JCN

REVIEW

Open Access

pISSN 1738-6586 / eISSN 2005-5013 / J Clin Neurol 2016;12(1):1-13 / http://dx.doi.org/10.3988/jcn.2016.12.1.1

The Diagnosis and Treatment of Autoimmune Encephalitis

Eric Lancaster
Department of Neurology, University of
Pennsylvania, Philadelphia, PA, USA

Autoimmune encephalitis causes subacute deficits of memory and cognition, often followed
by suppressed level of consciousness or coma. A careful history and examination may show
early clues to particular autoimmune causes, such as neuromyotonia, hyperekplexia, psychosis, dystonia, or the presence of particular tumors. Ancillary testing with MRI and EEG may
be helpful for excluding other causes, managing seizures, and, rarely, for identifying characteristic findings. Appropriate autoantibody testing can confirm specific diagnoses, although
this is often done in parallel with exclusion of infectious and other causes. Autoimmune encephalitis may be divided into several groups of diseases: those with pathogenic antibodies to
cell surface proteins, those with antibodies to intracellular synaptic proteins, T-cell diseases
associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders. Many forms of autoimmune encephalitis are paraneoplastic, and each of
these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary,
treatment is essential to proper management. Most forms of autoimmune encephalitis respond to immune therapies, although powerful immune suppression for weeks or months
may be needed in difficult cases. Autoimmune encephalitis may relapse, so follow-up care is
important.
Key Wordszzautoimmune, antibody, paraneoplastic, encephalitis, anti-NMDAR encephalitis.

INTRODUCTION
Autoimmune encephalitis is a difficult clinical diagnosis due to the similarities in the clinical, imaging and laboratory findings of many forms of autoimmune and infectious encephalitis. Patients generally have impaired memory and cognition over a period of days
or weeks. There may be clues to specific causes on history of physical examination, but
often these specific signs are absent. A broad approach to testing for infectious diseases and
various neuronal autoantibodies can lead to the correct diagnosis. If a clear autoimmune
cause for the symptoms is established, treatment usually involves escalating immune therapies. The process of caring for these patients requires patience and repeated evaluations
to determine the proper degree of immune therapy needed at any given time.

Received October 1, 2015

Revised October 2, 2015
Accepted October 3, 2015

Correspondence
Eric Lancaster, MD, PhD
Department of Neurology,
University of Pennsylvania,
3400 Spruce St., 3 W Gates,
Philadelphia, PA 19104, USA
Tel +1-215-898-0180
Fax +1-215-349-4454
E-mail [email protected]

SUBTYPES AND PATHOPHYSIOLOGY

OF AUTOIMMUNE ENCEPHALITIS
Autoimmune encephalitis involves several types of diseases with different pathophysiology. Understanding the pathophysiology of these diseases is helpful in using diagnostic
testing and choosing appropriate therapies. The first group includes the classic paraneoplastic disorders associated with antibodies to intracellular antigens, such as anti-Hu.
These disorders are strongly cancer associated and involve T-cell responses targeting neucc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.

Copyright 2016 Korean Neurological Association

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Autoimmune Encephalitis

rons. The prognosis tends to be poor due to irreversible

neuronal killing by these mechanisms, the severity of associated cancers, and the difficulty in controlling these sorts of
immune responsess. The antibodies in these disorders are
useful tumor markers, and in the appropriate context and
titer also useful markers of the paraneoplastic neurological
disorders. The antibodies themselves are not directly pathogenic. The second group involves autoantibodies to extracellular epitopes of ion channels, receptors and other associated
proteins, such as the NMDA receptor. The cancer associations are variable, and the prognosis tends to be much better.
The antibodies in these disorders are thought to be directly
pathogenic, causing reversible effects on synaptic function in
neurons with relatively little neuronal death. There are also
important tumor associations in this group of diseases. For
instance, patients with anti-NMDAR encephalitis commonly can recover from a totally unresponsive state to eventually
resume a good quality of life. Occupying an intermediate
position are diseases with autoantibodies to intracellular
synaptic proteins such as GAD65. It is unclear whether this
group involves T-cell responses and/or functional effects of
antibodies. A final group includes other forms of autoimmune encephalitis in which precise antigens are less clearly
established, such as lupus cerebritis or ADEM. Some diseases in this group have systemic manifestations outside the
nervous system. This review will focus on the disorders with
well-defined brain antibodies.

RECOGNIZING THE SYNDROMES

OF AUTOIMMUNE ENCEPHALITIS
Autoimmune encephalitis can manifest with several distinct

syndromes, complicating its recognition. The classical presentation of encephalitis consists of a subacute (days to a few
weeks) progressive decrease in the level of consciousness,
often with fluctuations, and altered cognition. Memory, especially retention of new information, may be impaired early in the clinical course. Patients may progress to coma.
While many cases of autoimmune encephalitis are indistinguishable from each other or viral encephalitis, there may be
clues to specific autoimmune etiologies (Table 1).
Psychiatric manifestations are common early in the
course of autoimmune encephalitis. These may include psychosis, aggression, inappropriate sexual behaviors, panic attacks, compulsive behaviors, euphoria or fear. Symptoms
may fluctuate rapidly. Although this presentation is well
known for anti-NMDAR encephalitis,1 anti-AMPAR and
anti-GABA-B-R both may have prominent early psychiatric
manifestations2 (Overall, anti-NMDAR encephalitis is more
common and should be suspected first, especially in young
adults and children, but they could each cause this presentation across a wide range of ages).
Abnormal movements may be the presenting symptom in
several types of autoimmune encephalitis. These include anti-NMDAR encephalitis, where movement symptoms may
occur early in the disease course, especially in children, who
generally have more motor symptoms and fewer psychiatric
symptoms than adults.3 These may resemble dystonia or chorea, with writhing and fixed abnormal postures of the limbs.
In adults with anti-NMDAR encephalitis, writhing movements of the face and limbs may be most prominent in the
comatose phases of the illness. GAD65 and GlyR autoimmunity may present with stiff person syndrome (SPS) or progressive encephalomyelitis with rigidity and myoclonus

Table 1. Clinical clues in the recognition of particular types of autoimmune encephalitis

Clinical finding
Psychosis

Associated autoantibody disorders

NMDAR, AMPAR, GABA-B-R

Dystonia, chorea

NMDAR, Sydenham chorea, D2R

Hyperekplexia

GlyR

Status epilepticus

Most characteristic of GABA-B-R and GABA-A-R but NMDAR is much more common;
may occur in other types as well

New onset type 1 diabetes

GAD65

Fasciobrachial dystonic seizures

LGI1

Neuromyotonia, muscle spasms, fasciculations

Caspr2

Stiff-person syndrome and/or exaggerated startle

GAD65, GlyR, Amphiphysin (with GAD65 being most common in stiff person/stiff limb and
GlyR in PERM, and Amphiphysin in women with breast cancer)

CNS (myoclonus, startle, delirium) and gastrointestinal

hyper-excitability

DPPX

Cranial neuropathies

Ma2, Hu, Miller-Fisher, Bickerstaff (but also infections like Sarcoidosis, Lyme, TB)

Cerebellitis

GAD65, PCA-1 (Yo), ANNA-1 (Hu), DNER (Tr), mGluR1, VGCC

CNS: central nervous system, TB: tuberculosis.

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(PERM).4 A striking feature of PERM with GlyR antibodies

is a pathologically exaggerated startle response, resembling
hereditary hyperekplexia, a genetic disease caused by GlyR
mutations.5 Although there is some degree of overlap, GAD65
is more associated with classical SPS while GlyR antibodies
may be seen more with symptoms of hyperekplexia and
myoclonus, which are prominent in PERM. Stiffness or exaggerated startle combined with other symptoms of encephalitis should raise concern for GlyR antibodies. Basal
ganglia encephalitis has also been reported with D2R antibodies, although this may be very rare.6 Sydenham chorea is
a well-recognized autoimmune movement disorder thought
to be triggered by streptococcal infections and should be
considered in children with this presentation.7
Seizures are common in autoimmune encephalitis and
may be a presenting symptom. In anti-NMDAR encephalitis
seizures may occur at any stage of the illness. Autoantibodies to two important inhibitory receptors in the brain, GABA-B and GABA-A receptors (at high titer) convey a high
risk of severe seizures and intractable status epilepticus.8,9
GAD65 antibodies may present with epilepsy, perhaps also
with memory impairment, but with few other symptoms to
suggest an autoimmune etiology. GAD65 autoimmunity may
therefore resemble other forms of treatmentresistant epilepsy.
Fasciobrachial dystonic seizures (FBDS) are brief seizures
consisting of rapid jerks of the face and/or ipsilateral arm and
shoulder.10 Seizures may be partial or associated with temporary disruptions in consciousness and may be multifocal
and variable on EEG. FBDS are characteristic of LGI1 autoimmunity and may precede other symptoms of the disease
by weeks or months. Patients may have hundreds of these
seizures per day. These seizures may have only limited response to seizure medications but respond well to immune
therapies.
Cerebellitis is a distinct syndrome of ataxia of gait, limb
movements, eye movements, voice, and/or swallowing. The
precise mixture of symptoms varies from patient to patient.
Vertigo and nystagmus are common. Cerebellitis may occur with infectious causes, but the presentation of a subacute cerebellar syndrome portends a good probability a
specific autoimmune etiology and also a significant risk of
tumors. Paraneoplastic cerebellar degeneration is associated
with conventional onconeuronal autoantibodies such as Yo,
but also with cell surface autoantibodies targeting mGluR1,
DNER, and other antibodies. GAD65 antibodies are perhaps the most common finding in this phenotype in my experience. Autoimmune cerebellitis may result in the irreversible loss of Purkinje neurons, and the prognosis is recovery
may be poorer than with other types of autoimmune encephalitis.

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Certain types of autoimmune encephalitis may precede

or follow neuromuscular manifestations, particularly acquired neuromyotonia (Isaacs syndrome). Isaacs syndrome
presents with muscle spasms, cramps and fasciculations due
to peripheral nerve hyper-excitability.11,12 Morvan syndrome
(Morvans fibrilllary chorea) consists of peripheral nerve hyper-excitability with encephalitis and severe insomnia. Some
cases of Isaacs syndrome are associated with autoantibodies
to Caspr2 or other, often undefined, members of the voltagegated potassium channel (VGKC) complex.13,14 Caspr2 antibodies are even more likely in patients with Morvan syndrome, especially patients with thymoma, who may have
multiple autoimmune disorders during their disease course.
Encephalitis with these neuromuscular manifestations (myasthenia gravis, neuromyotonia) therefore suggests a specific autoimmune etiology.
As discussed below, most of the autoimmune causes of encephalitis are paraneoplastic, each conveying a risk profile for
various tumors. Detecting particular tumors may therefore
also suggest particular autoimmune causes. For instance, the
likelihood of anti-NMDAR encephalitis is increased in a
young woman with ovarian teratoma, and the likelihood of
anti-DNER is higher in patients with cerebellar degeneration
and Hodgkin lymphoma.

EXCLUSION OF OTHER
AUTOIMMUNE DISORDERS
In addition to the antibody-mediated and paraneoplastic
forms of encephalitis, there are other autoimmune diseases
that may present with encephalitis. In the case of ADEM, encephalitis is a common presentation. The characteristic brain
lesions, and sometimes involvement of the optic nerves or
spinal cord, are an important clue to diagnosis.
Multiple sclerosis (MS) is generally easier to distinguish
from autoimmune encephalitis due to more focal symptoms
and characteristic brain imaging findings.
Lupus may affect diverse areas of the nervous system,
causing neuropathy, vasculitis, myelitis, venous sinus thrombosis, stroke, and other manifestations.15 Neuropsychiatric
lupus may manifest with seizures, psychosis, or neurovascular disease. These manifestations are most common with severe disease affected other organ systems such as the gastrointestinal, renal and hematological systems. In one large series,
one forth of deaths from lupus were related to CNS involvement and 16% were due to CNS infection, suggesting vigilance for both autoimmune and infectious encephalitis is
warranted for these patients.16
Vasculitis affecting the CNS may rarely present with symptoms resembling encephalitis. When this is suspected, imwww.thejcn.com

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aging of the cerebral vessels, search for other evidence of

vasculitis (such as serologies for lupus and other rheumatologic diseases) may be useful.
Bickerstaff encephalitis and Miller Fisher syndrome enter
into the differential diagnosis of autoimmune encephalitis
due to the presence of altered mental status and/or cranial
neuropathies. These diseases may at first resemble the
brain-stem syndrome associated with anti-Ri, but the loss
of reflexes is an important clue suggesting Miller Fisher
syndrome. Detection of the GQ1b antibody may be helpful
in securing these diagnoses.17

EXCLUSION OF INFECTIOUS CAUSES

It is typical for patients with autoimmune encephalitis to
have testing for various infectious etiologies and they are frequently covered with antibiotic and/or antiviral therapies
(such as acyclovir) empirically as infectious causes are excluded. Some of the relevant risk factors for various causes of encephalitis are listed in Table 2 and the major infections are
listed in Table 3.
Most cases of infectious encephalitis are viral. In the USA,
leading viral infections include are HSV, VZV, enterovirus,
and West Nile virus (WNV).18 Japanese encephalitis (JE) was
once the leading cause of viral encephalitis in East Asia, but
has declined dramatically in Korea and other nations due
to successful vaccination programs.19 Bacterial causes include listeria, atypical presentations of streptococcus, syphilis, Lyme disease, and tuberculosis. Fungal causes such as
Cryptococcus or aspergillis are particularly likely in immunocompromised patients.
A detailed travel and exposure history is essential. For instance, West Nile encephalitis has been reported only once in
Korea, in a patient who had recently traveled to Guinea.20
Travel to areas endemic for malaria or Lyme disease may be
similarly relevant. Exposure to persons with tuberculosis or
other infectious agents may be a clue to diagnosis.
Since the risk of various infections depends on the status
of the immune system, it is important to know patients
HIV status and consider whether other medical conditions
(transplantation, cancer) may have weakened immunity.

Certain types of tumors, such as lymphomas, may weaken

the immune system and also increase the risk of paraneoplastic/autoimmune diseases. A detailed review of encephalitis in immunocompromised patients highlighted HSV and
VZV as leading causes, along with a host of rarer entities.21
Infections have been transferred by the organ donor to an
organ transplant recipient, including rabies, LCMV, Westnile,
CMV, and EBV;22 these infections are a consideration in encephalitis in the weeks after transplantation.
Human herpesvirus 6 (HHV-6), and less often HHV-7,
may cause encephalitis and their reactivation may be an important cause of encephalitis in transplant patients.23-25 HHV6 and HHV-7 are diagnosed by PCR, although this may not
be positive initially.26 There are no approved treatments, but
ganciclovir, foscarnet, and cidofovir have been used.27 HHV6 may be more likely in cases whether the donor and/or recipient of a stem cell transplant carry a particular HLA type
(HLA-B*40:06).28
Due to the diversity of potential infections, using a separate test for each pathogen may not be practical. To address
this issue, advanced genetic techniques (e.g., metagenomic
deep sequencing of cerebrospinal fluid) have been proposed to screen for thousands of pathogens rapidly and efficiently. Early successes with this approach have included diagnosing cases of encephalitis due to leptospirosis, neurotropic
astrovirus infection, Balamuthia mandrillaris, and squirrel
bornavirus.29-32 This approach should assume a wider role in
diagnosing unusual CNS infections in the coming years.
Cerebellitis may occur as an infectious or post-infectious
phenomenon. Leading viral causes include VZV, JC virus,
influenza, EBV, and enterovirus. Numerous other bacterial,
fungal, malignant, and other causes have also been reported.33

EXCLUSION OF OTHER
MEDICAL CAUSES
Wernicke encephalitis, due to thiamine deficiency, is most
recognized in alcoholics but may also affect patients with
gastric bypass or other causes of insufficient nutrition.34 A
history of weeks to months of rapid weight loss is common

Table 2. Risk factors for autoimmune and infectious encephalitis

Risk factor
Travel
HIV
Transplantation
Systemic autoimmunity
Cancer
Prior encephalitis

Implications
Consider infectious causes of encephalitis in visited region
Opportunistic infections, risk depending on CD4 count
Opportunistic infections (CMV, VZV, HSV1, 6, 7); if recently transplanted, consider infection from donor
Consider lupus cerebritis, vasculitis
Consider specific paraneoplastic syndromes based on tumor, but also lymphomatous/carcinomatous tumor involvement
Consider relapse of initial encephalitis, secondary autoimmune causes, and (if immunosuppressed) opportunistic infections

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in the later group, who do not have alcohol as a supplemental source of calories (The complex nutritional deficiencies
after gastric surgery may present with several distinct syndromes. Of greatest relevance to this review, Wernicke encephalitis may occur along with or following an acute painful lower-extremity-predominant neuropathy.).35 Prompt
and thorough repletion with thiamine, often along with
other nutrients, may be life saving and should not wait on
laboratory confirmation of the diagnosis.
Intoxications such a neuroleptic malignant syndrome and
serotonin syndrome may often present with similarities to

autoimmune encephalitis. Conversely, patients with antiNMDAR encephalitis may develop psychosis as an initial
symptom and be treated with neuroleptics, then later show
catatonia, rigidity, autonomic instability and altered level of
consciousness; this pattern of findings may be mistaken for
neuroleptic malignant syndrome. Autoimmune encephalitis therefore should enter into the differential diagnosis of
any case of suspected neuroleptic malignant syndrome (Patients with anti-NMDAR encephalitis may be particularly
sensitive to strong dopamine antagonists, and our group attempts to avoid using these medications).

Table 3. Infectious causes of encephalitis

Pathogen

Test

Notes

HSV

PCR

A common cause in both healthy and immune-compromised patients,

with particular predilection for the temporal lobes86
Specific anti-viral therapy may be life-saving
Rare cases of secondary anti-NMDAR encephalitis afterwards85

CMV

PCR

VZV

PCR

JE

PCR

Once a leading cause in East Asia, but declining due to vaccination programs

Enterovirus

PCR

Other, non-polio, strains may also be neurotropic and it is a relatively common

cause of encephalitis

HHV6

PCR

Important cause in transplant patients

1% of persons have HHV-6 in their genome, so PCR test can be misleading

HHV7

PCR

Rare cause in immune compromised patients

Neuroborreliosis (Lyme disease)

Serology

10-15% of untreated patients have neurological symptoms

Manifestations include meningitis, encephalitis, radiculitis, cranial neuritis, and
peripheral neuropathy87

WNV (West Nile)

PCR, Serology

Widely distributed mosquito-born flavivirus

Most infections asymptomatic or minimally symptomatic
Encephalitis is the most common presentation, followed by meningitis and flaccid
paralysis88

Syphilis

Serologies

Most cases are sexually transmitter.

Neurological symptoms may occur years or decades after exposure.
Manifestations are protean

Cryptococcus

Latex agglutination antigen

test, culture

More often presents with meningitis in patients with AIDS and other
immune-compromised states
CSF opening pressure may be marked elevated

Aspergillus fumigatus

Culture, biopsy, antigen ELISA

and other methods

Disseminated CNS aspergillosus is mostly in immune compromised (transplant

patients), and pathology usually involves basal ganglia and/or thalami89

Mucor

Culture, biopsy (ideally

for nasal involvement)

May affect both immunocompromised and immune intact persons

Prognosis is grim

Tuberculosis

Chest X-ray, PPD, Serology

In one study the second most common cause of infectious temporal lobe
encephalitis behind HSV86
May also present with Rhombencephalitis

Listeria

Culture

Rhombencephalitis and meningitis are the two main manifestations

Streptococcus

Culture

Toxoplasmosis

Serology

Classically, a common cause of brain lesions in patients with AIDS

CNS: central nervous system.

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Lymphoma or carcinomatous meningitis may present

similarly to autoimmune encephalitis.36 Particularly, symptoms may have a subacute onset and involve multiple cranial
neuropathies. Both may occur in patients with or without
known tumors. Repeating CSF cytology, awareness of known
tumors, and screening for malignancy may all help lead to
recognition of these causes.

DIAGNOSTIC APPROACHES
Antibody testing

Autoantibody testing is extremely important for the proper

diagnosis of autoimmune encephalitis. However, the tests
have complexities that require consideration, and taking certain test results as conclusive evidence of autoimmune encephalitis can be a mistake.
Commercial tests for autoantibodies to NMDAR, LGI1,
Caspr2, AMPAR (GluR1, GluR2 subunits), and GABA-B-R
are widely available. Newer cell surface antigens like GABAA-R and DPPX are more difficult to test clinically. The synaptic intracellular antigens GAD65 and Amphiphysin, as
well as the conventional intracellular onconeuronal antibodies are widely available. In the correct clinical context,
these antibodies can be diagnostic. But there are complexities
to interpreting some of these tests.
NMDAR and other cell surface antibody tests are most
sensitive and specific with CSF. Serum may offer a low false
positive rate and a higher false negative rate. Pathogenic cell
surface or synaptic autoantibodies are IgG responses. NMDAR IgM and IgA responses have been reported in patients
with schizophrenia and other psychiatric disease but also in
up to 10% of normal controls; these IgM and IgA responses
have no established role in diagnosing autoimmune encephalitis.37 Conversely, the types of IgG responses associated
with anti-NMDAR encephalitis are not found in patients
with schizophrenia.38
The availability of titers for NMDAR antibodies has led
some practitioners to attempt to use these titers to guide
treatment. However, titers have limited clinical utility for several reasons: 1) absolute titers provide little information on
disease severity, 2) titers in serum do not correlate reliably
with disease status, and 3) CSF titers correlate only roughly
to disease status within a given patient using side-by-side
comparisons of multiple samples.39 Therefore, it is better to
focus on the clinical status of the patient and not changes in
antibody titer during the early phases of the illness. NMDAR CSF titers may be compared to earlier samples sideby-side in assessing whether clinical worsening represents a
true relapse, but this is only rarely helpful.
Caspr2 and LGI1 each associate with VGKCs. The VGKC

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antibody test is based on immunoprecipitation of a complex of protein containing VGKCs, LGI1, Caspr2 and other
proteins. The VGKC RIA was created 15 years before the recognition of LGI1 or Caspr2 antibodies,40 and patients with
these antibodies were thought, incorrectly, to actually have
antibodies to potassium channel subunits themselves.13,14,41
The VGKC test may still detect patients with LGI1 or
Caspr2 immunity, but low titer serum positive results have
uncertain clinical significance. For instance, Paterson et al.42
reported that only 4 of 32 patients with low titer VGKC results (100400 pM) actually had an autoimmune disorder.
Thus a low titer serum VGKC result without corresponding
evidence of LGI1 or Caspr2 antibodies, ideally in the CSF,
should not be taken as definitive evidence of autoimmune
encephalitis.
GAD65 antibodies have diverse clinical correlates, including SPS, cerebellar degeneration, epilepsy, and type 1 diabetes.43 In the context of encephalitis, especially with epilepsy,
a CSF GAD65 response is evidence of an autoimmune etiology. However, GAD65 may co-exist with other autoantibodies, such as GABA-B-R, so may or may not represent the
most relevant pathophysiological mechanism in some patients with multiple antibodies. In addition, low titer GAD65
serum responses may not be specific for a neurological disorder, and GAD65 serum antibodies provide little additional information in a patient with known type 1 diabetes.
Conversely, I have observed patients who develop type 1
diabetes after the onset of their neurological syndrome in
the context of GAD65 antibodies. Testing CSF of these patients for GAD65 and a panel of other autoantibodies may
be informative in these cases.
Hashimotos encephalopathy is generally defined as encephalopathy associated with thyroid autoantibodies that
responds to steroids or other immune therapies.44 It has not
been shown that thyroid antibodies can directly affect the
brain, and the abnormalities in thyroid hormone levels are
generally too mild to explain the brain disease. Some of these
cases are due to other autoantibodies, such as to the NMDAR or GABA-B-R, but the true cause of most cases is unknown. Thyroid antibodies are therefore sometime tested
in patients with autoimmune encephalitis. Finding thyroid
antibodies should prompt a careful search for responsive
other autoantibodies to brain that would provide a more
convincing explanation of the symptoms. But if these antibodies are not found immune therapy should be considered.

Imaging

Brain MRI in patients with NMDAR, AMPAR, LGI1, Caspr2,

and GABA-B antibodies may be normal or show increased
T2 signal, especially in the medial temporal lobes. 1,8,13,41

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This pattern is similar to the findings seen in HSV encephalitis, where 95% of patients have abnormalities on MRI,45
or other viral causes of encephalitis. Tuberculosis, Syphilis,
or other infections may present similarly. Autoantibodies to
DPPX or GABA-A may have less characteristic findings.9,46
Brain MRI therefore does not distinguish between infectious and autoimmune causes, and a normal brain MRI does
not exclude these causes.
Advanced brain imaging with PET or SPECT has shown
diverse areas of regional hyper- or hypo-metabolism in patients with NMDAR, LGI1, Caspr2 or other autoantibodies.47
These studies have not reached the point where any particular form of encephalitis can be distinguished from another,
so I do not generally rely on these studies to rule in or rule
out autoimmune causes in my practice.

EEG

EEG is useful in patients with autoimmune or infectious

encephalitis for excluding subclinical seizures, for prognosis,
and sometimes for suggesting particular diagnoses. In patients with HSV encephalitis, EEG may predict prognosis in
addition to helping exclude non-convulsive seizures; normal
EEG correlates with good outcomes independent of other
prognostic factors.48
Seizures may occur at any point during the disease course
of anti-NMDAR encephalitis, including at presentation.49
The extreme delta brush pattern may be observed in patients
with anti-NMDAR encephalitis, most often in patients who
are comatose.50 This distinctive EEG pattern should prompt
testing for NMDAR antibodies. Patients with anti-NMDAR
encephalitis and other forms of autoimmune encephalitis
may also have prolonged periods of unresponsiveness and
abnormal behaviors that are not due to seizures, so in these
cases prolonged EEG monitoring may be very helpful.
Status epilepticus may occur in several forms of autoimmune encephalitis. The highest risk appears to be in patients
with autoantibodies to the major brain inhibitory receptors
GABA-A and GABA-B. High-titer antibodies to either of
these antigens conveys a risk of status, which may be refractory to the unusual treatments. Since these antibodies are
both much rarer than other autoantibodies to the NMDA receptor, the status epilepticus in the setting of autoimmune
encephalitis probably occurs more frequently with NMDAR
antibodies overall.
LGI1 antibodies are associated with FBDS, which may
present weeks or months prior to other symptoms. The clinical characteristics of these seizures are distinctive, involving rapid jerking of one side of the face and/or upper extremity. Each seizure tends to be unilateral but they may occur
on both sides. Some events are simple partial and very rap-

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id, but complex partial seizures may occur as they become

more frequent. EEG may show multifocal onset seizures and
other abnormalities.
In my experience, seizures in autoimmune encephalitis are
associated with active disease (e.g., are unlikely to persist after remission of other symptoms of autoimmune encephalitis). These seizures may be very difficult to control with antiseizure medications until the autoimmune disease is treated.

Biopsy

Brain biopsy generally is not used in the diagnosis of encephalitis for several reasons. Infections may be detected by
PCR, culture or other less invasive methods. The well-defined autoantibody causes typically have antibody tests that
are much less invasive and much more definitive. In addition, the results of biopsy are generally not definitive for a
particular autoimmune etiology. Overall, the clinical impact
of biopsy done for suspected encephalitis is low, with only
about 8% of cases having clear benefit.51

Cancer screening

Paraneoplastic disorders are, in general, autoimmune disorders that are triggered by tumors. In many cases the target
antigen is expressed by tumor tissue, such as HuD proteins
in small cell lung cancer and NMDARs in ovarian teratoma.52,53 In these patients it is likely that presentation of the
antigen in the context of the tumor triggers the autoimmune
response. However, other patients without tumors may have
an identical clinical syndrome and immunological response
(antibody specificity, neuropathology, etc.).
It is important to detect tumors promptly for several reasons. 1) Treating the relevant tumor is thought to be helpful
for treating the autoimmune disorder. 2) Tumor therapy
and immune therapy may need to be given simultaneously
and in a coordinated fashion. 3) Treatment with steroids,
rituximab, or cyclophosphamide could complicate tumor
diagnosis in the case of tumors like lymphoma.
In the case of onconeuronal antibodies to intracellular
antigens such as Hu, the antibodies may occur more commonly in cancer patients than in patients with the autoimmune disease. For instance low titer serum Hu responses are
common in small cell lung cancer patients without the antiHu neurological syndromes. For this reason, finding such
an antibody should prompt a careful evaluation for tumor
even if there is not a corresponding autoimmune disease.
For instance, an elderly diabetic smoker may be tested (inappropriately) for anti-Hu to evaluate a mild slowly progressive small fiber neuropathy. In this case, a low titer serum
Hu antibody would be far less likely to explain the neuropathy than the diabetes, but should nonetheless prompt
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screening for lung cancer. Similarly, a patient with known

lung cancer may develop neuropathy after chemotherapy;
finding Hu antibodies in such a patient should not be taken
as definitive evidence of a paraneoplastic disorder.
Cell surface/synaptic antibodies are generally found in the
spinal fluid only in patients with the relevant neurological
disorder and are not found incidentally. Each of these antibodies has a cancer risk profile that should inform the search
for tumors.
The testing strategy depends on the specific autoantibody
and/or clinical syndrome. Where there is risk for lung cancer or other solid tumors, CT scans and PET/CT may be appropriate. In syndromes associated with ovarian teratoma,
evaluation with ultrasound or pelvic MRI. In young men
where Ma2 is diagnosed or suspected testicular ultrasound is
important. Breast imaging with mammogram or MRI, pap
smear, and pelvic imaging may be most helpful in women
with anti-Yo. Screening should be broad in patients with
high-risk syndromes such as cerebellar degeneration even
when a particular antibody is not identified. Tumors may be
very small when the neurological symptoms begin, so
screening is typically done on initial presentation and repeated at increasing intervals. For instance, a young woman with
anti-NMDAR encephalitis may have pelvic MRI at diagnosis,
and repeated studies at 6 months, 1 year, and 2 years. A patient with DNER antibodies (conveying a 90% risk of Hodgkin lymphoma) might have PET-CT at diagnosis then close
follow-up with an oncologist and repeat studies starting 34
months later.

SPECIFIC TYPES OF
AUTOIMMUNE ENCEPHALITIS
Autoantibodies to cell surface antigens

Anti-NMDAR (N-methyl-D-aspartate receptor) encephalitis has a characteristic clinical syndrome in most patients.
Symptoms of psychosis and memory impairment are commonly the initial findings with abnormal movements, seizures, and depressed level of consciousness emerging later.1
Patients may experience the psychotic symptoms again as
they wake form coma, a phenomenon analogous to the psychotic symptoms seen after recovery from phencyclidine
anesthesia (Phencyclidine, also known as PCP or angel
dust, is an NMDAR antagonist developed as an anesthetic
but is not used due to the high risk of psychosis). Ovarian
teratoma affects many female patients of reproductive age,
but other tumors (and tumors outside women of reproductive age) are rare. The response to immune therapy is generally good, particularly if the more effective treatments are
used promptly. However, treatment may take many months

J Clin Neurol 2016;12(1):1-13

to reach its full effects, and some patients have persistent

deficits, especially in the domains of memory and cognition.
The mechanisms of NMDAR antibodies have been extensively studied: these antibodies cross-link and internalize the
target receptors, depleting NMDARs from synapses.54 The
antibodies are clearly directly pathogenic; passive transfer into
the brains of rodents produced neurological symptoms that
correlate with reduction in surface NMDARs on neurons.55
Anti-LGI1 (Leucine-rich, glioma-inactivated 1) encephalitis accounts for most cases of encephalitis previously attributed to VGKC antibodies14,41 (The VGKC test, as described above, detects most LGI1 cases and also most Caspr2
cases). Myoclonus, hyponatremia, and fascio-brachial dystonic seizures are common. In some cases fascio-brachial
dystonic seizures precede other symptoms of the disease by
months. These seizures have characteristic appearance and
respond well to immune therapy.10,56 Respiratory failure and
critical illness are less common with LGI1 than NMDAR antibodies, but the course may be slower. The median age is
about 60 years, significantly older than anti-NMDAR encephalitis. LGI1 is a secreted synaptic protein that organizes
AMPA receptors and VGKCs at CNS synapses. LGI1 antibodies have been shown to affect AMPA receptor localization on cultured neurons,57 but additional mechanisms involving the localization of potassium channels are also
possible. Cancers are relatively rare in this disorder, and some
of these may be chance events in this older age group.
Anti-Caspr2 (contactin-associated protein-like 2) associate with encephalitis, Morvan syndrome and acquired neuromyotonia (Isaacs syndrome).13,14 The most common phenotype is Morvan syndrome, but peripheral nerve symptoms
may precede or follow encephalitis by months or years. Encephalitis tends to be slower in onset than anti-NMDAR encephalitis, and responds to immune therapy but is prone to
relapse with taper of immune therapy. Some patients may
have thymoma and this subgroup is particularly prone to comorbid myasthenia gravis and other autoimmunities found
in thymoma patients. The median age is about 60 years,
significantly older than anti-NMDAR encephalitis. Caspr2
is a cell adhesion molecule that organizes VGKCs at the
juxtaparanodes of myelinated axons in the central and peripheral nervous system. It is unknown why some patients
have CNS versus peripheral nerve symptoms since the antigen is the same on both types of axons.
Anti-AMPA (-amino-3-hydroxy-5-methy l-4isoxazolepropionic acid) receptor encephalitis may have
psychiatric symptoms on presentation like anti-NMDAR
encephalitis.58 AMPA receptors are a widely expressed type
of glutamate ionotropic receptors used for much of the rapid
excitatory transmission in the brain. There is significant risk

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of tumors of the lung, breast, and thymus in these patients.

Most patients are female and they are mostly middle-aged
and older.
Anti-GABA-B (-Aminobutyric acid B) receptor encephalitis is characterized by encephalitis with severe seizures or
status epilepticus.8 This is logical due to the inhibitory role of
the GABA-B receptor system in the brain (GABA-B receptors are important for limiting excessive neuronal activity).
About half of patients have small cell lung cancer and the
patients are mostly older adults. Antibodies to the GABA-B
receptor may be the most common type of immune cause
found in patients with lung cancer.
Anti-GABA-A (-Aminobutyric acid A) receptor encephalitis has been reported in children and adults. At high titer
these antibodies, which target the primary inhibitory ionotropic receptor in the brain, associate with severe encephalitis with status epilepticus or epilepsia partialis continua.9 So
far only 1 of 6 patients had a tumor, Hodgkin lymphoma,
but the full cancer associations will become clearer as more
cases are found.
Anti-mGluR1 (metabotropic glutamate receptor 1) have
been reported in a small number of patients with paraneoplastic cerebellar degeneration.59,60 There is a high risk of
Hodgkin lymphoma in these patients. Similarly, antibodies
to Homer-3, which organizes mGluR1 at synapses, have
been reported in a single patient.
Anti-mGluR5 (metabotropic glutamate receptor 5) have
been reported in a few patients with Ophelia syndrome, a
relatively mild form of encephalitis that occurs in patients
with Hodgkin lymphoma.60 Typically the patients become
confused and often seem adrift in time, as described by
Carr61 in his original reports. Patients do not generally have
the sorts of psychosis, agitation, seizures, and autonomic instability seen, for example, in patients with NMDAR antibodies. Patients improve dramatically with treatment of the
lymphoma. Although mGluR1 and mGluR5 are close homologs, the antibodies do not cross react and the clinical syndromes are distinct.
Anti-DNER (delta/notch-like epidermal growth factor-related receptor) target a transmembrane protein expressed on
Purkinje neurons and associate with cerebellar degeneration
and a very high risk (90%) of Hodgkin lymphoma.62,63 Before the precise definition of the antigen, these antibodies
were referred to as anti-Tr and often classified with the
conventional paraneoplastic disorders.64 Patients should be
carefully and repeated screened for Hodgkin lymphoma.
Even with successful tumor treatment there is often permanent cerebellar injury.
Anti-GlyR (Glycine receptor) target the primary inhibitor
ionotropic receptor in the spinal cord.65 Symptoms accord-

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ingly resemble strychnine toxicity: increased muscle tone,

spasms, and pathologically exaggerated startle response.
These antibodies should be considered in patients with SPS,
especially those showing a PERM-like phenotype.4 There is
some risk of cancer, although most patients do not have tumors.
Anti-DPPX (dipeptidyl-peptidase-like protein-6) associate
with a syndrome of gastrointestinal and nervous system hyper-excitability.46 In addition to memory loss, seizures, and
confusion, symptoms of exaggerated startle, myoclonus, rigidity and hyper-reflexia have been reported. Patients may
have severe diarrhea or alternatively have constipation. A
small group of these patients may have tumors such as lymphoma.

Autoantibodies to intracellular synaptic proteins

Anti-GAD65 (glutamic acid decarboxylase 65kd) target the

synaptic isoform of the enzyme necessary to synthesize
GABA. GAD65 antibodies have diverse clinical associations,
including type 1 diabetes, cerebellar ataxia and SPS.66 In patients with the neurological symptoms a strong antibody
response in the CSF is common. In the paraneoplastic context (that is, when cancer is present), GAD65 antibodies associate with diverse syndromes including encephalitis, SPS
and paraneoplastic cerebellar degeneration.67 When cancer
is present GAD65 antibodies more frequently co-existing to
autoantibodies to GABA-A or GABA-B.
Anti-Amphiphysin target an intracellular protein important for recycling synaptic vessicles.68 The antibodies are very
strongly associated with SPS in women with breast cancer.69
The SPS more often affects the cervical region and responds
to tumor therapy and/or immune therapy.

Autoantibodies to intracellular antigens

Anti-Hu (ANNA-1) was the first type of onconeuronal antibody described. Patients with anti-Hu most often have
sensory-predominant neuronopathy but may also or alternatively have cerebellar degeneration, encephalitis or encephalomyelitis.70 Multifocal involvement is common. The
antibodies target a family of intracellular proteins. These
antibodies are not directly pathogenic and do not cause
disease in active immunization or passive transfer animal
models. Pathology studies show CD8 positive T-cell infiltrates in affected tissues. The association with small cell lung
cancer is very strong (approximately 86% in one series) and
outcomes are often poor.
Anti-Ri (ANNA-2) associate with diverse syndromes including cerebellar degeneration and encephalitis. Most patients have lung or breast cancers.71
ANNA-3 have only rarely been described and the clinical
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Autoimmune Encephalitis

features are multifocal and have a similar range as anti-Hu.72

Anti-Yo (PCA-1) are found in women with breast or ovarian cancers in more than 90% of cases.73 Patients usually
have paraneoplastic cerebellar degeneration. Approximately
half of patients die of their tumors, and tumors are often only
detected after identification of the paraneoplastic disorder.74
There is some evidence that the antibodies may enter neurons, but other researchers think T-cell mechanisms are
more likely.75
PCA-2 have only rarely been reported and may associate
with encephalitis or cerebellar syndromes.76
Anti-CRMP-5 have diverse associations including cognitive impairment, cerebellar syndromes, abnormal movements (chorea), and cranial neuropathies. Optic neuritis has
also been reported.77-79
Anti-Ma2 (PMNA-2) are found most often in young men
with germ cell tumors. Neurological symptoms could include
encephalitis, cerebellar degeneration, or neuropathy. Limbic
and/or brainstem syndromes may be most common.80

TREATMENT APPROACHES
Treatment for suspected autoimmune encephalitis is often
given empirically prior to specific antibody test results. This
may include steroids and/or IVIG. If a cell-surface/synaptic
antibody disorder is diagnosed, initial treatments may include IVIG, plasmapheresis, and/or steroids. Steroids may be
beneficial in a range of autoimmune disorders but could potentially create problems with the diagnosis of certain disorders such as CNS lymphoma. IVIG offers an important
advantage of being unlikely to make infectious encephalitis
worse. Plasmapheresis is also unlikely to significantly worsen infectious encephalitis.
If a synaptic/cell-surface antibody is detected and the patient has any significant symptoms, first-line therapy should
be given if it has not already been tried. In general, prompt
treatment, and escalation of treatment in patients who remain ill, is associated with better outcomes. Although there
are not randomized treatment trials, protocols have been
proposed for anti-NMDAR encephalitis,1 and these approaches have been applied to other diseases in the cellsurface/synaptic autoantibody category. Our group often
uses IV solumedrol (1 gram daily for 35 days then a taper
over several weeks) and IVIg (0.4 g/kg/day for 5 days).
Other groups have advocated plasmapheresis instead of
IVIg, and so far there is not convincing evidence of superiority for either approach.
If the patient remains significantly impaired after first-line
therapy, second-line treatments are typically used. Some
groups might wait 2 weeks or longer to allow first-line ther-

10

J Clin Neurol 2016;12(1):1-13

apies time to work, but our group often proceeds more

quickly to second line therapy sooner is patients who are
very ill, for instance comatose patients with anti-NMDAR
encephalitis. Second line therapies include rituximab (often
375 mg/m2 weekly for 4 weeks) or cyclophosphamide (750
mg/m2 IV monthly until improvement is noted), or both.
Rituximab is a monoclonal antibody targeting CD20, so
plasmapheresis generally should not be done after it is administered. Rituximab depletes CD19+/CD20+ B-cells, and
circulating levels of these cells typically become undetectable for several months after treatment. Due to its relatively
favorable safety profile, rituximab is more often used as
monotherapy in children. Rituximab is thought to be generally effective against neurological diseases where the autoantibodies are of the IgG4 subtype.81 Since IgG4 responses
predominate in LGI1 and Caspr2 encephalitis this provides
an additional theoretical support for using rituximab in
those diseases. Cyclophosphamide has several important
toxicities, including a risk of infertility, especially in young
women who received repeated doses (The risk cumulatively
increases, potentially up to 40% after 12 doses). This risk be
can reduced with use of a GnRH agonist in women,82 or addressed with egg/sperm collection.

AUTOIMMUNE ENCEPHALITIS
IN CHILDREN
Anti-NMDAR encephalitis is by far the most common type
of antibody-mediated encephalitis in children. The age distribution of other types of synaptic autoimmune disorders
either skews much older (the median age for LGI1 or Caspr2
antibodies is about 60 years) or the disorders are much less
common (GABA-A antibodies) or both. In a study by the
California encephalitis project, anti-NMDAR encephalitis
was more common any single viral etiology.83
Anti-NMDAR encephalitis in children may present differently than in adults.84 Children are more likely to have abnormal movements (chorea, incoordination) early in the disease course and also may have atypical motor symptoms
such as ataxia or hemiparesis. Children more often have seizures than adults. The classic symptoms of psychosis seen in
adults are less common, but behavioral regression is frequently noted. Patients may have prominent speech difficulties. Treatment strategies are similar in children and adults,
but physicians may be more reluctant to use cyclophosphamide, relying more on rituximab as a second line treatment
(As with adults, the optimal treatment strategies are not
known). Responses to treatment are similar in children and
adults, with about half failing first line therapies. Ovarian
teratoma is less likely in female children before puberty, so

E Lancaster

tumors are uncommon in young children.

RELAPSING ENCEPHALITIS
Patients with encephalitis may recover, completely or partially, and then experience worsening symptoms. In autoimmune encephalitis, relapse tends to follow a similar clinical
course to the initial attack. In anti-NMDAR encephalitis,
these relapse tend to be milder than the initial attack and
manifest with confusion, worsening memory, personality
change, hallucinations or new seizures (In my experience,
seizures in my cases of autoimmune encephalitis remit with
appropriate treatment, and new seizure should always raise
concern for relapse). The risk of relapse in anti-NMDAR encephalitis in approximately 12% over two years (but continues beyond that) and is highest in untreated patients, intermediate in patients who had only first-line therapy, and
lowest in patients treated with second-line therapies.84 Relapsed patients are usually treated with second-line therapies, possibly after first line therapies. These patients may
be treated for longer periods of time with second line therapy, especially rituximab, but the optimal duration of treatment has not been established. In other types of autoimmune
encephalitis, the risk of relapse is less clearly established.
LGI1 antibodies and Caspr2 antibodies may associate with
milder encephalitis, compared with NMDAR antibodies,
than is chronic or relapsing. Similar treatment strategies may
be used with these antibodies.
An important recent advance has been the recognition
that patients with HSV encephalitis may rarely develop anti-NMDAR encephalitis several weeks later as a post-infectious complication.85 In these patients CSF from the initial
attack has no NMDAR antibodies with positive PCR for
HSV, but CSF from the second attack now has NMDAR antibodies with negative PCR for HSV. This phenomenon may
be due to exposure of CNS antigens to the immune system
in the presence of a powerful infectious stimulus. Patients
who worsen after infectious encephalitis should therefore
be carefully evaluated for both infectious and autoimmune
etiologies. Similarly, patients who have been treated for autoimmune encephalitis may be immunosuppressed and at risk
for diverse infections. However, opportunistic CNS infections after autoimmune encephalitis are probably very rare
compared to worsening of the autoimmune disease.

CONCLUSIONS
The proper diagnosis and management of autoimmune encephalitis requires an organized approach. Evaluation should
begin with a detailed history and physical examination to

JCN

detect clues to specific causes. A diverse range of infections

should be considered, and appropriate testing should be
done to exclude relevant pathogens. Ancillary testing with
MRI, EEG, and lumbar puncture may further support a diagnosis of encephalitis and potentially suggest particular
causes. A broad group of autoantibody tests may be used to
diagnose or exclude particular autoimmune causes, but these
tests are complex and not every positive result is definite evidence of an autoimmune disorder. The risk of neoplasm
should always be considered during initial treatment and
follow-up visits, both in terms of diagnosing serious cancers
and because specific tumors may suggest particular autoimmune causes. Treatment should depend on the pathophysiology of the disorder (e.g., T-cell-mediated or antibody mediated) and the clinical situation of the patient. Patients
may relapse and should receive appropriate follow-up care
from a physician familiar with the diseases.
Conflicts of Interest
The author has no financial conflicts of interest.

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