one should acknowledge that the above-mentioned classification is
not always thorough as there are more complex conditions (i.e.,
parasomnia overlap disorder) that would not fit in any of these
boxes. Moreover, as for all the classifications, which try to underpin
the complexity of human brain, this categorization may at times
sound artificial as in particular conditions more than one type of
dissociation may occur simultaneously. Examples are conditions
classified among the “within-mind” dissociation that may present
also with features of the “mind-body” dissociation (as seen in
automatic behaviors or in NREM parasomnia) or vice-versa as seen
in sleep paralysis (see later).
Dissociation from wakefulness
There are several examples of behaviors/disorders emerging
from the intrusion of other states into wakefulness.
Within-mind dissociation
In this subtype of dissociation from wakefulness, the mind
simultaneously contains elements of wake as subjects may retrieve
quite a good recollection of the mental experience and of the
environmental stimuli and a wake motor aspect (eyes open, motor
tone present with at times even complex motor behaviors) and
elements of REM sleep (vivid dreams) or of NREM sleep (dream-like
mentation).
They include hypnagogic or hypnopompic hallucinations, and
complex nocturnal hallucinations in which dream mentation oc-
curs during the transition from sleep to wakefulness and vice versa.
Hallucinations at the wakeesleep transition are typical of narco-
lepsy [5,6], although they can also be the consequence of alcohol/
drug intoxication or withdrawal, of brainstem or thalamic lesions,
severe visual loss (Charles Bonnet syndrome) and of other neuro-
logical conditions (autoimmune encephalitis) [5].
Yet, visual hallucinations are common in neurodegenerative
diseases, such as Parkinson disease (PD) and dementia with Levy
 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
bodies (DLB) [7] and reputedly related to the occurrence of REM
sleep mentation [8,9].
Moreover, even normal subjects may experience somatosensory
illusions or hallucinations at wakeesleep transitions, especially
during childhood or in the setting of sleep deprivation or stressful
events [10] underlining the fact that switch errors may frequently
occur also in the normal population in the “pre-dormitum”. The
latter, indeed, represents the natural setting for the onset of
physiological states of dissociation [4].
The intrusion of sleep elements into wakefulness would pro-
mote also the emergence of automatic behaviors. Automatic be-
haviors are difficult to capture in the laboratory setting and there
are no conclusive polysomnographic documentations of this con-
dition, therefore it is still unclear if they are due to NREM or REM
sleep intrusions. They are typically seen in pathological conditions,
such as idiopathic hypersomnia, and in narcolepsy, but may be
experienced also by healthy individuals [5]. During such dissocia-
tion, it may be seen that the subjects during a conversation pro-
nounce some out-of-context sentence or perform an inappropriate
action that are reputedly related to a brief dream mentation. At
times subjects may perform complex behaviors, for example
driving long distances.
Other examples are sleep drunkenness or sleep inertia, during
which an impairment of cognition and attention occurs, in the
transition between sleep and wake, with EEG features of wake and
light NREM sleep. Also this type of dissociation is common in
idiopathic hypersomnia [5].
Mind-body dissociation
In this subtype of dissociation from wakefulness the body is
“asleep” (paralyzed) while the mind is awake. Cataplexy and sleep
paralysis are examples of such dissociation.
Cataplexy is thought to be due to REM sleep muscle atonia
surfacing during wakefulness and triggered by strong, mainly
positive, emotions [5]. Cataplexy is the typical motor feature of
narcolepsy type 1.
Sleep paralysis is a conscious state of involuntary immobility
typically arising on awakening from REM sleep or at the beginning
of a REM sleep onset period (SOREMP) and due to persistence/
anticipation of REM sleep atonia, freezing voluntary movements in
an otherwise normally awake brain [5]. It is frequently reported in
narcolepsy or idiopathic hypersomnia but, less frequently, it may be
reported in the general population with similar triggers as for
hypnagogic hallucinations [5].
There is very scarce EEG documentation of sleep paralysis, but a
recent report highlighted that the EEG traces presented two main
frequency components, one in the wake state range with eyes
closed (9 Hz) and one in the REM sleep range (19 Hz) [11]. Hence,
this is suggestive of a dissociated state of mind as well.
Dissociation from NREM sleep
Within-mind dissociation
Examples of this subtype of dissociation are the disorders of
arousal. They include a spectrum of widely overlapping conditions,
ranging from confusional arousals, to somnambulism and to sleep
terrors, which are named NREM parasomnias, as a group. Some-
times, they may also present with peculiar behaviors, namely
“sleep-related eating disorder” and “sleep-related sexual activity”.
They result from an admixture of wakefulness and NREM sleep and
may present with different degrees of behavioral and autonomic
features [5].
7
Subjects typically present with eyes open, showing an empty
gaze and with retained muscle tone, preserving the ability to move
and to interact with the environment while performing inappro-
priate behaviors. Scalp EEG shows admixed features of NREM sleep.
The intracerebral EEG recording of a patient with confusional
arousals, as part of a presurgical study [12], demonstrated different
local activations with wake EEG on the motor and cingulate cortices
and increased delta activity on the fronto-parietal associative
cortices. Furthermore, activation of thalamo-cingulate pathways and
persistent deactivation of other thalamo-cortical arousal systems
have been shown by means of single photon emission computed
tomography while capturing an episode of sleepwalking [13].
NREM parasomnias often show a familial predisposition,
although no genes have been identified as yet. They are generally
more frequent during childhood, but may persist or even arise during
adulthood (even without any underlying psychopathology) [14e16].
Genetic factors, external triggers (sleep deprivation, sleeping in
novel or other particular settings, noise, etc.) or internal triggers
(anxiety, stress) may act by modifying the arousal threshold and
precipitating the persistence of such dissociation [15e17].
Dissociation from REM sleep
Mind-body dissociation: REM sleep behavior disorder
REM sleep behavior disorder (RBD), i.e., dream enacting be-
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 is asleep (REM dream mentation) while the body is awake
(spinal motor neurons are still excitable). RBD seems to be due to a
dysfunction of the brainstem structures regulating REM sleep ato-
nia, i.e., subceruleus and magnocellularis nuclei and their anatomic
connections, including those with the amygdala [5].
RBD may present as an acute phenomenon or as a chronic dis-
order. Acute/subacute RBD cases are rare and mainly seen during
intense REM sleep rebound states [5], such as during withdrawal
from alcohol abuse and from sedative-hypnotic agents, or in asso-
ciation with certain medications or drug intoxication mainly
involving antidepressants [18].
Transient RBD has also been reported in the context of auto-
immune diseases. In the anti-voltage-gated potassium channel
complex antibodies (VGKC-Ab) encephalitis, it has been argued that
RBD could be linked to the impairment of limbic structures [19,20].
In the Guillain Barre
syndrome (GBS), patients with RBD and SD
showed decreased cerebro-spinal fluid (CSF) levels of hypocretin-1
(Hcrt-1), leading to the hypothesis that the autoimmune process
can somehow involve also the central nervous system [21]. More-
over, a more complex dissociation of states, with clinical and
pathophysiological features of both RBD and narcolepsy, has been
reported in anti Ma 2 encephalitis [22e24].
The chronic idiopathic form is mainly seen as an early marker of
an impending neurodegenerative disease and recently identified as
a promising candidate for testing disease-modifying agents [25e30].
Even if RBD is most commonly a precursor of the a-synuclei-
nopathies, i.e., of PD, DLB and multiple system atrophy (MSA)
[28,30,31], it has sometimes been reported in tauopathies, as well
as in other neurological disorders as spino-cerebellar ataxia type 3,
brainstem lesions and myotonic dystrophy disease [5,32e34]. RBD
is also common in narcolepsy [35].
Sometimes full-blown RBD does not occur even if the physio-
logical atonia of REM sleep is lacking in the chin muscle (but not in
the limbs where atonia is preserved). Hence, RWA may be defined
as a neurophysiological dissociation (muscle tone is dissociated
from the parent state).
8 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
Within-mind dissociation: lucid dreaming
Lucid dreaming is the experience of being aware of dreaming
while asleep and continuing to dream. Lucid dreaming has been
documented by polysomnography (PSG) to occur during REM sleep,
indicating that lucid dreaming is a dissociated REM sleepewakeful
state. Lucid dreamers may recognize that they are dreaming, but
may also develop some control of the dreaming activity (changing
the setting, the characters or the scenario) as well as some control of
the eye movements (by displaying specific eye signals to be recog-
nized by the researcher when they are aware of dreaming).
Over a sample of nearly one thousand adults, 51% subjects re-
ported experiencing a lucid dream at least once in life, while the
monthly frequency of lucid dreams is higher in children than in
teenagers and adults. Of note, up to 78% of patients with narcolepsy
are lucid dreamers [36].
Intriguingly, it has been reported that healthy subjects during
REM sleep may generate some “conscious” experience (reflexive
consciousness), showing that the brain still keeps the capacity to
detect and categorize internal states of mind [36]. Moreover,
recently Mazza et al. [37] reported the observation of a patient who,
while being recorded with intra-cerebral electrodes for refractory
epilepsy, was able to reproduce during REM sleep a motor behavior
performed during wakefulness with EEG activity comparable to
that of wakefulness over the prefrontal and parietal areas and over
the anterior cingulate cortex.
Intrusion of NREM in REM sleep and vice versa
This type of dissociation includes conditions/disorders, which
can be better recognizable by polysomnographic recording rather
than clinically.
Examples are:
- “spindling” REM sleep (i.e., the presence of spindles during REM
sleep), as seen in patients taking benzodiazepines [5].
- muscle twitches, periodic leg movements (PLMs), and whole
body jerks during stage 3 NREM sleep, as seen in some PD, MSA
or DLB patients [38,39].
- REM sleep polygraphic features during NREM sleep, as seen in
some patients with PD or with DLB [39], or REMs during NREM
sleep in subjects taking antidepressants (“Prozac eyes”) [5].
Finally, as already mentioned, among the spectrum of state
dissociation disorders and SD there are borderline disorders, in
which different subtypes of state dissociation disorders may occur.
Indeed, in these conditions, elements of wake may occur either
during an ongoing NREM sleep or REM sleep and occasionally
features of these two latters as well may be merged together. We
report here some examples:
- conditions with admixture of features of stage 2 of NREM sleep
(spindles) with REM sleep features (electro-oculogram with
REMs, EMG phasic twitches) and complex behaviors as
described in neurodegenerative diseases or transiently before
the development of the full-blown SD [40,41].
- parasomnia overlap disorder (POD) [5,42,43].
Parasomnia overlap disorder
In the rare POD patients have both clinical and PSG evidence of
RBD and of a disorder of arousal from NREM sleep [5,42,43]. This
condition is male predominant. POD patients have an earlier age at
onset (childhood or adolescence) than patients with RBD alone, and
in most of them the disorder of arousal precedes RBD [5]. Both
idiopathic and symptomatic forms have been reported [5]. The list
of symptomatic forms is large even if coming essentially from single
case reports and it includes narcolepsy, multiple sclerosis, brain
tumor, rhombencephalitis, brain trauma, congenital Moebius syn-
drome, Machado-Joseph disease, various psychiatric disorders and
their pharmacotherapies, substance abuse disorders, and with-
drawal states. However, only few studies report details on neuro-
physiological investigations [43].
POD pathophysiology is unknown. Similarly to RBD and SD, in
POD there is a motor/behavioral disorder occurring during sleep
along with the presence of excessive phasic EMG twitching.
Currently, POD is classified as a variant of RBD [5]. However in
the idiopathic forms, a correlation with neurodegeneration is still
doubtful [44].
Still, pertinent to this category are also the arousal-related
motor-behavioral episodes (AMBEs) occurring from either REM or
NREM sleep in PD, DLB patients [41] and subjects with severe OSAS
[45]. They may represent confusional states arising from sleep.
Interestingly, in neurodegenerative diseases, it appears that
sometimes progressive thalamo-cortical network/neocortical
degeneration may lead from RBD to AMBEs and, in some cases, to
the full-blown SD [40,41].
Status dissociatus
SD represents the extreme expression of state dissociation, due
to the complete breakdown of state-determining boundaries.
Classically defined SD consists of nearly continuous motor and
verbal behavior, with experience of dreaming, in the absence of PSG
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
behavioral, neurophysiological, and autonomic patterns typical of
any state of being [2,3], and thus it is unable to produce a fully
blown state of being. Currently, SD is classified among the subtypes
of RBD [5].
Dissociated sleep was previously reported as a polysomno-
graphic trait in tricyclic-medicated narcoleptic patients [46], while
the concept of SD was first introduced by Mahowald and Schenck in
1991 [2], when they reported six patients, with different causal
triggers, of extreme state dissociation. The original paper reported
on six different conditions (chronic alcohol abuse and acute with-
drawal; olivopontocerebellar atrophy; cardiac surgery-related
central nervous system anoxic injury; OSA/narcolepsy-cataplexy
with methylphenidate/imipramine therapy; and narcolepsy-
cataplexy with methylphenidate/imipramine therapy) all charac-
terized by “ambiguous, multiple or rapid oscillation of state-
determining variables with simultaneous appearance of elements
of all three states, and with the only full-declared state being
wakefulness”. After this report, the literature on diseases/disorders
causing SD has expanded. SD has been recognized in a wide range
of clinical settings:
1) rapidly progressive neurodegenerative diseases, i.e., fatal fa-
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
withdrawal;
3) brain lesions, i.e., hypothalamic, thalamic and brainstem lesions;
4) neurodegenerative diseases (i.e., PD and DLB);
5) rare congenital malformative, possibly genetic, conditions such
as the Mulvihill-Smith syndrome.
 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
The hallmarks of “classically defined” SD are:
 lack of the conventional (PSG) features of NREM sleep, with
disappearance of spindle and delta activities. Neurophysiolog-
ical features of REM sleep, instead, persist but occur mainly in
the form of “covert” EEG REM sleep or RWA. Moreover, REM
sleep fails to stabilize, appearing in short recurrent episodes,
isolated, or mixed with stage 1 NREM potentials.
 motor agitation with enacted dreams, oneirism, continuous or
semi-continuous movements.
 impaired level of vigilance, with fluctuations in attention and,
sometimes, confabulation and mental confusion.
There are some reports on SD in the literature that do not render
the original concept. This is quite understandable because of the
complexity of the human brain engendering a wide spectrum of
state dissociations, which may not always fit into a “box”. In this
review, for the sake of simplicity, we will categorize the reported
cases of SD into two subtypes, based on severity, underlying dis-
eases, and the peculiar clinical and neurophysiological features
(Supplemental materials: Table 3):
1) classically defined SD with no recognizable neurophysiological
features of sleep, nearly continuous motor activity/hyperactivi-
ty, impaired vigilance and loss of circadian rhythm. Indeed, this
category includes the most severe form of SD, i.e., agrypnia
excitata.
2) the intermittent/intermediate SD, in which proper sleep may be
still recognizable, even if it sometimes clearly lacks of conven-
tional state PSG features for the simultaneous occurrence of
different states of being, but on occasions preserved circadian
pattern. Abnormal behaviors will be seen in both NREM and
REM sleep.
A borderline condition, which would not fit in any of the pre-
vious definitions is the “Indeterminate sleep” status as seen in
advanced PD and DLB patients, characterized by continuous slow
waves or continuous alpha rhythm (with absence of the markers
typical of other stages, namely theta, delta, spindles, k complex)
and frequently association with hallucinations, confusions and
delusions. Also in this case, circadian pattern may still be recog-
nizable. However, categorizing this entity as a different subtype of
SD is still premature because of the lack of PSG documentation in
this regard.
Classically defined/severe SD
This type of SD represents the most severe form of SD and has
been labeled as agrypnia excitata. The term put forth in 2001 by Elio
Lugaresi and coworkers [47], who first used it to lump together the
extreme sleep disorganization found in three different diseases,
namely FFI, alcohol withdrawal syndrome and Morvan's syndrome,
which share strikingly similar clinical and neurophysiological fea-
tures. FFI is as an autosomal dominant prion disease with selective
thalamic and inferior olivary degeneration at the pathologic ex-
amination [48]. It is caused by a missense mutation at codon 178 of
the prion protein gene co-segregating with methionine (met) at
methionineevaline (Val) polymorphic codon 129 in the mutated
allele [49]. Sporadic cases are rare. FFI starts at a mean age of 50 y.
There is a phenotype variability related mainly to the poly-
morphism at codon 129 of the prion protein-gene [50]. Patients
may have a short (from eight months) or a prolonged (up to 72 mo)
clinical course according to whether they are homozygote met/met
or heterozygote met/val at codon 129 [50].
9
Morvan's syndrome is a rare autoimmune disease due to anti-
bodies targeting the contactin-associated protein-2 (caspr2) of
potassium channels. It is characterized by acute or sub-acute onset
of insomnia, nearly continuous muscle activities (myokimias and
cramps), autonomic imbalance and pain in the extremities [51,52].
In most cases, the disease favorably responds to plasma exchange
or intravenous immunoglobulins within a few months, but some
cases do not recover, showing progressive worsening of symptoms,
followed by death [51,52].
Finally, alcohol withdrawal syndrome (delirium tremens) arises
after sudden alcohol withdrawal in alcohol abusers [53]. Usually
these patients present with tremors, nausea, anxiety, insomnia,
motor and autonomic activation with agitation, hallucinations and
violent dream enactment. An eventual pattern with calmer ges-
tures mimicking daily life activities similar to those described in
agrypnia excitata has been reported [2,53]. A similar condition may
occur after withdrawal from meprobamate, barbiturates, and ben-
zodiazepines [5].
The term “agrypnia excitata” aims to depict the common
framework of the above disorders. Indeed, all these three condi-
tions combine organic insomnia (i.e., the inability to initiate and
sustain sleep) with a confuso-oneiric state (dreaming behaviors
due to complex hallucinations/dreams), together with motor hy-
peractivity, autonomic hyperactivity (with tachycardia, tachypnea,
hypertension, fever, hyperhidrosis etc.) and increased blood cortisol
and plasma catecholamines [47,54,55]. Both the cyclic structure of
sleep and the circadian rhythmicity are lost. Motor activity is
increased throughout the 24 h without any circadian pattern [54].
Before reaching the state of agrypnia excitata, patients often present
with reduced sleep time, hypnagogic hallucinations and RBD, pin-
pointing the fact that agrypnia excitata may represent a continuum
with state dissociation disorders. With the progression of the dis-
ease, the patients become more and more confused, alternating
between wakefulness and oneiric confusional states, until they
reach the final state of akinetic mutism in FFI.
A state of sub-wakefulness, polygraphically characterized by
stage 1 NREM with interspersed short REM sleep episodes, be-
comes the dominant diurnal and nocturnal behavioral and neuro-
physiological pattern (Fig. 1). Clustered REM sleep episodes
frequently coincide with gestures mimicking task-oriented daily-
life activities, such as dressing, combing the hair, washing, or
manipulating an imaginary object. These episodes may also occur
with open eyes. If questioned at the end of these behaviors, patients
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
behavior, named “oneiric stupor”, represents in fact the behavioral
marker of agrypnia excitata. [55].
The full-blown picture of agrypnia excitata with the typical
neurophysiological and clinical features, leading to death, has also
been described in two unrelated cases affected by a very rare and
complex congenital neurodegenerative disease, the Mulvihill-
Smith syndrome, a rare condition characterized by progeria-like
aspect, peculiar multiple pigmented nevi, low stature, and cogni-
tive impairment (Fig. 2) [56,57].
Features of SD have been observed also in the sporadic and in
the variant forms of the CreutzfeldteJakob disease (CJD). However,
except for the form in which a prominent thalamic involvement has
been reported [58,59], the full-blown spectrum of Agrypnia Excitata
cannot be recognized [60,61].
SD has been reported also in chronic bilateral vascular para-
median thalamic lesions [62e64], and in a diencephalon and
medial pons lesion, after surgery for a tegmental ponto-
mesencephalic cavernoma [65]. These cases however lack auto-
nomic imbalance.
10 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
Fig. 1. Sleep histogram and polygraphic recordings from a 68 y-old man with Morvan's
syndrome. From top to bottom: sleep histogram showing sustained wakefulness (W)
interrupted by recurrent lapses into non-REM stage 1 sleep (N1) and into REM sleep
without atonia (REM*); polygraphic recordings showing continuous muscle-fiber ac-
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;
F3-A2, C3-A2, O1-A2, EEG channels; chin, mylohyoideus muscle; ECG, electrocardio-
gram; Airflow, oral respirogram; Thorax, thoracic respirogram; Abdomen, abdominal
respirogram; FDS-R, right wrist extensor muscle; FDS-L, left wrist extensor muscle;
Tib-R, right tibialis anterior muscle; Tib-L, left tibialis anterior muscle. Abdomen,
abdominal respirogram; Airflow, oral respirogram; chin, mylohyoideus muscle; ECG,
electrocardiogram; EOG-R, right electro-oculogram; EOG-L, left electro-oculogram; F3-
A2, C3-A2, O1-A2, EEG channels; FDS-L, left wrist extensor muscle; FDS-R, right wrist
extensor muscle; Thorax, thoracic respirogram; Tib-L, left tibialis anterior muscle; Tib-
R, right tibialis anterior muscle.
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
diffuse delta activity, typical of normal stage 3 NREM sleep, mixed
with spindles; 6) periods of normal stage 2 NREM and normal stage
3 NREM sleep, and 7) OSAS mainly during normal stage 3 NREM
sleep and inspiratory stridor secondary to vocal cord palsy. Longi-
tudinal follow-up by PSG showed no deterioration of these features
with time. Therefore, in these patients even if NREM sleep stages 2
and 3 are still recognizable, sleep architecture is unstable with
frequent stage transitions and with features of different states of
being that merge together generating behavioral manifestations,
such as undifferentiated NREM movements, RBD and even “pur-
poseful-mimicking” behavior resembling somehow those typical of
the oneiric stupor. Autoantibodies against IgLON5, a neuronal cell
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
not respond to immunotherapy and most died suddenly during
either wakefulness or sleep. Whether or not those antibodies are
the “primum movens” is still unclear, as the neuropathology per-
formed in two patients showed a previously not described neuronal
tauopathy, mainly involving the tegmentum of the brainstem and
the hypothalamus.
Moreover, a form of SD may eventually be recognized in meta-
bolic encephalopathies [72] or in critical illness due to metabolic
and functional disturbances of neurotransmitters or of brain
structures orchestrating sleep and the environmental entrainment.
However, sleep studies in such cohorts have been hampered by
cumbersome and time-consuming methods, thus we do not have
conclusive findings on this topic.
Finally, a milder form of this subtype of SD has been reported
in two middle-aged ladies affected from Harlequin syndrome [73],
which is a rare condition due to sympathetic nervous system le-
sions and characterized by asymmetric sweating and flushing on
the upper thoracic region of the chest, the neck, and the face. The
underlying nature of SD in this disorder is unknown, and authors
speculated on a possible implication of a pontine dysfunction [73].
Also SD in narcolepsy pertains to this subtype (see below).
Indeed, we have here reported a number of examples of state
dissociation disorders, which typically occur in this disease.
However, narcolepsy as a whole configures a status dissociatus
for the continuous shifts from a state dissociation to another,
which at times may even occur simultaneously (see below).
SD in narcolepsy
Narcolepsy is one of the most striking examples of state disso-
ciation. It is a hypersomnia of central origin due to loss of
hypocretin producing neurons in the hypothalamus and with a
strong genetic association with the human leukocyte antigen
DQB1*0602 haplotype, supporting the hypothesis of an autoim-
mune etiology [5]. Hence, narcolepsy (and in particular the type 1)
is not generally characterized by an increased amount of sleep but,
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
dissociated behaviors [5], as originally pointed out by Broughton in
1986 [74]. Thus, patients with narcolepsy type 1 experience a
number of state dissociation disorders, ranging from wakefulness
dissociation (cataplexy, sleep paralysis, hallucinations and auto-
matic behaviors) to REM sleep dissociation (lucid dreaming, RBD).
Such dissociated states may sometimes merge together, generating
complex admixtures such as cataplectic attacks occurring during
RBD episodes [75], or hallucinations or impaired consciousness
occurring during sleep paralysis [11,76].
Thus, all three types of dissociation may exist but patients are
still able to orchestrate the proper states of being, even if the
system is so unstable that dissociation occurs very frequently,
leading to the sudden occurrence of hallucinations or cataplectic
attacks.
The condition of “status cataplecticus” deserves a particular
mention in narcolepsy type 1. In fact, at times, the boundary
instability may be even more severe and cataplexy, in children at
disease onset, may present with an almost continuous or semi-
continuous state (status cataplecticus) during which fragments of
REM sleep may abruptly intrude into wakefulness. All through this
abnormal boundary state, children present with fluctuating
remarkable facial atonia along with stereotyped dyskinesia mainly
involving the face and the arms [77]. In adults, instead, status cat-
aplecticus is usually precipitated by anticataplectic drug with-
drawal and may consist in a prolonged period (up to several days),
with repetitive cataplexy episodes, hallucinations, automatic be-
haviors, sleep attacks, but no stereotyped dyskinesia [78].
The indeterminate sleep SD type
In clinical practice it is frequent to observe patients with
neurodegenerative diseases, such as PD and DLB, in whom the
progression of neurodegeneration and associated external trig-
gers (i.e., fever, metabolic abnormalities, hospitalization, drugs,
etc.) may eventually lead to a condition in which conventional
states of being are difficult to recognize, with EEG activity con-
sisting essentially of continuous theta or alpha activity (Fig. 4).
This EEG pattern is mainly associated with confusion, somno-
lence, hallucinations and sometimes delusions. One should
acknowledge that these conditions still need a full clinical and
neurophysiological characterization as PSG studies are currently
lacking and therefore we will not include this subtype in our
classification. However, we suggest that the term “indeterminate
sleep SD type” may be used to render this condition as it may
somehow recall what has been formerly labeled “indeterminate
sleep” in newborns [79,80].
Indeed, these conditions may represent a type of reversal of
sleep ontogenesis. In fact, NREM sleep stages, as defined in adult-
hood, do not fully develop until late infancy. Physiologically, during
the first months of life only two stages of sleep may be recognized,
i.e., the active (REM) sleep and the quiet (NREM) sleep. Yet, seldom
neither REM nor NREM sleep may be recognized configuring what
has been named “indeterminate” sleep [79]. Moreover, sleep or-
ganization represents one of the pivotal biomarkers of neuro-
developmental maturation in premature newborn [80], and
preborn infants have a greater proportion of indeterminate states
and poor sleepewake alternation [80].
Pathophysiology
So far, SD presenting as agrypnia excitata has been mainly linked
to a thalamo-limbic GABAergic dysfunction that releases the hy-
pothalamus and brainstem from the cortico-limbic control [55].
GABAergic impairment may be due to different causes, i.e., direct
degeneration of the thalamus in prion disease [47e50], autoanti-
bodies targeting the thalamo-limbic structures in autoimmune
encephalitis [51,52], and sudden change in GABAergic synapses in
the limbic system from a down-regulation induced by alcohol or
drugs [53]. Therefore, the thalamic involvement may be considered
 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
Fig. 4. Polysomnographic features of a 63 y-old female with a 13 y history of idiopathic
PD referred for nocturnal agitation. Over a time span of 8 h of night sleep, no sleep
figures can be recognizable on her PSG. In the upper panel (W) she is awake with eye
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-
tient stays with her eyes closed, quiet, displaying movements and behaviors. Abbre-
viations (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; Tib-R, right tibialis anterior muscle; Tib-L, left tibialis anterior
muscle; Airflow, oral respirogram; Thorax, thoracic respirogram; Abdomen, abdominal
respirogram.
to be the anatomical biomarker of agrypnia excitata [48,55].
Accordingly, in the case-reports describing the variant forms of CJD,
without prominent thalamic involvement, the full-blown spectrum
of agrypnia excitata cannot be recognized [60e65], and functional
or anatomical abnormalities of different parts of the brain have
been reported in the “intermittent/intermediate” subtype of SD. In
fact, in the autoimmune encephalitis other than Morvan's syn-
drome, different structures apart from the thalamus, seem to be
targeted by the neuropathological process, such as the dorsolateral
midbrain, the amygdala [23], the hypothalamus, and the
mammillary bodies [24] in anti Ma encephalitis, the neocortex and
the limbic area in anti Lgi1 antibodies encephalitis [67,68], the
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
represents the loss of the inhibition of motor activity and of muscle
tone that physiologically occurs during sleep. To some extent, this
motor hyperactivity may resemble that of the sleepewake transi-
tion and, thus represents the motor counterpart of sleep instability
or, alternatively, it may resemble the usual motor activity of a REM
sleep episode that would be rich in phasic events: body jerks, head
jerks, frequent twitching of the extremities.
Dream-enacting episodes are mainly reported in subtle forms of
SD, indicating that the neurophysiological substrate is that of RWA
and not of mixed W/stage 1 NREM REM/RWA. Such movements are
mainly reported in SD associated with autoimmune encephalopa-
thy or in prion diseases other than FFI, as well as in MSA [40].
In the stereotyped and “purposeful-resembling” behaviors of
oneiric stupor, gestures are different from the vigorous and
animated behaviors of the “typical” RBD. Studies on mental recall
after RBD episodes [88] report that mentation is mainly, but not
always, that of a dream, often brief, in which emotions and mem-
ories are transformed into a fantastic movie-like plot. Conversely, in
oneiric stupor a single oneiric scene is usually reported [89].
Moreover, oneiric stupor is an almost sub-continuous state, and
this is very visible if the patient is left alone and not stimulated [89],
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
(52 ± 47 s, mean ± SD), when compared to RBD episodes (16 ± 17 s)
[89].
Finally, while PSG displays the RWA pattern in RBD, it discloses
an admixture of stage 1NREM/REM sleep in oneiric stupor. Thus,
the different motor patterns may be the expression of the asso-
ciated sleep mentation, which in oneiric stupor is much more
similar to that reported in NREM sleep than in REM sleep. Indeed,
mentation during REM sleep seems to be more vivid, bizarre,
emotionally charged, hallucinatory and story-like (with a more
developed plot) [88,90] than that of NREM sleep, which is more
thought-like and linked to current concerns [91]. Recently, anti-N-
methyl-D-aspartate- (NMDA) receptor encephalitis has been pro-
posed to be to some extent a form of SD [92]. Hence, together with
impaired consciousness, autonomic instability and hypo-
ventilation, nearly 90% of these patients present complex bilateral
antigravity stereotyped movements of the arms, perioral and eye
movements and, less frequently, leg movements [93]. These
movements occur when patients enter in a state of subcon-
sciousness [94]. Moreover, severe organic insomnia has been re-
ported in these patients [95] and NMDA R antibodies may mediate
GABAergic dysfunction [94,95]. However, conclusive findings are
not available since PSG studies are lacking and the EEG during
these episodes has been reported to be characterized mainly by
generalized slowing [95].
Overall, two theories have been proposed to explain these
types of movements in SD. The first is that they represent the
expression of the related neurophysiological states [92]. Indeed,
patients are not able to reach any full-blown state of being, thus
the movements may reflect this “undefined” status, merging
mentation of NREM and REM sleep [55]. The second theory refers
to neuroethological models based on the possible release of
central pattern generators: species-specific innate stereotyped
motor patterns generated by neuronal networks located at the
subcortical level (brainstem and spinal cord) and under the in-
fluence of the phylogenetically recent neocortical structures [96].
Central pattern generators are under tonic supratentorial
GABAergic inhibitory control [97] and therefore the GABAergic
impairment may reduce corticostriatal input and pallidal-
mesencephalic tonic inhibition, releasing brainstem pattern
generators from inhibitory control. In this respect, the patterns of
facial and jaw movements are reminiscent of the oral and
masticatory automatisms observed in complex partial seizures
[96]. However, a part from this the movement pattern of SD is
quite different from that of other parasomnias or that of frontal
lobe epilepsy in which the release of central pattern generators
has also been invoked [96].
Discussion
With this review, we aimed to render a comprehensive
overview of conditions related to an impairment of state-
determining boundaries. Firstly, we divided these conditions in
state dissociation disorders and SD. Conditions characterized by
the intermittent/episodic occurrence of features of one state of
being into an ongoing main state belong to the first category.
Conditions in which the state-determining boundaries are
further compromised with inability to generate any convention-
ally defined state of being or frequent state transitions and
synchronous occurrence of features of different states of being,
belong to the second category. SD may be further divided, on the
basis of peculiar clinical, anatomical and neurophysiological
features, into two subtypes:
1) classically defined SD [47e57], which includes diseases grouped
under the name of agrypnia excitata, and which represents the
most severe form of SD. Peculiar features are: complete loss of
sleep (agrypnia), loss of circadian pattern, autonomic imbalance
and oneiric stupor. No conventional state of being can be iden-
tified anymore. This condition is related to functional (autoim-
mune or toxic) or structural (neurodegeneration) impairment of
the thalamus;
2) intermittent/Intermediate SD [21e24,66e72,74e78] in which
at times proper sleep may still be recognizable but features of
different states of being sub-continuously merge generating a
poorly structured and unstable sleep, along with motor
manifestations coming into the forms of excessive twitching
and jerks, dream enactment behaviors, or cataplexy. This
subtype is mainly linked to autoimmune diseases and narco-
lepsy Type 1. In this subtype, apart from the thalamus,
different brain structures (mainly of the forebrain) may be
involved.
Finally, there is some suggestion that in neurodegenerative
disorders, such as in parkinsonian conditions, there may be a pro-
gression from state dissociation disorders (namely RBD or AMBEs)
to SD [40,41]; and SD has been recently reported in the late stages
of congenital neurodegenerative diseases [56,57]. Thus, it seems
that progressive degeneration of brain structures and altered
neurochemistry with aging or pathological processes, in association
with internal or external triggers, may result in the dissociation of
states. In some way, this closes the cycle, as the reverse of sleep
ontogeny. In fact, during embryogenesis, there are no clear-cut
states, but rather a simultaneous admixture of all stages occurs.
Gradually, the currently unknown central networks responsible for
the synchronization of the state-specific variables develop. Func-
tional or structural damage or degeneration of these networks, at
different levels, will result in loss of this complex orchestrated
process. Indeed, even if sleep is a property of small groups of
neurons [4], usually in humans it manifests as a global phenome-
non with conventionally defined clinical and neurophysiological
descriptors of each different stage. However, if the central neural
network orchestrating the synchronization characterizing the
states of being fails (episodically or chronically), it will result in
admixed states, which would not fit anymore in any of the
conventionally defined states of being. There is evidence that the
structures most frequently involved/impaired in generating
extreme dissociation are located in the forebrain or brainstem,
which are known to orchestrate sleepewake regulation [98].
However, the impairment may arise at different nodes/levels, giv-
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
characterizing agrypnia excitata seem to be brought mainly by
thalamic involvement.
By reviewing the literature dealing with state dissociation dis-
orders and SD, it becomes evident how it is difficult to classify these
conditions according to the conventional/classical sleep classifica-
tion and to score sleep stages with the current scoring system.
Therefore, it emerges that new sleep stages need to be defined and
identified taking into account the results of the latest evidence
coming from studies using more precise techniques (such as
spectral EEG analysis, functional brain imaging), but also in light of
new knowledge advances by means of integrated study approaches
(as for example simultaneous high-density EEG recordings and
functional neuroimaging). The current sleep classification [5] as
well needs to be reviewed because conditions such as SD or POD
cannot be merged with RBD.
 E. Antelmi et al. / Sleep Medicine Reviews 28 (2016) 5e17
Moreover, most of the state dissociations disorders/SD reported
in the autoimmune encephalitis have been poorly investigated with
PSG studies and, therefore, conclusive remarks are not available
and additional researches/cohort-studies are needed in order to
better characterize the sleep pattern of these patients and to pro-
pose an evidence-based new classification.
There is some suggestion that SD may be the ending point of a
progressive degenerative process [40,41,56,57] and, accordingly, it
would be worthwhile in the future to characterize sleep pattern in
the advanced/final stages of neurodegenerative disorders.
Finally, as already prompted by Tononi and Cirelli [99], an
additional question emerges. Considering that one of the still
controversial function of sleep seems to be that of maintaining
synaptic homeostasis and to facilitate memory consolidation, how
is it possible that patients with SD present an impairment of vig-
ilance with preserved intellectual functions? [40] Is it then
possible that this function of sleep may be dissociated from the
polysomnographic and behavioral manifestation of sleep? If so, it
might be hypothesized that SD may represent a type of “mosaic
sleep”, so that some neurons still preserve sleep even if this is not
recognizable on the scalp EEG. Thus, focusing only on sleep
physiology to investigate such states of dissociation is no longer
sufficient and most likely in the near future new approaches, such
as high-density PSG/EEG, spectral EEG, functional brain imaging,
and molecular studies may facilitate the development of a deeper
and more refined understanding of this important area of sleep
science.
Practice points
1) State dissociation disorders may rarely occur physio-
logically, mainly at sleepewake transition, or be a “para-
physiological” phenomenon as seen in parasomnias or
in sleep inertia.
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
biomarker for impending neurodegeneration, such as
REM sleep behavior disorder in parkinsonian conditions.
3) Status dissociatus (SD) is the extreme expression of state
dissociation as the brain is no longer able to produce a
full-blown state of being or presents with frequent state
transitions and synchronous and aberrant occurrence of
features of different states of being.
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
motor activity/hyperactivity (oneiric stupor) and
impaired vigilance. This is typical of fatal familial
insomnia, alcohol withdrawal syndrome, Morvan's syn-
drome, and the very rare Mulvihill-Smith syndrome. This
condition is mainly related to thalamic damage.
5) In the intermittent/intermediate form, instead, even if
proper sleep may be still recognizable, there is a
continuous switching from a state of being to another
with intermittent occurrence of state dissociation and
with features of different states of being that at times
merge. This type is more typical of autoimmune en-
cephalitis and of narcolepsy type 1.
6) Extensive video-polysomnography is mandatory in or-
der to recognize all the above conditions.
15
Research agenda
1) Conventional/classical sleep classification and scoring
system are no longer able to define the complex nature of
the basic states of being. New (dissociated) sleep stages
need to be defined and identified taking into account the
recent findings but also by means of further studies using
multiple approaches (such as simultaneous high-density
EEG analysis and functional brain imaging). This prob-
ably would give more clues in order to understand the
mechanisms and networks underlying SD.
2) Additional research is warranted in order to better char-
acterize sleepewakefulness states macro and micro-
structural changes and in order to set up an original and
valid classification of state dissociation disorders and SD.
3) Are conditions such as “delirium/hallucinatory state” as
seen in critical illness or in some elderly inpatients, sub-
types of SD? PSG studies are lacking in these conditions.
4) May conditions such as hallucinatory states, seen in in-
patients with neurodegenerative disease or autoimmune
encephalopaties, be considered a form SD? These con-
ditions too need to be captured by means of extensive
video-PSG recordings.
5) Considering the pivotal role of Hcrt-1 in maintaining
arousal/states stability and in modulating REM sleep, it
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)?
7) May conditions such as daytime hallucinations or auto-
matic behaviors, often observed in schizophrenia be
linked somehow to a state boundary control impairment?
8) Do state dissociations occur, even if transiently, in the
very elderly shortly before death e i.e., in the “agonal
state?”
Conflicts of interest
The authors do not have any conflicts of interest to disclose.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.smrv.2015.07.003.
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