Brain Stimulation xxx (xxxx) xxx

Contents lists available at ScienceDirect

Brain Stimulation
journal homepage: http://www.journals.elsevier.com/brain-stimulation

Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA)

receptor encephalitis: A systematic review of cases
Nicola Warren a, b, *, Vanessa Grote a, b, Cullen O'Gorman b, c, Dan Siskind a, b
a
Metro South Addiction and Mental Health, Brisbane, Australia
b
University of Queensland, Brisbane, Australia
c
Department of Neurology, Princess Alexandra Hospital, Brisbane, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Background: Anti-NMDA receptor encephalitis most commonly presents with psychiatric symptoms
Received 3 August 2018 such as behavioural disturbance, catatonia and psychosis. Although the primary treatment is with
Received in revised form immunomodulatory therapy, psychiatric symptoms often require adjuvant management. Side effects and
15 November 2018
treatment resistance limits the use of psychotropics, but the role of ECT has been minimally reviewed.
Accepted 30 November 2018
Available online xxx
Objective: To review the safety and effectiveness of ECT for treatment of psychiatric symptoms in anti-
NMDA receptor encephalitis.
Methods: A systematic literature review of PubMed, Embase and PsycInfo was performed from inception
Keywords:
ECT
to June 2018.
NMDA Results: There were 30 cases of ECT used in anti-NMDA receptor encephalitis. Cases were typically young
Encephalitis (mean age 27.7 years, SD 15.2) females (73.3%) with catatonia (86.7%). There was improvement of these
Catatonia symptoms in 65.2% of cases, interestingly without immunomodulatory therapy in 17.4%. ECT proceeded
without complication in 86.7% of cases, with four cases prematurely ceasing ECT with further enceph-
alitic deterioration. There were no anaesthetic complications.
Conclusions: ECT appears to be an effective and safe adjuvant treatment in anti-NMDA receptor en-
cephalitis, particularly for catatonia.
© 2018 Elsevier Inc. All rights reserved.

Introduction immunomodulatory therapy are the standard treatments [1].

However, as the rate and the nature of the deterioration from
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an psychiatric symptoms is variable and there is often a delay before
autoimmune disorder that most commonly presents to mental CSF antibody confirmation of the disorder, an initial primary psy-
health services with psychiatric symptoms such as severe behav- chiatric diagnosis of mania or psychosis is common [5].
ioural disturbance, mood disorder, catatonia and psychosis [1,2]. Treatment of psychiatric symptoms of anti-NMDA receptor en-
Anti-NMDA receptor encephalitis is estimated to account for up to cephalitis is complicated by resistance to traditional psychotropic
3% of all first episode psychosis presentations [3]. Progression of the agents, increased risk of extra-pyramidal side-effects and concern
disorder sees the development of neurological symptoms such as for lowering seizure threshold in patients already at risk of seizure
movement disorders, seizures, cognitive deficits and autonomic [2,5]. Autonomic disturbance including cardiac arrhythmias and
disturbance, often requiring intensive care admission and lengthy reduced level of consciousness also increase the risk of drug-related
hospitalisation [1]. Anti-NMDA receptor encephalitis is more side-effects. Suspected neuroleptic malignant syndrome (NMS),
common in young females, with a reported ratio of approximately 3 seen more commonly in this disorder, often prompts anti-psychotic
females:1 male, and associated with ovarian teratoma or other withdrawal [2]. For these reasons, electroconvulsive therapy (ECT)
malignancies in around 50% [1,2,4]. Tumour removal and may be of use.
There is a limited body of literature describing use of ECT in
single cases or small case series [6]. With increasing awareness and
knowledge of this disorder among mental health professionals, we
* Corresponding author. c/- Princess Alexandra Hospital, 199 Ipswich Rd, Wool-
loongabba, Qld, 4102, Australia. aimed to systematically review all published cases of ECT used in
E-mail address: [email protected] (N. Warren). the treatment of symptoms in anti-NMDA receptor encephalitis,

https://doi.org/10.1016/j.brs.2018.11.016
1935-861X/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016
2 N. Warren et al. / Brain Stimulation xxx (xxxx) xxx

and ascertain whether it was safe and improved psychiatric was reported in 10 cases and impulsivity in 6 cases. Other psychi-
outcomes. atric symptoms seen, included delusions and/or hallucinations (25
cases, 83.3%), mood disturbance (17 cases, 56.7%), pathological
Methods laughter/yelling (4 cases, 13.3%) and self-injury (2 cases, 6.7%).
Anti-psychotic medications were used in 25 cases (83.3%), with
PubMed, Embase and PsycInfo databases from inception to June 17 cases requiring multiple anti-psychotics. Suspected neuroleptic
2018, were searched using terms: NMDA, NMDAR, NMDARE, N- malignant syndrome or severe extra-pyramidal symptoms resulted
methyl-D-aspartate encephalitis, ECT and electroconvulsive ther- in the cessation of anti-psychotics in 14 cases. A trial of benzodi-
apy. All articles types, including conference posters and abstracts, azepines (lorazepam) for catatonia was documented in 19 cases
that had data for individual cases were included. Search and (63.3%).
screening were independently conducted by two authors (NW, VG) The majority of cases (20/30, 66.7%) developed neurologic ab-
at title, abstract and then full text level. References of selected ar- normalities, most commonly limb dystonia [8], orofacial dyskinesia
ticles were cross-checked to identify other potentially eligible [5], choreo-athetosis [5] and rigidity [5]. Autonomic disturbance
studies. The Preferred Reporting Items for Systematic Reviews and (17/30, 56%) - including tachycardia [6], hyperthermia [6] and
Meta-Analyses (PRISMA) statement recommendations were fol- respiratory failure [5] - and seizures (16/30, 53%) were common.
lowed and the study was pre-registered with PROSPERO, Cognitive deficits during the active phase of illness were reported
CRD42018102106 [7]. in 13 cases (43.3%). Four cases (13.3%) had isolated psychiatric
Cases were included if they received treatment of psychiatric symptoms without other abnormalities. MRI brain was abnormal in
symptoms with ECT. Those psychiatric symptoms occurred in the 6/30 (20%) cases, reporting ischaemic foci [3], T2 FLAIR hyper-
context of anti-NMDA receptor encephalitis diagnosed by positive intensity [2] and one case of an incidental temporal lobe cyst with
serum or CSF IgG antibody. Cases with suspected but unconfirmed no oedema or mass effect. There were no identified contraindica-
anti-NMDA receptor encephalitis, or those receiving ECT for other tions to ECT on neuroimaging. EEG on presentation was abnormal
indications were excluded. in 14 cases (46.7%), documented as diffuse slow waves [12],
The pre-specified variables collected included: demographics, extreme delta brush [2] and one case demonstrating epileptiform
past medical and psychiatric history, initial and subsequent clinical features.
presentation of encephalitis, investigations, psychotropic and other ECT was commenced prior to the diagnosis of anti-NMDA re-
treatments, ECT timing and prescription, noted ECT side effects or ceptor encephalitis in 21 cases (70%). Only one case reported a
other ECT considerations. Missing data was noted. Recognised anti- relative contraindication for ECT; a history of pulmonary stenosis.
NMDA receptor encephalitis symptom clusters: behaviour distur- In 5 cases antipsychotics were documented to continue during the
bance, psychosis, cognitive, movement, seizures and autonomic, course of ECT. The average number of sessions of ECT was 10 (range
were used to classify initial presentation and course of illness [2,8]. of 1e33 sessions), although this was not documented in 9 cases.
Catatonia, considered for this study part of the behavioural Overall, the ECT dosage, placement and treatment course was
disturbance cluster, was recorded if there was clear documentation poorly documented.
of diagnosis using established criteria. The Bush Francis Catatonia
Screening Instrument (BFCSI) was used to document the signs of Effectiveness
catatonia and the Bush Francis Catatonia Rating Scale (BFCRS) noted
when reported [9]. Treatment response and outcome was based on There were 23 cases which provided information on effective-
the information provided in the case reports and categorised as ness of ECT in anti-NMDA receptor encephalitis (Table 1). Of those,
resolved, improved, no improvement or deterioration. Symptoms 15/23 (65.2%) noted improvement of psychiatric symptoms, and in
following treatment were recorded. Descriptive statistics were nine of the cases the improvement was seen prior to immuno-
employed for analysis of the data. therapy. In four cases it was documented that there was complete
resolution of psychiatric symptoms (catatonia [2], not stated [2])
Results with ECT, without any immunotherapy and after treatment resis-
tance had been noted with psychotropics. In the six cases which
There were 781 citations identified in the databases after du- improved with ECT and immunotherapy, it was documented that
plicates removed. Following screening at title, abstract and full text ECT was given due to insufficient response to immunotherapy
level, 29 studies comprising 30 cases were identified from 2007 to alone. Interestingly, in two cases cognitive deficits were noted to
2018 (Fig. 1). There were 22 females and 8 males with a mean age of resolve following ECT and in three cases there was also improve-
27.7 years (SD 15.2). The youngest case was 9 years and there were ment of movement disorders, such as dyskinesia and rigidity.
10 cases under the age of 18 years. Encephalitis associated with Catatonic symptoms were noted to improve in the 5 cases in which
ovarian teratoma accounted for four cases, with no other malig- anti-psychotics were never used and in the 5 cases where anti-
nancy noted in the remaining cases. psychotics were continued throughout the ECT course.
The most common presenting feature of anti-NMDA receptor ECT was felt to be ineffective in four cases and was ceased
encephalitis in these cases was behavioural disturbance 21/30 prematurely in four cases. In the four cases in which ECT was felt to
(70%), all of these cases reporting agitation or severe irritability. be ineffective the indication was catatonia, there was more than
There were 9 cases (30%) documenting catatonia on presentation one anti-psychotic trialled prior to ECT and the mean number of
and psychosis in 8 (36.7%). The presenting symptoms and those sessions was 9.5.
during the course of anti-NMDA receptor encephalitis can be seen
in Fig. 2. During the illness course, catatonia developed in 26/30 Safety
cases (86.7%), and was noted to be fluctuating in 11 cases. An
additional 3 cases which did not document catatonia had a BFCSI In 26/30 cases (86.7%) there were no safety concerns with ECT,
over 2, indicating a catatonic syndrome. The mean BFCSI was 4.3 however ECT was ceased prematurely in 4 cases (13.3%). In 2 cases
and the most common catatonic symptoms were, in descending (6.7%) ECT was ceased after one session due to development of
order, excitement, immobility/stupor, mutism, withdrawal, seizures. In the other 2 cases (6.7%), ECT was ceased after 2 sessions
posturing, rigidity, stereotypy and perseveration. Combativeness due to concerns for neurological deterioration with limb dystonia

Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016
 N. Warren et al. / Brain Stimulation xxx (xxxx) xxx 3

Fig. 1. PRISMA 2009 flow diagram.

ECT for Anti-NMDA receptor encephalitis.

and oro-facial dyskinesia reported. There were no documented and long turnaround times for antibody testing. Almost all of these
complications from anaesthesia, with no requirement for reintu- cases had catatonia, and ECT was used for refractory psychiatric
bation or additional bloods pressure/cardiac rhythm support. symptoms, or when side effects required cessation of psychotropic
Overall, complete recovery from anti-NMDA receptor encepha- medications. Catatonia is common in anti-NMDA receptor en-
litis was documented in 18 cases, partial recovery in 10 cases, and cephalitis, present in around a third of cases overall, and carries
not documented or lost to follow up in two cases. Of note, the four significant risks of long-term immobility, deconditioning and hos-
cases in which ECT was prematurely ceased made full recoveries pital acquired infections as well as the severe consequences of
following immunotherapy. In the four cases in which ECT was felt to malignant catatonia [2,10].
be ineffective, two had complete recovery with immunotherapy ECT is highly effective in treating all types of catatonia with
and in two there was no documentation. When recovery was par- reported catatonic remission rates between 82% and 96% [10e12].
tial this was due to ongoing cognitive deficits, as seen in Fig. 2, and Both excited and stuporous catatonic symptoms were effectively
in five of these cases the cognitive deficits were only documented treated in these cases at a comparable efficacy. ECT is thought to
after treatment. Recurrence of anti-NMDA receptor encephalitis be the primary treatment of choice for catatonia with autonomic
was seen in one case, treated successfully with further disturbance, malignant catatonia or where a rapid treatment
immunotherapy. response is required [12]. This may be particularly important for
catatonia associated with anti-NMDA receptor encephalitis,
where dysautonomia is common and where prolonged catatonia
Discussion
may have more severe sequalae in the setting of additional
neurological concerns [1]. It should be noted that potentially the
The cases described here, which have used ECT for the treat-
use of antipsychotics may have contributed to the catatonic motor
ment of psychiatric symptoms, have similar demographic and
symptoms in these cases, and anti-psychotic withdrawal rather
initial clinical presentation characteristics as the broader group of
than commencement of ECT, may have resulted in symptom
anti-NMDA receptor encephalitis cases [1,2,8]. Interestingly, most
improvement. However, catatonia was seen at presentation in
cases received ECT prior to a definitive diagnosis of anti-NMDA
nine cases, and developed in five cases untreated with antipsy-
receptor encephalitis, a not uncommon occurrence given the
chotics. Additionally, improvement of catatonic symptoms
diagnostic delay from a complex clinical presentation, potential
occurred in five cases where antipsychotics had been continued
reluctance to perform lumbar punctures on psychiatric patients

Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016
4 N. Warren et al. / Brain Stimulation xxx (xxxx) xxx

Fig. 2. Anti-NMDARE symptom clusters.

during ECT. Thus, catatonic improvement was felt to be primarily progression of the disorder occurs. First line immunotherapy or
related to the use of ECT. tumour removal achieves symptom improvement for around 50%
In addition to the impact on psychiatric symptoms, ECT may of anti-NMDA receptor encephalitis patients over 4 weeks [5,8].
have other beneficial effects for cases with anti-NMDA receptor However, for some, improvement may come up to 24 months later,
encephalitis. ECT has been shown to be efficacious in NMS, status even with second line immunotherapy, during which time the
epilepticus, and for the dyskinesias and other motor symptoms in person is exposed to the risks of ongoing encephalitis such as
disorders such as Parkinson's disease; potentially accounting for sustained catatonia [5,8].
some of the beneficial motor effects seen in these cases [13e15]. There are several important considerations that should be borne
ECT has a known anti-convulsant effect and has been demonstrated in mind prior to ECT commencement in cases of anti-NMDA re-
in animal models to prevent kindling, which may be beneficial to ceptor encephalitis including appropriate consent and exclusion of
cases of anti-NMDA receptor encephalitis, known to progress to relative contraindications. In this series, one-third of cases were
seizures in around 70% [8,16]. Case series of epileptic psychiatric under 18 years of age and although(22) [22] ECT is rarely used to
patients undergoing ECT, have shown it to be a safe and effective treat adolescents and children, it is indicated for debilitating or life-
treatment, with no anti-epileptic medication dose adjustments threatening conditions such as malignant catatonia [13]. Consent
required in the majority [17]. It is possible that in the cases here in and other legal obligations require thorough discussion with family
which ECT was ceased due to seizure development, or other and other decision makers, not only for adolescents but for all
neurological symptoms, this was more reflective of the natural without capacity, expected to be the majority of cases with anti-
progression of anti-NMDA receptor encephalitis rather than a true NMDA receptor encephalitis. Relative contraindications to ECT
side effect of ECT. such as raised intracranial pressure and space occupying lesions are
The mechanisms of action of ECT remain unclear, although an- uncommon in anti-NMDA receptor encephalitis. Although, neither
imal studies have shown complex effects on NMDA receptor occurred in these cases, ECT proceeded safely in the context of
number and activity, as well as effects on glutamate, GABA and neurological symptoms, seizures, autonomic disturbance, EEG and
dopaminergic neurotransmitters, all of which are proposed to be MRI abnormalities. Further reassurance may be provided by the
dysregulated in catatonia [18e20]. It has therefore been hypoth- literature examining ECT use in post stroke and subcortical vascu-
esised that ECT may be particularly beneficial in anti-NMDA re- lopathies, having similar neuropathological insults as encephalitis.
ceptor encephalitis, targeting the neurocircuitry effects of the This suggests efficacy and tolerability but potentially increased
antibodies on the brain, although this has not been further rates of post-ECT delirium [22].
confirmed [21]. Conversely, it could be considered that ECT may The anaesthetic considerations highlighted in the anti-NMDA
just be temporarily attenuating the catatonic and motor symptoms, receptor encephalitis literature were not raised in any of these
whilst effect of the immunomodulatory treatments or the natural cases, perhaps reflecting the brief anaesthetic required for ECT

Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016
 N. Warren et al. / Brain Stimulation xxx (xxxx) xxx 5

Table 1
ECT for Anti-NMDA receptor encephalitis.

Author Year Gender Age Indication for ECT BFCSI ECT details ECT Outcomes

Florence 2009 F 16 N.S. 3 N.S. Improved symptoms

Khadem 2009 F 57 Catatonia 4 12 sessions N.S
Braakman 2010 M 47 Catatonia 4 7 sessions Bi-lateral Resolved catatonia
Gonzalez- 2010 F 15 Catatonia I.I. 12 sessions Resolved catatonia, relapsed after 1 year
rcel
Valca
Caplan 2011 F 27 N.S. 1 6 sessions Partial improvement with some ongoing behavioural
disturbance
Creten 2011 M 9 Catatonia 2 N.S. Resolved catatonia
Kamran Mirza 2011 F 14 Catatonia 4 7 sessions No improvement
Torgovnick 2011 M 52 Catatonia 3 12 sessions No improvement. Lost to follow up
Matsumoto 2012 M 18 Catatonia 4 13 sessions Resolved catatonia
Mann 2012 F 14 Catatonia 8 7 sessions Improved catatonia, cognition, mobility and autonomic
features
Wilson 2013 F 14 Catatonia BFCRS21 14 sessions Improved catatonia and movement
Ramanathan 2013 F 17 Catatonia 5 13 sessions Improved catatonia
Yuksel 2014 F 23 Catatonia I.I. N.S. N.S.
Hermans 2015 F 20 Catatonia 2 N.S. Improved catatonia
Hermans 2015 F 23 Catatonia 6 N.S. No improvement
Huang 2015 F 25 N.S. 2 1 session Ceased due to neurological deterioration
Jones 2015 M 17 Catatonia 7 2 sessions Bi- Improved catatonia
temporal
Koksal 2015 F 25 Catatonia 2 2 sessions Ceased due to seizures
Kramina 2015 F 15 Catatonia 6 2 sessions Ceased due to neurological deterioration
Peng 2015 F 30 N.S 2 31 sessions Not stated
Rajahram 2015 M 35 Behaviour refractory to 5 Multiple sessions N.S.
immunotherapy
Miller 2016 F 30 Catatonia 2 33 sessions N.S.
Murdie 2016 F 17 Catatonia I.I. N.S. Improved catatonia and paranoia
Sunwoo 2016 F 27 Catatonia and refractory dyskinesia 5 13 sessions, brief Improved catatonia and dyskinesia
pulse
Gough 2017 F 71 Catatonia I.I Multiple sessions N.S.
Hermans 2017 F 25 Catatonia 6 1 session Ceased due to seizures
Kar 2017 M 21 Catatonia 7 12 sessions Improved catatonia
Medina 2017 F Catatonia BFCRS24 6 sessions bi- Resolved catatonia
temporal
Rong 2017 F 52 Psychotic depression 5 2 sessions N.S.
Palakkuzhiyil 2018 M 47 Catatonia 7 N.S. No improvement

N.S.: Not stated.

I.I.: Insufficient information.
BFCSI: Bush Francis Catatonia Screening Instrument.
BFCRS: Bush Francis Catatonia Rating Scale.

compared with that for surgical removal of teratomas and other The cognitive effects of ECT in anti-NMDA receptor encephalitis
malignancies. Anaesthetics that act at the NMDA receptor, such as are unclear, with both the resolution of cognitive deficits and onset
nitrous oxide and ketamine, may behave unpredictably in anti- of such deficits reported in these cases. Cognitive deficits, as initial
NMDA receptor encephalitis [23]. Ketamine was not used in any symptoms as well as in both the active and recovery phases of anti-
of these cases, but has been the subject of increasing interest for NMDA receptor encephalitis are common, thought to be due to
potential anti-depressant and neuroprotective cognitive effects, impact on mesial-temporal structures [1,19,28]. Early effective
with less anti-convulsant activity than proprofol [24,25]. Propofol, treatment may result in improved cognitive outcomes, of which
the most common ECT anaesthetic, has been used without concern ECT may assist [8]. However, ECT has known cognitive side-effects,
in anti-NMDA receptor encephalitis [23]. A non-depolarising generally limited to the first few days after treatment, with reso-
muscle relaxant may be a safer alternative to succinylcholine, in lution beyond baseline seen after that in domains such as working
the setting of potential hyperkalaemia with catatonic rigidity or memory, processing speeds, anterograde memory and executive
longstanding immobility [26]. functioning [29]. Conflicting results may also be related to the
Autonomic disturbance with alterations of temperature, heart inconsistent or non-specific documentation of cognition in these
rate and blood pressure, as well as respiratory depression, ar- cases.
rhythmias and asystole have been described in anti-NMDA re- The cases identified represent a small fraction of published anti-
ceptor encephalitis [1]. Tachycardia and fever occurred in over half NMDA receptor encephalitis cases and cannot be generalised to
of these cases without disruption to the ECT course, however, those with non-psychiatric symptoms [1,2]. Since data was
more severe autonomic disturbances such as central hypo- collected from case reports, the results are subject to selection,
ventilation may pose greater concern, especially as prolonged reporting and publication bias. Poor documentation potentially has
airway protection with intubation does not routinely occur with led to an underestimation of catatonic symptoms and reduced
ECT administration [27]. ECT can result in a brief parasympathetic BFCSI scores and results in lack of clarity to which symptoms have
mediated bradycardia, hypotension and asystole, followed by a improved following ECT. There was limited documentation of ECT
more prominent sympathetic response with hypertension and frequency, dose, electrode positioning, seizure quality and duration,
tachycardia [4]. Awareness, assessment and availability of support response and adverse events, preventing further analysis for ECT
is recommended. optimisation.

Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016
6 N. Warren et al. / Brain Stimulation xxx (xxxx) xxx

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Please cite this article as: Warren N et al., Electroconvulsive therapy for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic
review of cases, Brain Stimulation, https://doi.org/10.1016/j.brs.2018.11.016