Pearls & Oy-sters:
Electroconvulsive therapy in anti-NMDA
H.M.H. Braakman, MD
B.M.G. Arts, MD, PhD
R.M.M. Hupperts, MD,
J. Nicolai, MD, PhD
CLINICAL PEARLS The clinical picture of anti-
NMDA receptor (NMDAR) encephalitis is highly
characteristic; the presence of NMDAR antibodies
confirms the diagnosis.
With its poor diagnostic criteria, encephalitis lethar-
toms that likely represent multiple distinct disorders.
Sporadic EL is a diagnosis of exclusion, only to be
made after appropriate exclusion of anti-NMDAR
encephalitis and other (auto)immune phenomena.
INTRODUCTION NMDAR are ligand-gated cation
channels with crucial roles in synaptic transmission
and plasticity. The receptors are heteromers of NR1
subunits that bind glycine and NR2 subunits that
bind glutamate.1NMDA receptors are expressed on
neurons throughout the brain; their highest densities
are found in the amygdala, hypothalamus, prefrontal
cortex, and hippocampus. Overactivity of NMDA
receptors is a proposed underlying mechanism for
epilepsy, dementia, and stroke, whereas low activity
produces symptoms of schizophrenia.1Antibodies
against NR1-NR2 heteromers can result in a charac-
teristic neuropsychiatric syndrome, anti-NMDAR
encephalitis.2Its characteristic clinical presentation
resembles acute psychosis, with catatonia or, less fre-
quently, memory deficits, followed by a rapid decline
in the level of consciousness, central hypoventilation,
seizures, involuntary movements, and autonomic
instability. Although this syndrome was described re-
cently,3the ensuing report of numerous cases sug-
gests that this is not a rare disorder.2
dition, although, if recognized timely, good treatment
options exist. We present a case to illustrate that anti-
NMDAR encephalitis should be considered in patients
possibly adds an effective treatment option.
CASE REPORT A previously healthy 47-year-old
man reported to the outpatient department. After an
upper respiratory tract infection, he had persisting
malaise and excessive sweating. Over a 3-week pe-
riod, he developed derealization, intense anxiety, and
eventually auditory hallucinations consisting of vari-
ous kinds of music. Neurologic examination and
brain CT revealed no abnormalities, including no
brain tumor. The consultant psychiatrist diagnosed
psychosis with hallucinations of unknown origin.
Three days later, the patient reported insomnia, dis-
orientation, and suicidal thoughts. Neurologic exam-
ination showed disorientation in place, memory
disturbances, bradyphrenia, restlessness, and exces-
sive sweating. Our differential diagnoses included
(infectious) encephalitis, mainly herpes simplex en-
cephalitis, Creutzfeldt-Jacob disease, and, less likely,
leptomeningeal metastases of an unknown primary
tumor. Brain MRI demonstrated no abnormalities.
CSF analysis revealed a pleocytosis of 30 cells/mm3
(normal value ?5/mm3) with 100% lymphocytes
and normal glucose and protein concentrations. The
patient was admitted and received 10 mg/kg acyclo-
vir 3 times daily based on a presumptive diagnosis of
herpes simplex encephalitis. Microbiologic examina-
tion of CSF did not detect any viral or (myco)bacte-
rial causative agents. Neither malignant cells nor the
14–3-3 protein were detected in the CSF. Based on
these results, acyclovir was withdrawn.
After a few days, the patient developed paroxys-
mal sustained upward eye deviations, extreme agita-
tion, dystonic posturing, rigidity, dyskinesias,
dyspnea, and severe laryngospasms with saturation
drops. These paroxysms were followed by periods of
apathy and akinesia. Pathologic laughing and yelling
eventually progressed to complete mutism. Based on
the nonspecific and progressive clinical features, the
differential diagnosis now included autoimmune,
paraneoplastic, and postinfectious disorders. CSF
and serum analysis showed intrathecal synthesis of
multiple oligoclonal bands, with unique oligoclonal
CSF bands. Antibodies against human basal ganglia
antigens, paraneoplastic antibodies (anti-Hu, anti-
Address correspondence and
reprint requests to Dr. H.
Braakman, Department of
Neurology, Maastricht University
Medical Center, PO Box 5800,
6202 AZ Maastricht, the
From the Departments of Neurology (H.M.H.B., V.M.P.M.-H., J.N.) and Psychiatry (B.M.G.A.), Maastricht University Medical Center,
Maastricht; and Department of Neurology (R.M.M.H.), Orbis Medical Center, Sittard, the Netherlands.
Disclosure: Author disclosures are provided at the end of the article.
Mitchell S.V. Elkind,
Copyright © 2010 by AAN Enterprises, Inc.
Yo, anti-Ma2), as well as antiganglioside antibodies
could not be detected. Serum antistreptolysin and
antistreptodornase titers were negative. Total body
PET-CT revealed no abnormalities. EEG showed
diffuse slow waves of bilateral frontal dominancy, in-
dicating diffuse encephalopathy. A second brain
MRI again failed to demonstrate any abnormalities.
Based on the clinical features including the extrapy-
ramidal symptoms, oculogyric crises, psychiatric
symptoms, catalepsy, mutism, respiratory failure, in-
somnia, and apathy, we eventually made a presump-
tive diagnosis of EL. IV administration of lorazepam
up to 10 mg daily was initiated, as well as methyl-
prednisolone pulse therapy (1,000 mg daily for 3
days). This therapy did not result in clinical improve-
convulsive therapy (ECT). After 7 bilateral ECT
treatments, he regained a normal level of consciousness;
agitation, laryngospasm, mutism, hallucinations, cata-
tonia, oculogyric crises, and extrapyramidal symptoms
had disappeared. Without additional treatments, atten-
tion and memory deficits resolved over a 1-year time
course and fatigue persists. At 2 years follow-up, he has
returned to his former employment as a teacher.
Because the clinical picture resembled that of the
recently reported anti-NMDAR encephalitis, we in-
vestigated this possible association. An archived CSF
sample from his initial presentation was submitted to
the University of Pennsylvania, where antibodies
against NMDAR were detected in the sample; the
final diagnosis was anti-NMDAR encephalitis.
DISCUSSION Exclusion of neurologic disease, in-
cluding anti-NMDAR encephalitis, remains impor-
tant in patients presenting with psychosis. The
clinical features of anti-NMDAR encephalitis usually
include a prodromal episode of fever, headache, or
malaise, followed a few days later by mood and be-
havioral changes, and severe psychiatric symptoms
suggestive of psychosis or catatonia.3,4A psychiatric
disorder is usually considered and patients are often
admitted to psychiatric centers. Organic illness is
considered only after patients develop seizures, auto-
nomic instability, dyskinesias, or a decreased level of
MRI findings in anti-NMDAR encephalitis are
diverse. In the majority of patients, no abnormalities
are noted.2In some patients, transient cerebral, cere-
bellar, or brainstem hyperintensities have been
noted, as well as transient contrast enhancement of
the cerebral cortex, overlaying meninges, or basal
ganglia.2The EEG shows diffuse slowing or epilepti-
form activity.2CSF analysis reveals pleocytosis,
elevated protein levels, oligoclonal bands, and anti-
NMDAR antibodies. Anti-NMDAR encephalitis
predominantly affects young women, as it is gener-
ally a paraneoplastic phenomenon associated with
ovarian teratoma. Associations with teratoma in the
mediastinum and testes, as well as small-cell lung car-
cinoma, are rare.2,3It has been postulated that ec-
topic expression of NR1 subunits by the nervous
tissue contained in the teratoma itself contributes to
breaking immune tolerance.2Still, in about half of
the cases, anti-NMDAR encephalitis occurs in the
absence of teratoma. Thus, other unknown immuno-
logic triggers seem to be involved. The frequent
prodromal flu-like symptoms in anti-NMDAR en-
cephalitis are intriguing and possibly indicate a pre-
ceding viral infection. This preceding infection, and
perhaps a genetic predisposition, could play addi-
tional roles in the initiation of the immune response.
Microorganisms are an unlikely direct cause; exten-
sive studies of CSF samples, brain biopsies, and au-
topsies failed to detect any microorganisms.2
Our patient was first diagnosed with sporadic EL.
EL was a devastating epidemic of the early 20th cen-
tury that killed an estimated 500,000 people world-
wide.6Nowadays, EL is still sporadically diagnosed.
The etiology of EL remains unknown. The criteria
for EL are poorly defined, and a clinical diagnosis of
EL can be made if an acute or subacute encephalitis
illness has at least 3 of the following features: 1) signs
of basal ganglia involvement; 2) oculogyric crises; 3)
ophthalmoplegia; 4) obsessive-compulsive behavior;
5) akinetic mutism; 6) central respiratory irregulari-
ties; and 7) somnolence and/or sleep inversion.7Our
patient met criteria 1, 2, 4, 5, 6, and 7, and was thus
diagnosed with EL; this diagnosis was made prior to
the first description of anti-NMDAR encephalitis as
a separate clinical entity. After its description, the
anti-NMDAR antibodies were detected in our pa-
tient’s archived CSF sample. Many of the “idiopathic
encephalitis,” “encephalitis of unknown etiology,” or
“EL” cases may have in fact been anti-NMDAR en-
cephalitis.8,9Therefore, anti-NMDAR encephalitis
should be excluded prior to diagnosing sporadic EL,
which is mainly a diagnosis of exclusion.
Anti-NMDAR encephalitis can be severe and
even fatal, but it is potentially reversible; most pa-
tients recover if the disorder is recognized and treated
in time.2In anti-NMDAR encephalitis, a potentially
treatable primary disease (e.g., teratoma) may be
present. In fact, the most favorable outcomes occur
with tumor removal, usually in combination with
immunotherapy (IV steroids, IV immunoglobulin,
or plasma exchange).3,10Still, good clinical outcomes
have been reported in patients treated with immuno-
therapy without tumor removal.4,11Additional treat-
ment with cyclophosphamide2,3,5and rituximab2,12has
also proven to be effective in selected cases. Besides tu-
Neurology 75September 7, 2010
mor removal and immunotherapy, symptomatic treat-
partially relieve symptoms.4,12
In our patient, ECT proved effective. In one pre-
vious case series, one patient was found to respond to
ECT.13Two patients have been reported with para-
neoplastic catatonia and ovarian teratoma that par-
tially improved with ECT, but full recovery was only
attained after tumor removal.5,14Still, the temporal
association between ECT and recovery may have
been fortuitous; the condition may have been self-
limiting. However, our patient deteriorated clinically
in a period of 10 weeks, and recovered in a period of
3 weeks after ECT was started. The mechanism of
action of ECT remains largely unclear. Still, in ani-
mal models it has been shown to upregulate NMDA
receptors.15This may, in part, explain the efficacy of
ECT in our patient.
Anti-NMDAR encephalitis has become an essen-
tial consideration in the diagnosis of subacute or
acute encephalopathies with a clinical presentation of
psychosis-like symptoms, particularly in young peo-
ple. The diagnosis of EL can only be made after ex-
clusion of anti-NMDAR encephalitis. We report
dramatic recovery of our patient following ECT.
Further clinical observation or studies in patients
with anti-NMDAR encephalitis are needed to deter-
mine the relevance of our observation.
The authors thank Professor Dalmau and his laboratory at the University
of Pennsylvania for analysis of anti-NMDAR antibodies.
Dr. Braakman, Dr. Moers-Hornikx, Dr. Arts, and Dr. Hupperts report
no disclosures. Dr. Nicolai has received funding for travel from UCB and
has received research support from the Dutch Epilepsy Fund.
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H.M.H. Braakman, V.M.P. Moers-Hornikx, B.M.G. Arts, et al.
Pearls & Oy-sters: Electroconvulsive therapy in anti-NMDA receptor encephalitis
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