ANNALS OF CLINICAL PSYCHIATRY

REVIEW ARTICLE

ANNALS OF CLINICAL PSYCHIATRY 2014;26(1):e1-e9

Anti-N-methyl-d-aspartate receptor
encephalitis: A targeted review of clinical
presentation, diagnosis, and approaches to
psychopharmacologic management
Jennifer L. Kruse, MD*
Jessica K. Jeffrey, MD, MPH, MBA*
Michael C. Davis, MD, PhD
Joanna Dearlove, MD, MPH
Waguih William IsHak, MD, FAPA
John O. Brooks III, PhD, MD

BACKGROUND: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) enceph-

alitis was formally described in 2007 and includes a range of psychiatric

and neurologic symptoms. Most patients with anti-NMDAR encephalitis
initially present to psychiatrists for diagnosis and treatment. However, there
is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article
provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical
context for the literature review.
METHODS: The authors conducted a PubMed search.

Prominent psychiatric symptoms of anti-NMDAR encephalitis

include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be
helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for
agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR
encephalitis, while benzodiazepines and electroconvulsive therapy have
been used for catatonia associated with this condition.
RESULTS:

Psychiatrists play an important role in the diagnosis and

treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms
will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering.
CONCLUSIONS:

CORRESPONDENCE

John O. Brooks III, PhD, MD

UCLA Semel Institute
760 Westwood Plaza, B3-267
Los Angeles, CA 90024-1759 USA
E-MAIL

john.brooks@ucla.edu

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N-methyl-d-aspartate receptor, limbic encephalitis, behavioral

symptoms, benzodiazepines, antipsychotic agents
KEYWORDS:

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ANTI-NMDA RECEPTOR ENCEPHALITIS

I N T RO D U C T I O N
Encephalitis is defined as inflammation of the brain parenchyma. The condition is life threatening and requires
prompt diagnosis and treatment. Etiologies comprise a
range of inflammatory conditions including those of paraneoplastic, autoimmune, and infectious origin (TABLE 11,2).
Encephalitis presents with a variety of symptoms, which
may vary depending on the etiology of the encephalitis or
the particular regions of the brain that are affected. Across
the range of etiologies, common symptoms of encephalitis may include headache, confusion, altered level of
consciousness, memory disturbances, seizures, and hallucinations. Particular symptom clusters may lead the clinician to consider one etiology over another.
Recently, a previously unknown autoimmune cause
of encephalitis has been identified, which presents with
prominent psychiatric symptoms. When the presenting
signs of encephalitis are primarily psychiatric in nature,
patients may be diagnosed mistakenly with a primary
psychiatric disorder, and definitive diagnosis and treatment for encephalitis is delayed. Psychiatrists must be
aware of medical or neurologic disorders that present
with psychiatric symptoms to rule out organic etiologies, such as anti-N-methyl-d-aspartate receptor (antiNMDAR) encephalitis.
This article presents 2 cases illustrating dramatic psychiatric presentations of autoimmune encephalitis, and
includes an overview of the clinical presentation, diagnosis, and management of this condition.

mild pleocytosis. An electroencephalogram (EEG) demonstrated diffuse slowing of background activity, more
prominent in the right temporal region. All infectious
studies were negative.
Because of the patients demographics (young female)
and prominent psychiatric symptoms, anti-NMDAR
encephalitis was suspected and confirmed via detection of
serum antibodies to the NMDA receptor. Plasmapheresis
and high-dose IV methylprednisolone were initiated. The
patient was evaluated for ovarian teratoma, which is frequently associated with this condition; pelvic ultrasound
and a positron emission tomographycomputed tomography (PET-CT) scan were negative. Psychopharmacologic
treatment in the general medical hospital included olanzapine as needed for agitation.
The patient continued to exhibit echolalia, waxing and
waning mental status, intermittent agitation, catatonia,
and auditory and visual hallucinations. Olanzapine was
ineffective at reducing psychotic symptoms and impractical to administer orally during acute periods of agitation;
therefore, it was discontinued. IV lorazepam was effective
in reducing agitation, and because of its theoretical benefits for catatonia, this agent was administered on a scheduled basis. Diphenhydramine also was used as needed for
milder agitation, with good effect. After 5 treatments with
plasmapheresis, Ms. As mental status improved markedly.
She continued to have difficulty with short-term memory,
but no longer displayed motor or behavioral abnormalities. She was discharged for outpatient rehabilitation after
3 weeks in the general medical hospital.

Case 1
Ms. A, a 16-year-old, previously healthy adolescent, presented with fatigue, headache, and diarrhea followed 1
week later by insomnia, mood lability, auditory and visual
hallucinations, and agitation. She began to have difficulty
recognizing her parents and misidentified them as intruders, even making a 911 call when panicked that intruders
(her parents) had entered the home. During a 6-day psychiatric hospitalization she was treated with risperidone,
aripiprazole, chlorpromazine, and lorazepam for agitation.
Ms. A developed ataxia and had a generalized tonicclonic seizure, prompting transfer to a medical facility. At
time of transfer, she was disoriented and began to exhibit
echolalia, prolonged staring episodes, and difficulty following simple commands. Magnetic resonance imaging (MRI) findings were unremarkable, and results of a
lumbar puncture were within normal limits except for

e2

DISCUSSION
Ms. A suffered from anti-NMDAR encephalitis, which is
an autoimmune encephalitis first described in 2007 as a
paraneoplastic syndrome associated with ovarian teratomas.3 However, analysis of the increasing number of
cases of anti-NMDAR encephalitis reveals that only 38%
of patients have an underlying neoplasm. To date there
have been >570 reported cases of anti-NMDAR encephalitis, with those affected ranging in age from 8 months
to 85 years. Patients who were age 18, such as Ms. A,
accounted for 37% of cases; 19% of total cases were in
children age 13.4
Etiology of anti-NMDAR encephalitis. The NMDAR is
an ionotropic glutamate receptor that plays an important
role in memory and learning; it has been studied in brain

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ANNALS OF CLINICAL PSYCHIATRY

TABLE 1

Selected causes of encephalitis1,2

Infectious
Viral

HSV, enteroviruses, arboviruses, mumps, measles, varicella zoster, rubella, influenza,

HIV, rabies virus

Bacterial

Tropheryma whipplei, Mycoplasma pneumonia, Bartonella henselae, Listeria

monocytogenes, Borrelia burgdorferi, Treponema pallidum

Parasitic

Toxoplasma gondii, malaria, primary amoebic meningoencephalitis

Fungal

Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides

Immune-mediated
Acute disseminated encephalomyelitis (ADEM)

Classically associated with post-immunization or following a systemic viral infection

Antibody-associated

Anti-NMDA receptor encephalitis (sometimes paraneoplastic)

Anti-VGKC encephalitis (sometimes paraneoplastic)
Other paraneoplastic etiologies include antibodies to Hu, Ma2, CRMP5, AMPA,
GABA (B), among others

AMPA: -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CRMP: collapsin response mediator protein; GABA: -aminobutyric acid; HIV: human immunodeficiency virus;
HSV: herpes simplex virus; NMDA: N-methyl-d-aspartate; VGKC: voltage-gated potassium channel.

disorders ranging from Alzheimers disease to schizophrenia. Some NMDAR antagonists, such as ketamine and
phencyclidine, cause psychotic and dissociative symptoms.5 In the case of Ms. A and many patients with antiNMDAR encephalitis, symptoms are first mistaken for a
psychiatric disorder.
Three possible mechanisms for the development of
NMDAR autoimmunity have been suggested.6 Because
of the frequent association with ovarian teratoma, there
is likely a mechanism by which expression of NMDAR
in the teratoma leads to a downstream autoimmune
response. Pathologic examination of 25 ovarian teratomas from patients with anti-NMDAR encephalitis
revealed the presence of NMDAR in all cases.7 In cases
where no tumor is identified, Peery et al6 suggest 2 alternate mechanisms for development of autoimmunity,
both of which remain unproven:
1. Infectious agents may lead to development of
autoantibodies, perhaps by epitope similarity between
a pathogen and the NMDAR. However, no consistent
infectious agents have been identified.
2. Tissues outside the CNS that normally express
NMDAR may become infected or damaged, leading to
immune activation and eventual loss of self-tolerance to
the receptor.
Incidence of anti-NMDAR encephalitis. Because
of the recent identification of anti-NMDAR encephalitis, incidence estimates are not available. However, this
syndrome may represent a relatively common cause of

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encephalitis. In the California Encephalitis Project (CEP),

established to study the epidemiology and etiologies of
encephalitis, anti-NMDAR encephalitis was the most frequently identified etiology for encephalitis in patients age
30, between September 2007 and February 2011. The
CEP cohort is biased toward diagnostically challenging
cases; therefore, anti-NMDAR encephalitis may be overrepresented in this cohort compared with encephalitides
that are more routinely included in a diagnostic evaluation.8 It should be noted that encephalitis is a rare disorder, and anti-NMDAR encephalitis represents a small
proportion of cases of an already rare clinical disorder. As
awareness of anti-NMDAR encephalitis becomes more
widespread and screening becomes more routine in the
assessment of encephalitis, incidence estimates may
become available.
Presentation of anti-NMDAR encephalitis. In Case
1, we met Ms. A, an otherwise healthy adolescent girl
who presented with classic symptoms of anti-NMDAR
encephalitis. She experienced a typical prodrome, including fatigue, headache, nausea, and diarrhea, followed
days later by onset of psychiatric symptoms, including
hallucinations, agitation, insomnia, mood lability, and
delusional thought content.
A variety of psychiatric symptoms are associated
with anti-NMDAR encephalitis, including anxiety, sleep
disturbances, mood disturbances including depression
or mania, mood lability, psychosis, agitation, and catatonia. Behavioral abnormalities are the rule rather than the

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TABLE 2

Clinical manifestations of anti-NMDAR encephalitis in adults and children

Adults

Children

Prodrome
(0 to 2 weeks)

Seen in 70% of cases; may include headache,

fever, nausea, vomiting, diarrhea, upper respiratory
symptoms7

As per adults

Initial presentation

In a series of 100 patients, 77 were first seen by

a psychiatrist, with symptoms including anxiety,
agitation, bizarre behavior, delusions, paranoia, and
auditory or visual hallucinations9

Behavioral symptoms such as temper tantrums,

hyperactivity, and irritability are common7

Most develop seizures, decreased level of

consciousness, and alternating periods of agitation
and catatonia

As per adults, but possibly decreased occurrence of

catatonia12

Dyskinesias, choreoathetoid movements, dystonic

posturing, and abnormal ocular movements are
common

Tend to experience insomnia more commonly than

hypersomnia10

Progression

Initial presentation is more likely to be non-psychiatric

than in adults, with symptoms including seizures and
motor abnormalities11

70% develop mutism12

Sleep disturbances (sleep inversion, insomnia,

hypersomnia) are frequent9
Autonomic
instability

In a series of 100 patients, 69% had autonomic

instability, including tachycardia, bradycardia, central
hypoventilation, hypotension, and hyperthermia9

Autonomic instability and central hypoventilation are

reported to be less severe than in adults, possibly
related to developmental differences in autonomic
function11

NMDAR: N-methyl-d-aspartate receptor.

exception in anti-NMDAR encephalitis, developing early

in the progression of this syndrome, as seen with Ms. A.
Psychiatrists often are the first clinicians to have contact
with an affected patient and must keep a healthy degree
of suspicion regarding the possibility that a patients psychiatric symptoms may be secondary to anti-NMDAR
encephalitis. In 1 series, 77% of adult and adolescent
patients were evaluated by a psychiatrist before diagnosis of anti-NMDAR encephalitis.9 This was true for Ms. A,
who was admitted to a psychiatric facility before consideration of encephalitis as the etiology of her symptoms.
The course of Ms. As illness progressed fairly stereotypically from prodrome to psychiatric symptoms
to neurologic symptoms to autonomic instability. See
TABLE 27,9-12 for a summary of typical clinical manifestations and progression of anti-NMDAR encephalitis, noting the differences in presentation between adults and
children. Although Ms. A was only age 16, her symptoms
and presentation were consistent with those commonly
seen in adult patients. In children, psychiatric symptoms may be less dramatic, though temper tantrums,
hyperactivity, and irritability are common. Autonomic
instability and central hypoventilation may be less

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severe in children compared with adults.13 Although

Ms. A had hypotension and tachycardia, her autonomic
instability was not severe, she did not develop central hypoventilation, and did not require intubation.

Case 2
Ms. B, a previously healthy 19-year-old woman, had a
generalized tonic-clonic seizure followed by several days
of intermittent psychiatric symptoms, including paranoia, auditory hallucinations, and disorganized behavior.
Initial emergency department (ED) workup, including
head CT, urine toxicology, urinalysis, and thyroid studies, were negative. She was discharged, but symptoms
continued and progressed; family reported that she
appeared fearful, was not acting like herself, and was
unable to carry on a conversation. Approximately 1 week
after initial presentation to the ED, Ms. Bs mother found
her with eyes closed, gurgling, with hands clenched and
pulled up against her chest while her upper body was
shaking. She was transported by ambulance back to the
community hospital, where she received phenytoin for
the presumed seizure, and was admitted to the psychiatric unit for treatment of recent-onset paranoia and audi-

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TABLE 3

Tumors among 577 patients reviewed by Titulaer et al4

Patients with tumor

38%

Female patients with tumor

46%

Male patients with tumor

6%

Among patients with tumor, % ovarian teratoma

94%

Other tumors identified

Extra-ovarian teratomas (4): breast, lung, testicular (2 each); ovarian, thymic,

and pancreatic carcinomas (1 each)

tory hallucinations.
Over several days, Ms. B became mute and required
feeding assistance. She exhibited increasingly disorganized behavior and confusion, wandering into patient
rooms, banging on doors, and demanding to leave the
hospital. She had persecutory delusions and auditory
hallucinations, and became increasingly aggressive. She
was managed with haloperidol and lorazepam for episodes of aggression.
Ms. B became incontinent of urine, developed mandibular stiffness, copious oral secretions, and myoclonus
involving her upper body and face. Status epilepticus was
suspected, and she was transferred from the psychiatric
unit to the intensive care unit and intubated. Neuroleptic
malignant syndrome (NMS) was considered, after altered
mental status and muscle stiffness occurred following
treatment with haloperidol; antipsychotics were discontinued. Cerebrospinal fluid (CSF) examination was remarkable only for mild pleocytosis. Extensive infectious workup was negative. Multiple head CTs, brain MRIs, lumbar
punctures, and ultrasound studies were unrevealing. Ms.
B further deteriorated clinically, developing autonomic
instability and intractable myoclonus. After over 40 days
at a community hospital without a diagnosis or improvement in her condition, Ms. B was transferred to a tertiary
care center.
Her exam on arrival to the neurological ICU at the tertiary care center was significant for bilateral choreoathetoid movements, rigidity in the bilateral lower extremities,
and occasional left-gaze nystagmus. An MRI of the brain
demonstrated subtle fluid-attenuated inversion recovery (FLAIR) abnormalities in the bilateral hippocampi.
CSF was sent for additional studies and was positive for
NMDAR antibodies. Plasmapheresis and methylprednisolone were started for treatment of anti-NMDAR encephalitis, but there was no improvement in her condition.
Second-line treatment (rituximab) was initiated. Extensive

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work-up for an underlying malignancy was pursued and

was negative. After 4 weeks on rituximab with no significant improvement, the decision was made with Ms. Bs
family to perform bilateral salpingo-oophorectomy, given
association of anti-NMDAR encephalitis with ovarian teratoma. Pathological specimens from the fallopian tubes
and ovaries were unremarkable.
With no clinical improvement 1 week following bilateral salpingo-oophorectomy, Ms. B was started on weekly
cyclophosphamide IV for additional immunotherapy.
After approximately 3 months at the tertiary care center,
Ms. B had not regained the ability to follow commands,
was not visually tracking consistently, and did not demonstrate purposeful movement. She was transferred to
a skilled nursing facility >4 months after her symptoms
began. Her hospital course had been complicated by
Acinetobacter pneumonia, enterococcus percutaneous endoscopic gastrostomy site infection, syndrome
of inappropriate antidiuretic hormone secretion, acute
renal insufficiency due to early treatment with acyclovir,
hemorrhagic cystitis and neutropenia due to cyclophosphamide, unexplained vaginal bleeding, and refractory
seizures requiring a multi-drug anticonvulsant regimen.

DISCUSSION
Ms. A and Ms. B had psychotic symptoms that were initially misconstrued as evidence of a primary psychiatric
disorder, leading to admission to inpatient psychiatric
facilities. Diagnosis of anti-NMDAR encephalitis was
delayed for over a month in the case of Ms. B, although
her first symptoms were neurologic (generalized tonicclonic seizure). Ms. Bs long and complex hospital course
demonstrates the severity and high morbidity of antiNMDAR encephalitis.
Diagnosis of anti-NMDAR encephalitis. `Detection

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ANTI-NMDA RECEPTOR ENCEPHALITIS

of NMDAR antibodies in the patients serum or CSF is

considered the gold standard diagnostic test for antiNMDAR encephalitis. If this condition is suspected based
on clinical characteristics and compatible laboratory,
EEG, and imaging studies, evaluation for antibodies to
the NMDAR should be pursued. Most laboratories do not
perform the assay for this antibody; therefore, most institutions send specimens to outside laboratories to complete the assays for anti-NMDAR, which can take several
days. Detection of antibodies in the CSF is more sensitive than detection in serum. In 250 patients diagnosed
with anti-NMDAR encephalitis, 100% had anti-NMDAR
detected in the CSF, but only 85% had anti-NMDAR
detected in serum.4 Most patients have intrathecal synthesis of NMDAR antibodies.7
CSF may reveal other abnormalities, most commonly lymphocytic pleocytosis. Protein concentration
often is normal or mildly increased.7 Ms. A and Ms. B
both had mild CSF pleocytosis.
MRI of the brain is abnormal in 33% of cases. When
findings are present, they are present on T2 or FLAIR
sequences, with hyperintensity in a variety of regions.7
Neither Ms. A nor Ms. B had neuroimaging abnormalities
early in the course of their illness. However, later in the
course of Ms. Bs illness, once she had been transferred to
a tertiary care facility (after >40 days), subtle hyperintensities were noted on FLAIR, in the bilateral hippocampi.
Given non-specific and often absent findings on imaging
studies, imaging is not particularly helpful in diagnosing anti-NMDAR encephalitis, except to rule out other
etiologies.
EEG. EEG studies are not particularly helpful in
making a specific diagnosis of anti-NMDAR encephalitis. However, EEG is helpful in differentiating between
psychiatric and encephalitic etiologies of psychiatric
and behavioral disturbances, because most patients
with encephalitis will have EEG abnormalities. In
anti-NMDAR encephalitis, EEG is abnormal in 90% of
patients.4 EEG may reveal seizure activity if the patient is
having seizures, and otherwise may reveal slow disorganized activity.7
In case 1 (Ms. A), an EEG demonstrated diffuse slowing of background activity and mild asymmetry, with
more prominent slowing in the right temporal region.
In case 2 (Ms. B), non-convulsive status epilepticus was
diagnosed on EEG. In both cases, the EEG indicated
abnormal brain function, but did not provide a specific diagnosis. In tandem with a diagnostic work up for

e6

TABLE 4

Summary of treatments for selected

symptoms of anti-NMDAR encephalitis
Target
Symptom

Treatment

Dose range
(total daily)

Psychosis

Risperidone
Aripiprazole
Olanzapine

1 to 2 mg15
30 mg22
5 mg22

Agitation

Lorazepam
Diazepam
Midazolam
Risperidone
Olanzapine
Aripiprazole
Amisulpride
Haloperidol
Diphenhydramine

2 to 4 mg23,15
5 to 7 mg16
0.1 mg/kg IV16
1 to 4 mg16,10
5 mg23
30 mg22
100 mg22
5 mg22
25 to 100 mg10

Dystonia

Benztropine
Trihexyphenidyl
Biperiden
Levodopa/carbidopa

1.5 mg15
8 mg15
2 to 4 mg16
20 mg/200 mg10

Insomnia

Trazodone
Diphenhydramine

75 to 100 mg15,10,22
25 to 100 mg10

Catatonia

Electroconvulsive therapy
Lorazepam

7 sessions10,19,21
8 to 30 mg10,21

anti-NMDAR encephalitis, other potential etiologies for

presenting symptoms should be evaluated. This would
include completing an evaluation for infectious etiologies and other immune-mediated etiologies. If a patient
is found to have NMDAR antibodies, one must evaluate for an ovarian teratoma or other occult malignancy
(TABLE 34).
In both cases presentations, investigations for ovarian
teratoma or other underlying malignancies were negative.
For Ms. B, in the context of severe and recalcitrant symptoms, bilateral salpingo-oophorectomy was pursued, with
the goal of potentially removing a microscopic teratoma
unidentifiable via imaging studies. Pathologic examination of the ovaries and fallopian tubes did not reveal teratoma or other gynecologic malignancy. In some cases,
teratoma not previously identified on imaging has been
identified microscopically after removal of the ovaries.14
See the FIGURE7 for a summary of diagnostic work up.

Treatment of anti-NMDAR encephalitis

The treatment of anti-NMDAR encephalitis is complex,
multi-disciplinary, prolonged, and has been reviewed

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ANNALS OF CLINICAL PSYCHIATRY

FIGURE

Overview of evaluation and treatment of anti-NMDAR encephalitis7

Evaluation

EEG: Nonspecific;
may show slow
disorganized activity.
Will detect seizure
activity if present

LP: CSF may show

lymphocyte pleocytosis
or oligoclonal bands.
Antibodies to NMDAR
are gold standard for
diagnosis

Serum: Antibody to
NMDAR confirms
diagnosis, but false
negative possible
(15%)

MRI: Abnormal in
33% of cases. May
have T2 or FLAIR
hyperintensities in
varied locations

Anti-NMDAR
Encephalitis
Treatment

Definitive
treatment
Surgical removal of
tumor, if identified
Immunotherapy:
First line:
corticosteroid + IVIG
or plasmapheresis
Second line:
cyclophosphamide or
rituximab

Psychiatric symptom
management

Agitation:
Benzodiazepines
Diphenhydramine
Antipsychotics (agents
with low EPS risk
preferred)

Psychosis:
Antipsychotics with
low risk for EPS may
be helpful in some
patients

Supportive medical
care

Insomnia:
Benzodiazepines and
diphenhydramine

Catatonia:
Benzodiazepines
may be helpful. ECT
reported helpful in
refractory cases

CSF: fluid; ECT: electroconvulsive therapy; EEG: electroencephalogram; EPS: extrapyramidal symptoms; FLAIR: fluid-attenuated inversion recovery; IVIG: intravenous
immunoglobulin; LP: lumbar puncture; MRI: magnetic resonance imaging; NMDAR: N-methyl-d-aspartate receptor.

extensively elsewhere.7 See the FIGURE for a summary of

management principles proposed by Dalmau et al.7 Ms.
A had a good response to first-line treatment with IV glucocorticoids and plasmapheresis. Unfortunately, Ms. Bs
diagnosis of anti-NMDAR encephalitis was delayed for
more than a month, and she did not have an underlying
tumor that could be removed; prompt initiation of immunotherapy and tumor removal, if applicable, are positive
predictors of treatment response. Ms. B did not respond
to first-line treatment with IV glucocorticoids and plasmapheresis; she required advancement to second-line
treatments, including rituximab and cyclophosphamide,
to which she also did not demonstrate clinical response.
The 2 cases presented demonstrate the discrepancy in clinical outcome between 2 young women
with anti-NMDAR encephalitis. Both demonstrated
dramatic behavioral changes and psychosis, and were

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initially admitted to inpatient psychiatric units before

consideration of encephalitis in the differential diagnosis. These cases outline the importance of rapid
recognition of this disorder, and draw attention to
the important role that psychiatrists can play if they
consider this syndrome early in the course of illness.

Management of psychiatric symptoms

We have thus far discussed the diagnosis of anti-NMDAR
encephalitis and the treatment of the underlying autoimmune process. Now we will focus on the management of
psychiatric symptoms, given their ubiquity in the illness
and the important role psychiatrists play in management. TABLE 4 provides a summary of target symptoms
and effective reported drug dosages. Of note, positive
response to psychotropic medications may depend on
when these agents are administered in the course of over-

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ANTI-NMDA RECEPTOR ENCEPHALITIS

all treatment, with generally improved responses if given

in combination with aggressive immunotherapy.
Psychosis. Case reports have illustrated use of both
typical and atypical antipsychotics for psychosis in patients
with encephalitis. Chapman et al15 described successive
trials of aripiprazole, 2.5 mg/d, and haloperidol, 4 mg/d,
which were associated with worsening motor symptoms
(increased facial masking, bradykinesia, drooling, and
decreased blink rate) in a 16-year-old male. The patient
later tolerated and responded well to risperidone, 2 mg/d,
as evidenced by decreased response to internal stimuli.15
A general caution in the use of antipsychotics is the potential for worsening of abnormal movements associated
with anti-NMDAR encephalitis itself, thus complicating
the clinical picture. Close observation following antipsychotic administration, and selection of pharmacologic
agents with decreased propensity toward extrapyramidal
side effects (EPS), is recommended. In the case of Ms. B,
NMS was considered in the differential diagnosis after her
mental status worsened and she developed muscle rigidity
following treatment with haloperidol. No further antipsychotics were used during her inpatient treatment.
Agitation. Benzodiazepines have been used successfully to manage agitation and also may treat insomnia,
which often is associated with anti-NMDAR encephalitis.15
With severe agitation, parenteral benzodiazepines may be
required.16 With Ms. A, lorazepam was favored over antipsychotics for the treatment of agitation, as it provided more
rapid and effective sedation and could be administered
via IV route. Diphenhydramine also has been described
as effective for treating both agitation and insomnia,10
which is consistent with our clinical experience with Ms.
A. The anticholinergic effect of diphenhydramine also may
reduce rigidity or dystonias associated with anti-NMDAR
encephalitis. Both typical and atypical antipsychotics have
been used for agitation, with mild to moderate benefit, but
they may worsen motor symptoms.15
Dystonia/rigidity. Dystonic symptoms and muscle
rigidity frequently occur in the course of anti-NMDAR
encephalitis, as a consequence of the illness itself, and
may be exacerbated by antipsychotic use. Anticholinergic
medications are the most commonly used medications to
treat dystonia in anti-NMDAR encephalitis, and are used
in the same general dosage range as in the treatment of
antipsychotic-induced EPS. Chapman et al15 reported
decreased jaw dystonia and rigidity with the use of benztropine, 0.5 mg 3 times daily, but noted that they later
transitioned the patient to trihexyphenidyl liquid, 4 mg

e8

twice daily, when he could no longer swallow capsules or

tablets. In 1 case report, the use of carbidopa-levodopa
was described as a treatment for muscle rigidity.10
Insomnia. In addition to benzodiazepines and
diphenhydramine, trazodone has been described as a
useful treatment for insomnia. In 1 case report, trazodone, 100 mg/d, was continued even after other psychotropics were no longer needed, due to continued sleep
difficulties in the course of rehabilitation.15
Catatonia. General recommendations for managing catatonia associated with psychiatric illness suggest
the liberal use of benzodiazepines, progressing to electroconvulsive therapy (ECT) for resistant or malignant
catatonia.17 These guidelines have been used for catatonia in patients with anti-NMDAR encephalitis. Consoli
et al18 reported the case of a 17-year-old female with
anti-NMDAR encephalitis who developed malignant
catatonia. The symptoms did not improve until immunotherapy (prednisone and cyclophosphamide) was initiated, despite use of lorazepam, 15 mg/d. Mann et al10
described dramatic, but temporary, improvement in an
anti-NMDAR encephalitis patient with catatonia upon
treatment with lorazepam, 2 mg IV every 6 hours; this
patient soon required emergent ECT and showed marked
improvement with a course of 7 ECT sessions scheduled
every other day. ECT also was reported to dramatically
improve catatonia, as well as other clinical symptoms of
anti-NMDAR encephalitis, in a case report by Braakman
et al.19 The authors hypothesized that ECT may upregulate expression of NMDA receptors, as has been shown in
animal studies.20 Wilson et al21 described improvement in
malignant catatonia upon combining benzodiazepines
and ECT with immunotherapy. See TABLE 410,15,16,21-23 for a
summary of psychiatric treatments for select symptoms
of anti-NMDAR encephalitis.

CONCLUSIONS
Anti-NMDAR encephalitis, initially described in 2007,
presents with psychiatric symptoms accompanied by
other encephalitic symptoms including memory problems, seizures, and/or abnormal movements. The majority of patients are seen by a psychiatrist before definitive
diagnosis. Thus, psychiatrists have a crucial role in the
recognition of anti-NMDAR encephalitis and must be
vigilant in their assessment of patients presenting with
new-onset psychosis or behavioral changes.

February 2014 | Vol. 26 No. 1 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

If a patient without a history of psychiatric illness

presents with rapid onset of psychiatric symptoms and/
or behavioral change, this should prompt the psychiatrist
to include a thorough evaluation of neurological signs
and symptoms, as part of the diagnostic evaluation. The
psychiatrist should be alert for common accompanying
neurologic signs and symptoms of anti-NMDAR encephalitis, including memory problems, seizure, and abnormal movements. Presence of such neurologic symptoms
should prompt referral for further diagnostic evaluation.
Prognosis of anti-NMDAR encephalitis is improved
if the diagnosis is made early, facilitating rapid initiation of treatment. Our 2 cases anecdotally demonstrate
the discrepancy in clinical outcome between 2 young
women with anti-NMDAR encephalitis.

Psychiatrists also play an important role as

consultants in recommending appropriate pharmacological treatments for behavioral symptoms of
anti-NMDAR encephalitis. One must pay particular
attention to selecting agents that are likely to reduce
agitation and suffering, while avoiding those that may
exacerbate or confound symptoms of anti-NMDAR
encephalitis.
Dr. Brooks has received a research grant
from Pfizer, and is a speaker for Sunovion. Drs. Kruse,
Jeffrey, Davis, Dearlove, and IsHak report no financial
relationships with any company whose products are
mentioned in this article or with manufacturers of competing products.
DISCLOSURES:

REFERENCES
1. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the
Infectious Diseases Society of America. Clin Infect Dis.
2008;47:303-327.
2. Vincent A, Bien CG, Irani SR, et al. Autoantibodies
associated with diseases of the CNS: new developments
and future challenges. Lancet Neurol. 2011;10:759-772.
3. Dalmau J, Tzn E, Wu HY, et al. Paraneoplastic antiN-methyl-d-aspartate receptor encephalitis associated
with ovarian teratoma. Ann Neurol. 2007;61:25-36.
4. Titulaer MJ, McCracken L, Gabilondo I, et al.
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol.
2013;12:157-165.
5. Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its
implication for treatment. Neuropsychopharmacology.
2012;37:4-15.
6. Peery HE, Day GS, Dunn S, et al. Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the
immunobiology. Autoimmun Rev. 2012;11:863-872.
7. Dalmau J, Lancaster E, Martinez-Hernandez E, et
al. Clinical experience and laboratory investigations in
patients with anti-NMDAR encephalitis. Lancet Neurol.
2011;10:63-74.
8. Gable MS, Sheriff H, Dalmau J, et al. The frequency

of autoimmune N-methyl-d-aspartate receptor encephalitis surpasses that of individual viral etiologies in young
individuals enrolled in the California Encephalitis Project.
Clin Infect Dis. 2012;54:899-904.
9. Dalmau J, Gleichman AJ, Hughes EG, et al. AntiNMDA-receptor encephalitis: case series and analysis of
the effects of antibodies. Lancet Neurol. 2008;7:1091-1098.
10. Mann A, Machado NM, Liu N, et al. A multidisciplinary approach to the treatment of anti-NMDA-receptor antibody encephalitis: a case and review of the literature. J Neuropsychiatry Clin Neurosci. 2012;24:247-254.
11. Florance-Ryan N, Dalmau J. Update on anti-Nmethyl-d-aspartate receptor encephalitis in children and
adolescents. Curr Opin Pediatr. 2010;22:739-744.
12. Dale RC, Irani SR, Brilot F, et al. N-methyl-d-aspartate
receptor antibodies in pediatric dyskinetic encephalitis
lethargica. Ann Neurol. 2009;66:704-709.
13. Florance NR, Davis RL, Lam C, et al. Anti-N-methyld-aspartate receptor (NMDAR) encephalitis in children
and adolescents. Ann Neurol. 2009;66:11-18.
14. Tanyi JL, Marsh EB, Dalmau J, et al. Reversible
paraneoplastic encephalitis in three patients with ovarian neoplasms. Acta Obstet Gynecol Scand. 2012;91:
630-634.
15. Chapman MR, Vause HE. Anti-NMDA receptor
encephalitis: diagnosis, psychiatric presentation, and
treatment. Am J Psychiatry. 2011;168:245-251.

16. Maggina P, Mavrikou M, Karagianni S, et al. Anti-Nmethyl-d-aspartate receptor encephalitis presenting with
acute psychosis in a preteenage girl: a case report. J Med
Case Rep. 2012;6:224.
17. Francis A. Catatonia: diagnosis, classification, and
treatment. Curr Psychiatry Rep. 2010;12:180-185.
18. Consoli A, Ronen K, An-Gourfinkel I, et al. Malignant
catatonia due to anti-NMDA-receptor encephalitis in a
17-year-old girl: case report. Child Adolesc Psychiatry
Ment Health. 2011;5:15.
19. Braakman HM, Moers-Hornikx VM, Arts BM, et al.
Pearls & Oysters: electroconvulsive therapy in anti-NMDA
receptor encephalitis. Neurology. 2010;75:e44-e46.
20. Watkins CJ, Pei Q, Newberry NR. Differential effects
of electroconvulsive shock on the glutamate receptor
mRNAs for NR2A, NR2B and mGluR5b. Brain Res Mol
Brain Res. 1998;61:108-113.
21. Wilson JE, Shuster J, Fuchs C. Anti-NMDA receptor encephalitis in a 14-year-old female presenting as
malignant catatonia: medical and psychiatric approach
to treatment. Psychosomatics. 2013;54:585-589.
22. Barry H, Hardiman O, Healy DG, et al. Anti-NMDA
receptor encephalitis: an important differential diagnosis
in psychosis. Br J Psychiatry. 2011;199:508-509.
23. Sansing LH, Tzn E, Ko MW, et al. A patient with
encephalitis associated with NMDA receptor antibodies.
Nat Clin Pract Neurol. 2007;3:291-296.

Jennifer L. Kruse, MD*

Michael C. Davis, MD, PhD

Waguih William IsHak, MD, FAPA

Department of Psychiatry
and Biobehavioral Sciences
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA
Department of Psychiatry and Psychology
Mayo Clinic
Rochester, Minnesota, USA

VA Greater Los Angeles

Los Angeles, California, USA
Department of Psychiatry
and Biobehavioral Sciences
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA

Department of Psychiatry
and Behavioral Neurosciences
Cedars-Sinai Medical Center
Department of Psychiatry
and Biobehavioral Sciences
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA

Jessica K. Jeffrey, MD, MPH, MBA*

Department of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA

Department of Psychiatry
and Biobehavioral Sciences
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA

Joanna Dearlove, MD, MPH

John O. Brooks III, PhD, MD

Department of Psychiatry and
Biobehavioral Sciences
The David Geffen School of Medicine at UCLA
Los Angeles, California, USA

*These authors contributed equally

AACP.com

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