The Distinct Movement Disorder in Anti-NMDA ReceptorEncephalitis May Be Related to Status

Dissociatus: A Hypothesis

Maria Stamelou, MD, PhD,1 Giuseppe Plazzi, MD,2 Elio Lugaresi, MD,2

Mark J. Edwards, MRCP, PhD,1 and Kailash P. Bhatia, FRCP1*

1Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom2Department of Neurological Science, Universit�a di Bologna, Bologna, Italy

ABSTRACT: The majority of patients with anti-N-methyl-D-aspartate-receptor encephalitis (NMDAE)present a characteristic movement disorder, which con-sists of complex bilateral stereotyped movements ofthe arms, with perioral and eye movements, and lessfrequently involvement of the legs. We have observedstriking similarities in the characteristics of the abnormalmovements observed in NMDAE and those describedin Status Dissociatus, which is characterized by a com-plete breakdown of state-determining boundaries(wakefulness, REM and NREM sleep) and can resultfrom pathophysiologically diverse disorders (e.g. fatalfamilial insomnia, delirium tremens, Morvan’s syn-drome). Here, we suggest that the state of paradoxicalresponsiveness in which NMDAE patients present these

stereotyped movements may be that of Status Disso-ciatus and discuss the clinical similarities and patho-physiological explanations that support such asuggestion. This hypothesis explains why patients thatseem to be unconscious have a movement disorderthat is not epileptic and may have management implica-tions, since many patients with NMDAE-related move-ment disorder are treated with anticonvulsants that maynot be indicated. VC 2012 Movement Disorder Society

Key Words: Anti-NMDA-receptor encephalitis; move-ment disorder; agrypnia excitata; narcolepsy with cata-plexy; fatal familial insomnia; Morvan’s syndrome;status dissociatus

Anti-N-methyl-D-aspartate-receptor encephalitis(NMDAE) presents with fairly typical clinical charac-teristics; these include initial symptoms similar toacute psychosis and subsequent development of seiz-ures, decreased level of consciousness, autonomicinstability, hypoventilation, and a characteristic move-

ment disorder found in up to 89% of patients, oftentermed as ‘‘dyskinesia.’’1–8 This usually consists ofcomplex bilateral antigravity stereotyped movementsof the arms, with perioral and eye movements, and,less frequently, involvement of the legs (see Video,Segment 1). This is characterized to be the distinctmovement disorder of NMDAE.4

Although epileptic seizures could be the cause ofabnormal movements in an unconscious state, and cer-tainly do occur in some patients with NMDAE, thiscannot be the explanation for these movementsbecause they do not correlate with EEG dis-charges.2,3,5,6 Instead, the usual EEG abnormality dur-ing these movements is that of generalized slowing in80% of cases.3 Frontal lobe seizures may not showepileptic activity in EEG; however, there are a numberof reasons why these movements in NMDAE areunlikely to reflect frontal lobe epilepsy (FLE). First,FLE occurs mostly with the patients ‘‘awakening’’from sleep and they are conscious during the

------------------------------------------------------------Additional Supporting Information may be found in the online version ofthis article.

*Correspondence to: Prof. Kailash P. Bhatia, Sobell Department ofMotor Neuroscience and Movement Disorders, UCL Institute of Neurology,Queen Square, London, WC1N 3BG United Kingdom; k.bhatia@ucl.ac.uk

Funding agencies: M.S. is supported by a European Federation ofNeurological Societies scientific grant. M.J.E. is supported by an NationalInstitute for Health Research Clinician Scientist Fellowship.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 9 January 2012; Revised: 19 April 2012; Accepted: 8 May2012Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.25072

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attacks.9,10 Second, the semiology of the FLE attackswith extension of the head and movements of thearms, and kicking movements of the legs, since mesialfrontal involvement, is quite different from the repeti-tive, stereotyped perioral and arm movementsobserved in NMDAE (see Video, Segment 1).9,10

Third, the EEGs in none of the NMDAE casesreported in the literature have been found to showtypical findings for FLE, namely mesiofrontal epilepticactivity during these movements.3 Fourth, in none ofthe NMDAE patients do the movements respond toantiepileptic treatment, whereas classically nocturnalFLE has a good response to carbamazepine and otherantiepileptic treatments.9,10 Hence, it is highly unlikelythat these movements represent FLE.Importantly, these movements occur when patients

enter what has been described as ‘‘a state of paradoxi-cal and alternating responsiveness, varying betweenwakefulness and catatonia,’’2–5 where movements canbe influenced by sensory stimulation. Therefore, cur-rently, there is a rather unclear description of both thestate of being that these patients are in, when thesemovements occur, and the phenomenology of themovements per se.We have observed striking similarities in the charac-

teristics of both the conscious state and the abnormalmovements observed in NMDAE and those describedin Status Dissociatus, which can result from pathophy-siologically diverse disorders. We suggest that the stateof paradoxical responsiveness in which NMDAEpatients present these stereotyped movements may bethat of Status Dissociatus. This may assist in ourunderstanding of these movements in NMDAE andmay also have management implications, as manypatients with NMDAE-related movement disorder aretreated with anticonvulsants that may not beindicated.

Status Dissociatus

Three states of being in healthy individuals can berecognized: wakefulness, rapid eye movement (REM)sleep, and non-REM (NREM) sleep. State dissocia-tions are the consequence of errors in the normal pro-cess of the dynamic changes of the central nervoussystem as it moves from one state of being to another,where elements of one state persist or are recruitederroneously into another state.11–14

There are a number of well-documented state disso-ciations in humans that can occur spontaneously or asthe result of neurologic dysfunction or medicationadministration. These have been classified accordingto the prevailing present state, namely wakefulness(e.g., cataplexy or sleep paralysis in narcolepsy), REM(e.g., REM sleep behavior disorder; RBD), and NREMsleep variations (e.g., disorders of arousal).12–15 Over-

lap between these state dissociations also exists (e.g.,narcolepsy patients may also have RBD).16

The most extreme form of state dissociation istermed Status Dissociatus and results from a completebreakdown of state-determining boundaries.12 StatusDissociatus has been reported in several clinical andexperimental situations, such as hypothalamic, tha-lamic and brainstem lesions, pharmacological inter-ventions, or after sleep deprivation.11–14 StatusDissociatus is characterized by nearly continuousmotor and/or verbal behavior in the absence of poly-somnographically defined conventional REM andNREM sleep stages.11–14

Disorders Associated With StatusDissociatus

A variety of disorders with diverse pathophysiologyhave been well documented in the literature to lead toStatus Dissociatus. These include delirium tremens(DT), which occurs after sudden withdrawal of alco-hol or benzodiazepines,17 Morvan’s syndrome (MS)caused by paraneoplastic or antibodies against volt-age-gated potassium-channel–associated proteins,characterized by neuromyotonia, severe sleep disturb-ance and other features of limbic encephalitis,18,19 andfatal familial insomnia (FFI), which is a hereditaryprion disease, in which selective thalamic degenerationcauses inability to generate slow-wave sleep.19–22

The pathophysiology of Status Dissociatus is associ-ated with a thalamolimbic GABAergic dysfunctionthat releases hypothalamus and brainstem from corti-colimbic control.22–26 The GABAergic dysfunctionresults from diverse disease-specific alterations in eachdisorder: the sudden change on GABAergic synapsesin the limbic system downregulated by alcohol in DT,autoantibodies to the thalamolimbic system in MS,and direct thalamic degeneration in FFI.22,27 Patientsin Status Dissociatus, regardless of the cause, presentwith movements very similar to those observed inNMDAE (see Video, Segment 2).Another cause of dissociative state, where fragments

of REM sleep may abruptly intrude into wakefulness,is childhood-onset narcolepsy with cataplexy (NC), ahypersomnia of central origin characterized by day-time sleepiness, cataplexy, sleep paralysis, hypnagogichallucinations, and disturbed nocturnal sleep. NC islinked to the loss of hypothalamic hypocretin-1-pro-ducing neurons,28 and the strong genetic associationswith the human leukocyte antigen DQB1*0602 haplo-type29 as well as the T-cell-receptor alpha andP2RY11 receptor loci30,31 support the hypothesis thatNC is an autoimmune disease affecting hypocretinneurons. Recently, a movement disorder with stereo-typed antigravity movements of the arms, perioral and

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tongue movements, and grimacing has been describedalso in NC (see Video, Segment 3).32,33

Patients with probable multiple system atrophyaffected by RBD have also been reported later in thedisease course to develop abnormal motor, behavioral,and neurophysiological patterns during sleep consist-ent with Status Dissociatus.34 In these patients, StatusDissociatus appeared to represent the evolution ofRBD, which is not surprising because Status Dissocia-tus is the most extreme state of state dissociations,one of which is RBD.34

Could NMDAE Lead to StatusDissociatus?

We suggest here that NMDAE could also lead toStatus Dissociatus in some patients, since there arestriking clinical similarities and also pathophysiologi-cal explanations to support such a suggestion. Apartfrom the clinical characteristics of the state, includingthe characteristic movement disorder, autonomic dys-function, and paradoxical responsiveness, NMDAEpatients are also reported to suffer prodromal severesleep disturbances (mostly insomnia) in the earlystages, and later in the disease course sleep dysfunc-tion, erratic sleep patterns, insomnia, or hypersom-nia.2,6,35 In the long term after recovery, prominentsleep dysfunction, hypersomnia and sleep/wake inver-sion has been reported.6,35

The pathophysiology of Status Dissociatus inNMDAE could be related to NMDA receptor anti-body-mediated GABAergic dysfunction, leading to dis-inhibition of excitatory pathways and causing afrontostriatal syndrome and disinhibition of the brain-stem.2,4,5 Consistent with this, several NMDA-recep-tor antagonists such as MK801, ketamine, andphencyclidine cause symptoms similar to NMDAE,including psychotic behavior, purposeless movementsand autonomic dysfunction.36–40 Thus, we hypothesizethat the abnormal conscious state and movement dis-order in patients with NMDAE could be classified asStatus Dissociatus. This would explain why patientsthat seem to be unconscious have a movement disor-der that is not epileptic. Status Dissociatus seems to usto be an accurate term to describe their consciousstate, which has been characterized as reduced or par-adoxical responsiveness alternating between wakeful-ness with agitation and catatonia.2–5

Why This ParticularMovement Disorder?

It is an intriguing question why this particularmovement disorder, consisting of stereotyped antigrav-ity movements of the arms and mouth, should occur

in Status Dissociatus. Movement disorders are charac-teristically absent during sleep, although they canemerge when normal processes that maintain limb pa-ralysis are disturbed (e.g., in patients with RBD) thatin its extreme form can develop into Status Dissocia-tus.14 In RBD, movements highlighted in the literatureare those thought to represent dream enactment, suchas complex purposeful movement patterns (sometimesdescribed as ‘‘scenic’’ movement) that can in somepatients be correlated with dream content. Thesemovements likely reflect normal brain activity duringphysiological REM sleep, which is manifested asmovement by the lack of normal limb atonia duringsleep.We speculate that in the neurological conditions we

highlight here, patients rarely achieve normal wakeful-ness, normal REM or normal NREM sleep, and there-fore have movements reflecting this ‘‘twilight’’ state.Indeed, such movements may be observed in patientswith RBD, perhaps when they shift between differentsleep states. Reported movements in RBD include‘‘complex’’ antigravity stereotyped movements of thearms; abnormal tonic and phasic activity in mentalisreflecting perioral movements is commonly used as amarker for RBD.41 Another explanation could be thatcentral pattern generators in the brainstem that havebeen described to cause certain stereotyped movementsin parasomnias are released, but these movements areless complex than those observed in StatusDissociatus.42

Conclusion

Our suggestion is that NMDAE can lead to StatusDissociatus, in which ‘‘state’’ patients also manifestthis characteristic movement disorder. This is of clini-cal importance, because such patients should not betreated with unnecessary anticonvulsant medication, inthe absence of seizures, to treat this movement disor-der. It would be of interest to investigate this hypothe-sis further by performing videopolysomnographicstudies in NMDAE. This may well be technically chal-lenging due to the psychosis, behavioral disturbanceand agitation that these patients show, which requirestreatments that may alter EEG activity, as well as dueto the widespread initial involvement of the cortex,which is not the case in the other diseases we highlighthere. Polysomnography in patients not severelyaffected or during recovery as well as long-term fol-low-up polysomnographic studies could also be ofhelp in the investigation of this hypothesis.

Legends to the Video

Segment 1. A patient with NMDAE demonstratesstereotyped antigravity movements of the hands while

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in an unresponsive state with paradoxical response tostimuli. The movements are complex, with repetitivewrist movements as well as alternating movements ofthe hands from radial to ulnar deviation. This patientalso exhibited typical stereotyped perioral dyskineticmovements that can be observed at the end of thissegment.Segment 2. 3 patients, respectively, with FFI, DT,

and MS illustrating typical complex stereotyped move-ments of the hands.Segment 3. A patient with narcolepsy with cataplexy

with stereotyped perioral and arm movements.

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