Review Article

Autoimmune Epilepsy
Address correspondence to
Dr Nicolas Gaspard, Neurology
Department, Universit Libre
de Bruxelles Hpital Erasme,
Nicolas Gaspard, MD, PhD Route de Lennik, 808 1070
Brussels, Belgium,
ngaspard@ulb.ac.be.
Relationship Disclosure:
ABSTRACT Dr Gaspard receives royalties
from UpToDate, Inc, and
Purpose of Review: This review presents recent developments in the clinical fea- Wolters Kluwer and research
tures, immunologic basis, and treatment options for autoimmune encephalitis, sei- support from Fonds Erasme
zures, and epilepsy. Pour la Recherche Mdicale
and the Belgian National Fund
Recent Findings: In addition to the expansion of our knowledge on classic paraneo- for Scientific Research.
plastic limbic encephalitis with onconeural antibodies, recent years have witnessed the Unlabeled Use of
development of the category of encephalitis associated with antibodies directed toward Products/Investigational
neuronal surface antigens. Antibodies against the voltage-gated potassium channel Use Disclosure:
Dr Gaspard discusses the
are, in fact, directed toward an array of targets within a large molecular complex. The unlabeled/investigation use of
most common target, leucine-rich, glioma inactivated 1 (LGI1), is associated with a syn- steroids, IV immunoglobulins,
drome of limbic encephalitis, sometimes preceded by disease-specific faciobrachial plasma exchange, tacrolimus,
natalizumab, rituximab,
dystonic seizures, which could allow early diagnosis and treatment. Encephalitis with and cyclophosphamide
N-methyl-D-aspartate (NMDA) receptor antibodies, only discovered a few years ago, for the treatment of
has emerged as the leading syndrome of this new category. Its clinical features and autoimmune encephalitis.
* 2016 American Academy
EEG signature are well defined, which should allow prompt recognition and treatment. of Neurology.
The list of antibodies is still growing as new antibodies are identified that recognize
other synaptic proteins, such as the +-aminobutyric acid (GABA), !-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid (AMPA), and glycine receptors. The role of glutamic
acid decarboxylase 65 (GAD65) antibodies is still a controversy, as is the cause of
Rasmussen encephalitis and syndromes of cryptogenic refractory status epilepticus
and the mechanisms of seizures in systemic autoimmune diseases. A link between
autoimmunity and epilepsy has been substantiated by large epidemiologic studies,
but the nature of the causality requires more research.
Summary: Autoimmune encephalitis is an important cause of seizures to recognize as
it entails a specific therapeutic approach. Paraneoplastic limbic encephalitis and NMDA
receptor and LGI1 encephalitis are well-characterized immunoclinical associations. Other
syndromes and antibodies are being actively identified and described. A concept of
autoimmune epilepsy is emerging and, if confirmed, is likely to alter the therapeutic
approach and improve the outcome of some patients with pharmacoresistant epilepsy.

Continuum (Minneap Minn) 2016;22(1):227245.

INTRODUCTION situations where seizures might com-

Almost 50 years ago, the report of a
syndrome of encephalopathy, seizures,
and strokelike episodes associated with
Hashimoto thyroiditis marked the first
description of a possible link between
the central nervous system (CNS) and an
autoimmune process.1 This entity, ini-
tially called Hashimoto encephalopathy
and more recently referred to as steroid-
responsive encephalopathy associated
with autoimmune thyroiditis (SREAT),
is now known to be one of the many
plicate a systemic autoimmune disorder.
Around the same time, the first cases
of limbic encephalitis, defined by the
triad of cognitive decline, behavioral
changes, and seizures, were reported in
patients with systemic cancers.2 Initially
thought to be a rare disorder, the iden-
tification of specific autoantibodies led
to its increased recognition in the 1980s
and 1990s and to the demonstration of
an autoimmune link between the neo-
plasm and the encephalitis. While limbic

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 Autoimmune Epilepsy
KEY POINTS
h Paraneoplastic limbic encephalitis was initially described in
encephalitis presents association with systemic cancer, non-
with memory loss, paraneoplastic cases of limbic and dif-
seizures, and behavioral fuse encephalitis have been increasingly
and sleep disturbances. recognized, which led to the discovery
The condition can of several new pathogenic antibodies
occur in isolation targeting neuronal cell-surface antigens.
or in association with Recent data also suggest that not only
signs of widespread might acute encephalitis with seizures
neurologic involvement. have an autoimmune basis, but so might
h Hu, Ma2/Ta, CV2/collapsin some forms of chronic epilepsy, while
response mediator other epileptic syndromes exist in which
protein-5 (CRMP-5), an inflammatory or autoimmune etiol-
amphiphysin, ogy is suspected but not yet proven.
voltage-gated calcium
Altogether, these advances have led
channel (VGCC), and
to the concept of autoimmune epilepsy,
metabotropic glutamate
receptor 5 (mGluR5)
recognized in the recent proposal for
antibodies have been the new classification of epilepsy by the
associated with International League Against Epilepsy
paraneoplastic limbic (ILAE) as epilepsy with evidence of auto-
encephalitis. Small cell immune mediated CNS inflammation.3
lung carcinoma is the The recognition of an autoimmune
most commonly etiology to seizures is of paramount
encountered neoplasm. importance as it will entail a specific
therapeutic approach that differs from
antiseizure medications.
This article reviews the clinical fea-
tures, immunologic basis, and treat-
ment options for autoimmune seizures
and epilepsy.
PARANEOPLASTIC LIMBIC
ENCEPHALITIS ASSOCIATED WITH
ONCONEURAL ANTIBODIES
Limbic encephalitis is characterized by
cognitive, especially memory, impair-
ment; behavioral changes; temporal lobe
seizures; and sleep disturbance.2 Sei-
zures can be dyscognitive or secondary
generalized, and status epilepticus may
occur. Pathologic examination and brain
MRI show evidence of inflammation in
the limbic structures, particularly the
mesial temporal lobes. Patients often
also exhibit signs of wider involvement
of the central and peripheral nervous
systems, such as widespread encepha-
lomyelitis, cerebellar degeneration, and
sensory neuronopathy (Table 12-1).
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Hypothalamic dysfunction is a common
feature of the encephalitis associated
with Ma2/Ta antibodies and testicular
cancer.4,5 Ophelia syndrome is a rare
disorder of paraneoplastic limbic enceph-
alitis in patients with Hodgkin lymphoma
and is characterized by the presence of
antibodies against the metabotropic
glutamate receptor 5 (mGluR5).6,7 CSF
analysis is abnormal in at least two-thirds
of cases, showing a mildly elevated pro-
tein level and pleocytosis.
Classic limbic encephalitis has been
reported with a wide array of onco-
neural antibodies, including Hu, Ma2/
Ta, CV2/collapsin response mediator
protein-5 (CRMP-5), amphiphysin,
voltage-gated calcium channel (VGCC),
and mGluR5 (Table 12-1). These anti-
bodies are detected in the serum of the
majority of patients, but seronegative
cases still occur. Conversely, while
onconeural antibodies are almost in-
variably associated with a systemic
neoplasm, they can rarely occur in its
absence.8 The antibodies recognize in-
tracellular antigens shared by the tumor
and the neurons. They are not believed
to play a direct pathogenic role and are
mostly biomarkers, and neurologic in-
volvement is attributed to a cell-mediated
immune reaction.9 Response to immune
therapies is often disappointing. Suc-
cessful treatment of the underlying neo-
plasm is sometimes associated with
partial neurologic improvement.
Paraneoplastic limbic encephalitis pre-
cedes the diagnosis of cancer in up to
half of the cases. Its occurrence should
prompt thorough and repeated inves-
tigations for an occult neoplasm, most
frequently small cell lung carcinoma
(Table 12-1). Guidelines for the screen-
ing for occult malignancy have been
published.10 Whole-body fluorodeoxy-
glucose positron emission tomography
(FDG-PET) is more sensitive than CT in
demonstrating occult neoplasms or small
metastatic lesions. A negative PET/CT scan
February 2016

does not rule out underlying cancer, and
repeating a PET/CT scan after a 6-month
interval is recommended, followed
by screening every 6 months up until
4 years if testing remains unrevealing.10
LIMBIC ENCEPHALITIS
ASSOCIATED WITH ANTIBODIES
AGAINST THE VOLTAGE-GATED
POTASSIUM CHANNEL COMPLEX
Initially thought to target the potas-
sium channels themselves,11 antibodies
directed toward the voltage-gated potas-
sium channel (VGKC) complex are now
known to bind other components of a
multiprotein complex that anchors the
channels in the neuronal membrane
close to the nodes of Ranvier.12,13 The
most common molecular targets are
the leucine-rich, glioma inactivated 1
(LGI1); contactin-associated proteinlike
2 (Caspr2); and contactin 2 proteins.
LGI1 antibodies are associated with a
typical course of limbic encephalitis,
while Caspr2 antibodies are more com-
monly associated with neuromyotonia
and Morvan syndrome.12 Low titers of
antibodies can be seen in individuals
with various unrelated nonautoimmune
disorders and in some patients with pe-
ripheral nerve hyperexcitability, while
high titers are the rule in patients with
clear limbic encephalitis.14 In cultured
neurons, LGI1 antibodies disrupt the
synaptic clustering and availability
of glutamate !-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid
(AMPA) receptors and interfere with
synaptic transmission.15 This type of en-
cephalitis is more common in men and
occurs mostly after the age of 40.11,16
Seizures occur in 80% of cases and can
be dyscognitive or secondary general-
ized seizures. Ictal autonomic manifes-
tations, such as piloerection, have been
reported. Hyponatremia (less than
130 mEq/L) occurs in 30% to 60% of
the cases due to the syndrome of inap-
propriate secretion of antidiuretic hor-
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KEY POINTS
mone (SIADH) and should raise h A diagnosis of limbic
suspicion of the diagnosis. encephalitis should
A peculiar type of seizure, termed prompt thorough and
faciobrachial dystonic seizure, has been repeated investigations
recently described in a subset of patients for an occult malignancy.
with anti-LGI1 encephalitis.17 These sei- Positron emission
zures occur frequently, up to hundreds tomography is
of times per day, and are characterized superior to CT for
by brief tonic contraction of the arm
the detection of
small lesions.
and face, either on one side or, more
commonly, alternating between both h The most common
sides. EEG changes during faciobrachial
antigen recognized by
voltage-gated potassium
dystonic seizures vary but most often channel antibodies
consist of diffuse attenuation or bursts is leucine-rich, glioma
of slow waves. Brain FDG-PET may show inactivated 1 (LGI1).
hypermetabolism in the basal ganglia. The syndrome is one
As illustrated in Case 12-1, faciobrachial of limbic encephalitis in
middle-aged men,
dystonic seizures precede the manifes-
often associated
tations of limbic encephalitis and do not
with hyponatremia.
respond to antiseizure medications.17
h Faciobrachial dystonic
In contrast, immune treatment is effica-
seizures consist of brief
cious and might prevent the develop-
tonic contractions of the
ment of cognitive impairment.18
face and arm that occur
CSF analysis is most often normal.
exclusively in association
Brain MRI is abnormal in half the cases, with leucine-rich,
commonly showing hyperintensities in glioma inactivated 1
the mesial temporal lobes and some- (LGI1) antibodies and
times basal ganglia. Most patients with precede the manifestations
anti-VGKC complex antibodies do not of limbic encephalitis.
have an associated neoplasm, but rare
paraneoplastic cases exist. Treatment
with steroids, IV immunoglobulin (IVIg),
or plasma exchange is efficacious, and
most patients make a full recovery. Clin-
ical improvement usually mirrors the de-
crease in antibody titer in the serum.11
ENCEPHALITIS ASSOCIATED
WITH N-METHYL-D-ASPARTATE
RECEPTOR ANTIBODIES
Although the clinical entity was de-
scribed only 10 years ago and the anti-
body discovered a few years later,19 the
encephalitis associated with N-methyl-
D -aspartate (NMDA) receptor anti-
bodies has quickly emerged as the most
common encephalitis associated with
antibodies against a neuronal surface
www.ContinuumJournal.com 229
 Autoimmune Epilepsy

TABLE 12-1 Immunophenotypes of Autoantibody-Associated Encephalitis

Antibody Clinical Features CSF Brain MRI

Hu Rarely isolated limbic encephalitis Abnormal in 66% of Mesial temporal or
(LE); often signs of widespread cases (elevated protein diffuse changes in
nervous system involvement (eg, level in 66%, elevated 100% of cases
cerebellar degeneration, peripheral white blood cell count
neuropathy, radiculopathy, in 50%)
neuronopathy, autonomic dysfunction)
Ma2/Ta Isolated LE or combined with Abnormal in 70% Mesial temporal or
cerebellar degeneration, brainstem of cases diffuse changes in
encephalitis, hypothalamic dysfunction 100% of cases
CV2/CRMP-5 Isolated LE or in association with Abnormal in 70% Mesial temporal or
signs of widespread nervous of cases diffuse changes in
system involvement 100% of cases
Amphiphysin Rarely isolated LE; often signs Abnormal in 70% Mesial temporal or
of widespread nervous of cases diffuse changes in
system involvement 100% of cases
P/Q-type VGCC Rarely isolated, associated with Limited data available Limited data available
paraneoplastic cerebellar degeneration,
or paraneoplastic sensory
neuronopathy (but not Lambert-Eaton
myasthenic syndrome)
GAD65 LE, epilepsy, diabetes mellitus Often normal Mesial temporal

NMDA receptor Prodromal symptoms, behavioral Abnormal in 80% Neocortical, mesial

changes, hallucinations, psychosis, of cases temporal, basal
seizures, memory impairment, ganglia, and
catatonia, autonomic instability, brainstem changes
orofacial dyskinesia, coma in 33% of cases
LGI1 Typical LE with rapidly progressive Abnormal in 30Y40% Mesial temporal
cognitive decline; often preceded of cases (oligoclonal changes in 80%
by faciobrachial dystonic seizures; bands or mildly of cases
frequent hyponatremia; rapid eye elevated protein)
movement sleep behavior disorder
Caspr2 LE but seizures are less frequent Abnormal in 30Y40% of Mesial temporal
than with anti-LGI1; more commonly cases (oligoclonal bands or
neuromyotonia or Morvan syndrome mildly elevated protein)
Adenylate LE Limited data available Limited data available
kinase 5
AMPA receptor LE Abnormal; elevated Mesial temporal or
protein or white blood neocortical changes
cells in 100% of cases in 70Y90% of cases

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 Other Antibodies Percent Response to
That May Be Present Paraneoplastic Neoplasm Immune Therapy
Amphiphysin, 990% Lung (mostly small cell lung Poor
CV2/CRMP-5, Ri carcinoma), melanoma,
prostate, breast

Limited data available 990% Testicular Poor

Hu, amphiphysin 990% Lung, thymoma Poor

Hu, CV2 990% Breast Poor

GABA-A Frequent Small cell lung carcinoma Limited data available

TPO, TG, GAD65, Rare Lung, pancreas, thymus Usually incomplete

GABA-A, GABA-B, ANA
ANA, TPO 10Y50% depending Ovarian teratoma in young Excellent but requires
on age and gender women second-line therapy in
up to 50% of cases;
occasional relapses

ANA, TPO, contactin 2 Rare Thymoma, lung (small cell Good but often slow
lung carcinoma) and incomplete;
occasional relapses

MusK, ACh receptor, 30% Thymoma Good in

GAD65, contactin 2 nonparaneoplastic cases

Limited data available Limited data available Limited data available Limited data available

VGCC 70% Lung, breast, thymic carcinoma Good but frequent

relapses

Continued on page 232

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 Autoimmune Epilepsy

TABLE 12-1 Immunophenotypes of Autoantibody-Associated Encephalitis Continued from page 231

Antibody Clinical Features CSF Brain MRI

GABA-B receptor LE with prominent seizures
Glycine receptor LE with status epilepticus;
refractory epilepsy
GABA-A Encephalopathy with seizures;
receptor often refractory status epilepticus
mGluR5 Isolated LE (Ophelia syndrome)
Most often abnormal Mesial temporal changes in
50Y80% of cases
Limited data available Limited data available
Often abnormal Mesial temporal, neocortical,
brainstem, or basal ganglia
changes in 50% of cases
Limited data available Limited data available

ACh = acetylcholine; AMPA = !-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; ANA = antinuclear antigen; Caspr2 = contactin-
associated protein-like 2; CRMP-5 = collapsin response mediator protein-5; CSF = cerebrospinal fluid; GABA-A = ,-aminobutyric acid A;
GABA-B = ,-aminobutyric acid B; GAD65 = glutamic acid decarboxylase 65; LGI1 = leucine-rich, glioma inactivated 1; mGluR5 = glutamate
receptor, metabotropic 5; MRI = magnetic resonance imaging; MusK = muscle-specific tyrosine kinase; NMDA = N-methyl-D-aspartate; TG =
thyroglobulin; TPO = thyroperoxidase; VGCC = voltage-gated calcium channel.

KEY POINTS
h N-Methyl-D-aspartate
(NMDA) receptor
antibodies are the most
commonly identified
antibodies directed to
neuronal surface
antigens. The syndrome
is one of behavioral and
psychiatric manifestations,
followed by a severe
catatonic phase with
movement disorders and
autonomic instability.
h Extreme delta brushes
are a specific EEG feature
of N-methyl-D-aspartate
(NMDA) receptor
encephalitis. They are
encountered in
approximately half of
the cases.
antigen. The syndrome is now well char-
acterized and several hundred cases
have been reported.20 A striking female
predominance exists, and most patients
are young adults. The encephalitis
often begins with a nonspecific febrile
illness. A couple of weeks later, patients
present with behavioral changes, de-
lusions, hallucinations, and anxiety.
Short-term memory loss can also occur
at this stage, as well as seizures. Seizures
are most commonly of the generalized
tonic-clonic type, but dyscognitive sei-
zures have been reported. For an un-
known reason, male patients tend to
present more frequently with seizures
at onset than female patients.21 Status
epilepticus can occur and can be refrac-
tory. The encephalopathy then prog-
resses to a severe catatonic stage, during
which patients alternate between pe-
riods of akinesis and periods of violent
agitation. At this stage, most patients
develop typical orofacial dyskinesia, au-
tonomic instability, and hypoventilation,
often requiring prolonged ventilator
support. In most cases, the EEG shows
generalized delta activity, which is often
rhythmic.22 As shown in Figure 12-2, at
least half of the patients exhibit a pe-
culiar and probably disease-specific pat-
tern of generalized rhythmic delta
activity with superimposed beta or even
gamma activity, termed extreme delta
brushes because of their resemblance
to the delta brushes of neonates.23
CSF analysis is abnormal in more than
90% of cases, most commonly showing
a mild lymphocytosis. Brain MRI shows
T2/fluid-attenuated inversion recovery
(FLAIR) hyperintensities in neocortical
areas or, less commonly, in the mesial
temporal lobes, basal ganglia, or brain-
stem. Cortical atrophy usually develops
with time. Approximately half of the fe-
male patients have an ovarian teratoma.
Pelvic MRI is more sensitive than CT
scan and ultrasound, but the tumor can
be microscopic and escape imaging tech-
niques. In cultured neurons, the anti-
bodies induce the internalization of
NMDA receptors, demonstrating their
direct pathogenic role.22
Treatment includes tumor resection
and immune therapy. In half the cases,
first-line treatment (most commonly ste-
roids or IVIg) fails and second-line ther-
apy with cyclophosphamide or rituximab

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 Other Antibodies Percent Response to
That May Be Present Paraneoplastic Neoplasm Immune Therapy
TPO, TG, GAD65, 50% Lung (small cell lung Good but often
Sox1, VGCC carcinoma), thymoma incomplete
Unknown Rare Small cell lung carcinoma Limited data available

TPO, TG, GAD65, GABA-B Uncommon Uncommon Variable

None 990% Hodgkin lymphoma Limited data available

is required. Most patients ultimately
respond, and many regain near-normal
functional status. Early treatment and re-
sponse to first-line therapy are associ-
ated with better outcome.20 Long-term
deficits may include frontal lobe dys-
function and sleep disturbances.
ENCEPHALITIS ASSOCIATED WITH
ANTIBODIES AGAINST OTHER
NEURONAL SURFACE ANTIGENS
Several syndromes of autoimmune en-
cephalitis with antibodies against neuro-
nal surface antigens have been recently
described. They seem to be much rarer
than the most common encephalitis as-
sociated with NMDA receptor and VGKC
complex antibodies.
Approximately 40 patients with an-
tibodies against the R1 subunit of the
+-aminobutyric acid (GABA)-B receptor
have been reported.24Y27 Almost all pre-
sented with limbic encephalitis and pro-
minent seizures or status epilepticus.
GABA-B receptor antibodies may be
absent from patients serum and
detected only in the CSF. Brain MRI and
CSF analysis are abnormal in two-thirds
of the cases, demonstrating T2/FLAIR
KEY POINT
hyperintensities in the mesial temporal
h Antibodies directed
lobes and pleocytosis, respectively. Half
toward neuronal surface
the cases are associated with a neoplasm, antigens, such as the
most commonly small cell lung carci- !-amino-3-hydroxy-5-
noma. Between one-third and one-half methylisoxazole-4-
of paraneoplastic cases exhibit onco- propionic acid (AMPA),
neural antibodies (eg, Sox1, Hu, +-aminobutyric acid
amphiphysin). Several patients had other (GABA)-A receptor,
autoimmune diseases (including type 1 GABA-B receptor, and
diabetes mellitus, idiopathic thrombo- glycine receptors have
cytopenia, and thyroiditis) or antibodies been identified but
(eg, glutamic acid decarboxylase 65 need to be further
characterized. They
[GAD65], thyroperoxidase [TPO], thyro-
are associated with
globulin [TG]). Most patients respond at
limbic encephalitis or
least partially to immune treatment and neocortical encephalitis
tumor removal, and some make a full with seizures and status
recovery. epilepticus and are
More recently, high titers of antibodies sometimes associated
against the !1, $3, or ,2 subunits of the with neoplasms or
GABA-A receptor were identified in the autoimmune diseases.
serum or CSF of 51 patients.28,29 In one
series, clinical presentation was reported
in 15 patients and was variable, although
it was consistent with limbic encephalitis
in some patients.29 In the other series,
the syndrome was one of refractory sta-
tus epilepticus and multifocal cortical
MRI abnormalities.28 Similar to patients
with GABA-B receptor antibodies, many

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 Autoimmune Epilepsy

Case 12-1
A 71-year-old man presented to an outside hospital with frequent brief tonic contractions of the face
and arm, occurring independently on each side of the body, several times per hour. A diagnosis of
paroxysmal dyskinesia was made, and he was treated with carbamazepine without success. He was
admitted a few weeks later at the authors institution with behavioral changes and memory loss.
The episodes of tonic contractions were thought to be consistent with faciobrachial dystonic seizures.
An EEG performed during
those episodes revealed
transient diffuse background
attenuation followed by
bilateral synchronous rhythmic
delta waves (Figure 12-1A).
Antibody testing was positive
for voltage-gated potassium
channel complex antibodies,
specifically leucine-rich, glioma
inactivated 1 (LGI1) antibodies.
Brain MRI revealed bilateral
hippocampal fluid-attenuated
inversion recovery (FLAIR)
hyperintensities (Figure 12-1B).
Screening for an occult
malignancy was negative, but
brain fluorodeoxyglucose
positron emission tomography
(FDG-PET) revealed
hypermetabolism of the mesial
temporal structures
(Figure 12-1C) and basal
ganglia (Figure 12-1D). Seizures
ceased after treatment with
IV steroids and
cyclophosphamide, but some
memory impairment remained.
Comment. This case
illustrates the importance of
recognizing faciobrachial
dystonic seizures as the first
manifestation of LGI1
encephalitis. Earlier recognition
and treatment might have
prevented the evolution to FIGURE 12-1 EEG and imaging of the patient in Case 12-1. An EEG
full-blown limbic encephalitis. performed during episodes of tonic contractions revealed
transient diffuse background attenuation followed by bilateral
synchronous rhythmic delta waves (A). EEG settings: low-frequency filter 0.5 Hz;
high-frequency filter 70 Hz; notch filter is off. Axial brain MRI revealed bilateral
hippocampal fluid-attenuated inversion recovery (FLAIR) hyperintensities
(B; arrows). Brain fluorodeoxyglucose positron emission tomography (FDG-PET)
revealed hypermetabolism of the mesial temporal structures (C) and basal ganglia (D).

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FIGURE 12-2 Extreme delta brushes in a 22-year-old woman with N-methyl-D-aspartate (NMDA) receptor encephalitis. The
pattern consists of rhythmic delta activity with superimposed beta activity. EEG settings: low-frequency filter
0.5 Hz; high-frequency filter 70 Hz; notch filter is off.

patients in both series had other auto-
immune diseases (eg, type 1 diabetes
mellitus, idiopathic thrombocytopenia,
thyroiditis, celiac disease) or antibodies
(eg, GAD65, TPO, TG, endomysium,
VGKC complex, NMDA receptor). Half
of the patients who received immune
therapies responded at least partially.
In one study, 13 patients with a typi-
cal course of limbic encephalitis, often
with prominent psychiatric symptoms,
were found to have antibodies directed
against the glutamate receptor (GluR) 1
or GluR2 subunits of the AMPA recep-
tor.30Y32 Most of these patients were
middle-aged women. Similar to other
antibodies against neuronal surface an-
tigens, AMPA receptor antibodies may
be absent from the patients serum and
only detectable in the CSF. Nine patients
had an associated neoplasm, most com-
monly small cell lung carcinoma. Patients
responded well to treatment (immune
therapy with or without tumor removal)
but most experienced recurrent relapses
even after tumor removal.
Glycine receptor (GlyR) antibodies
have been mainly reported in associa-
tion with stiff person syndrome and
progressive encephalomyelitis with ri-
gidity and myoclonus, but a few cases
of limbic encephalitis with seizures and
status epilepticus have been described.33
An association with cancer is rare.
LIMBIC ENCEPHALITIS ASSOCIATED
WITH GLUTAMIC ACID
DECARBOXYLASE 65 ANTIBODIES
Elevated titers of antibodies against
GAD65 are found in patients with stiff
person syndrome or with a specific form
of cerebellar ataxia associated with type
1 diabetes mellitus. They are also pres-
ent, at lower titers, in most patients with

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 Autoimmune Epilepsy

KEY POINTS
h Glutamic acid
decarboxylase 65
(GAD65) antibodies are
associated with a wide
range of autoimmune
neurologic disorders
and with type 1
diabetes mellitus. A
few cases of limbic
encephalitis have
been reported.
h Rasmussen encephalitis
presents with refractory
focal epilepsy, neurologic
decline, and progressive
cortical atrophy.
Antibodies directed
toward the glutamate
receptor 3 are no longer
thought to be causal and
T-cellYmediated immunity
is incriminated. Treatment
includes antiseizure
medications, immune
therapy, and
often surgery.
type 1 diabetes mellitus and no neuro-
logic syndrome. GAD65 is an intracellu-
lar protein, and the pathogenic role of
the autoantibodies is debated, espe-
cially since the neurologic manifesta-
tions are so variable and some patients
with GAD65 antibodies and encephali-
tis also have antibodies against neu-
ronal surface antigens. Nonetheless,
well-described cases of encephalitis or
epilepsy associated with GAD65 anti-
bodies have been reported,34Y37 and the
antibodies trigger a cellular inflamma-
tory response9 and exert direct neuro-
toxic effects in vitro and in vivo.38,39
Clinical manifestations are similar to
limbic encephalitis due to VGKC complex
antibodies, but patients tend to be youn-
ger women and exhibit a more chronic
course.34,37 All patients had high serum
titers of the antibody and, when tested,
showed intrathecal synthesis. Most
cases are unrelated to cancer, but a
few patients may have small cell lung
carcinoma.35,36 Response to immune
therapy seems less satisfactory than in
limbic encephalitis with VGKC complex
antibodies; in one series, no patient
achieved seizure freedom and all re-
tained significant memory impairment.37
RASMUSSEN ENCEPHALITIS
Rasmussen encephalitis is an uncommon
disorder characterized by refractory sei-
zures, progressive cortical atrophy, and
progressive neurologic impairment.40
It is mostly a pediatric condition but
can occur in adults, as demonstrated by
Case 12-2. Typically, one hemisphere
is affected, but bilateral, lobar, and even
brainstem variants have been reported.
Seizures can be simple or complex partial;
epilepsia partialis continua is common.
An autoimmune origin has been sug-
gested. Antibodies to GluR3 were ini-
tially thought to be responsible for the
encephalitis but are not invariably found
and also are not specific to the syn-
drome.43 More recent studies indicate
a role for T-cellYmediated inflammation,
leading to lymphocyte infiltration,
microglial activation, gliosis, and neuro-
nal loss in the affected hemisphere.
As in Case 12-2, some patients with
Rasmussen encephalitis also present
with other autoimmune disorders, a
finding that is possibly not attributable
to chance only and, thus, further sug-
gests its autoimmune origin.42
If left untreated, Rasmussen enceph-
alitis relentlessly evolves to severe cogni-
tive and functional disability. Adult-onset
forms have a more protracted course.
Diagnosis is based on clinical, EEG,
and neuroradiologic criteria.41 The goal
of treatment is to control seizures and
prevent further neurologic decline. Anti-
seizure medications have only a limited

Case 12-2
A 57-year-old woman with a history of Crohn disease was admitted to the hospital with partial motor
status epilepticus. She was treated with multiple antiseizure medications but did not improve. Her initial
brain MRI demonstrated atrophy of the right mesial temporal lobe (Figure 12-3A), and her CSF showed
a mild lymphocytosis. She received IV steroids, and her condition steadily improved. She was discharged
under oral steroids and antiseizure medications and was subsequently lost to follow-up. She was readmitted
10 months later with increasing seizure frequency, left-sided hemianopia, neglect, and pyramidal signs.
Her brain MRI demonstrated severe cortical atrophy, predominating in the right temporal and occipital
lobes, and fluid-attenuated inversion recovery (FLAIR) hyperintensity in the occipital lobe (Figure 12-3B). A
brain fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed severe hypometabolism
in the right temporal and occipital lobes (Figure 12-3C). Her EEG showed focal slowing and attenuation,
as well as spikes (Figure 12-3D) and seizures (Figure 12-3E) originating from the right posterior region. Her
seizures ceased again after she received IV steroids, but her neurologic examination did not improve.
Continued on page 237

236 www.ContinuumJournal.com February 2016

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Continued from page 236

FIGURE 12-3 Imaging and EEG of the patient in Case 12-2. The patients initial brain
MRI demonstrated atrophy of the right mesial temporal lobe (A). Her
brain MRI 10 months later demonstrated severe cortical atrophy,
predominating in the right posterior temporal and occipital lobes, and fluid-attenuated
inversion recovery (FLAIR) hyperintensity in the occipital lobe (B). A brain
fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed severe
hypometabolism in the right temporal and occipital lobes (C). Her EEG showed
focal slowing and attenuation, as well as spikes (D) and seizures (E) originating from
the right posterior region. EEG settings: low-frequency filter 0.5 Hz; high-frequency
filter 70 Hz; notch filter is off.

Comment. According to published criteria,41 this patient has adult-onset Rasmussen encephalitis. An
association with other autoimmune disorders, including Crohn disease, has recently been reported.42

Continuum (Minneap Minn) 2016;22(1):227245 www.ContinuumJournal.com 237

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 Autoimmune Epilepsy
KEY POINT
h Uncommon cases of
currently cryptogenic
refractory status
epilepticus, termed
febrile infectionYrelated
epilepsy syndrome
(FIRES) and new-onset
refractory status
epilepticus (NORSE) in
adults, may have an
autoimmune origin.
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
effect on seizures. Surgical interven-
tions, either hemispherectomy or he-
mispherotomy, are highly efficacious,
achieving seizure control in up to 85%
of patients at the cost of spastic hemi-
plegia. Most patients who were able to
walk before the intervention retain this
ability, but fine hand motor skills are
lost. Language can be profoundly im-
paired if the dominant hemisphere is
affected. The decision to perform sur-
gery is thus based on both the severity
of epilepsy and the risk of functional
deterioration after the intervention. If
this risk is deemed too high and on-
going progression occurs, immune ther-
apies are indicated. Steroids, IVIg,
plasma exchange, tacrolimus, and, more
recently, natalizumab or rituximab are
possible options.41,44 Currently, no data
exist in favor of one specific treatment,
although anecdotal evidence suggests
that adult cases may respond more fav-
orably to IVIg.
SYNDROMES OF DE NOVO FEBRILE
ILLNESSRELATED REFRACTORY
SEIZURES AND STATUS EPILEPTICUS
In up to 15% of cases, the cause of
status epilepticus is unknown. Recent
studies have drawn attention to auto-
immune encephalitis as an infrequent
but diagnosable and often overlooked
etiology.27,28,45 Others have reported
febrile illness proceeding refractory
status epilepticus syndromes of unclear
origin in both children and adults.46
These syndromes have received various
names, including new-onset refractory
status epilepticus (NORSE), febrile
infectionYrelated epilepsy syndrome
(FIRES), and acute encephalitis with
refractory repetitive partial seizures
(AERRPS). As described in Case 12-3,
these syndromes are characterized by
the sudden onset of frequent seizures
and status epilepticus in an otherwise
healthy individual, often bilateral or
multifocal. CSF analysis and MRI often
show changes suggestive of encephalitis
(eg, mild pleocytosis, elevation of protein
level, and T2/FLAIR hyperintensities in
neocortical or mesial temporal struc-
tures), but no causative virus or antibody
is found, despite extensive investiga-
tions. Status epilepticus is usually highly
refractory and can last for weeks. Mor-
tality is high, and most survivors develop
pharmacoresistant epilepsy. Long-term
cognitive impairment is frequent but
some patients make a full recovery. The
cause of these syndromes is currently
unknown. Recent studies have shown
high levels of proconvulsant cytokines
in the CSF of children with AERRPS.47
Treatment with antiseizure medications
and anesthetics is often disappointing,
but immune therapies48,49 and the keto-
genic diet50 may be effective treatments.
SEIZURES IN PATIENTS WITH
OTHER AUTOIMMUNE AND
INFLAMMATORY DISORDERS OF
THE CENTRAL NERVOUS SYSTEM
Despite variability among studies, there
seems to be a twofold to threefold in-
creased seizure incidence in patients
with multiple sclerosis compared to the
general age-matched population.51 The
mechanisms are incompletely under-
stood but might involve cortical demy-
elination and inflammation.
Seizures are more common in patients
with acute disseminated encephalomy-
elitis (ADEM), especially in severe cases,
where they can occur in up to two-thirds
of patients.52,53 Epilepsia partialis con-
tinua and nonconvulsive status epilepticus
are infrequent but possible manifesta-
tions. Seizures occur in 20% of patients
with primary CNS vasculitis.54
SEIZURES AND EPILEPSY IN
PATIENTS WITH SYSTEMIC
AUTOIMMUNE DISORDERS
Seizures can be the manifestation of
cerebral involvement in the setting of a
systemic autoimmune disorder. A re-
cent population-based retrospective co-
hort study using claims data from an
February 2016
 Case 12-3
A 21-year-old man with no significant past medical history was admitted to the intensive care unit
after having experienced three consecutive generalized tonic-clonic seizures. He had had a flulike
illness 2 weeks prior to admission. He was stuporous and had multiple complex partial seizures while
being evaluated. Continuous EEG revealed that he was having left hemispheric seizures at a rate
of 5 to 10 per hour. His brain MRI revealed left hemispheric diffusion-weighted (Figure 12-4A) and
fluid-attenuated inversion recovery (FLAIR) (Figure 12-4B) hyperintensities and gadolinium enhancement
(Figure 12-4C). A thorough workup, including extensive autoimmune and viral testing, was unrevealing.
After 3 weeks of continuous infusion of anesthetics, his seizures abated and he progressively regained
consciousness. He was discharged to a rehabilitation facility and reevaluated several months later. He
made a full recovery but still had occasional seizures.

FIGURE 12-4 Imaging of the patient in Case 12-3. Brain MRI revealed left hemispheric
diffusion-weighted imaging hyperintensities (A), mild fluid-attenuated inversion
recovery (FLAIR) edema (B), and gadolinium enhancement on postcontrast
T1-weighted images (C).

Comment. Cases of new-onset refractory status epilepticus (NORSE) are characterized by the sudden
onset of frequent seizures or status epilepticus, which often prove highly refractory, in otherwise healthy
individuals. A prodromal febrile illness is often reported. Outcome is variable, with one-third of patients
making a full recovery. Epilepsy is a frequent complication. The etiology is unknown, but immune
mechanisms have been suggested.27,47

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 Autoimmune Epilepsy
KEY POINT
h Epilepsy and seizures
are more common in
patients with systemic
autoimmune disorders.
Potential mechanisms
include cerebral
inflammation, ischemic
complications, metabolic
disturbances, or the
presence of concomitant
pathogenic antibodies
directed toward
neuronal antigens.
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
insurance company on over 2.5 million
patients found a twofold to ninefold risk
of seizures and epilepsy among patients
with one of the 12 most common au-
toimmune diseases.55 The highest risk
was seen with systemic lupus erythe-
matosus (SLE), the antiphospholipid
syndrome, and type 1 diabetes mellitus.
The mechanisms of seizures in sys-
temic autoimmune diseases are not
restricted to the direct involvement of
the CNS by the autoimmune process and
include ischemic injury to the brain,
complications of organ failure, toxicity
of treatment, and opportunistic infec-
tions. Another recently described po-
tential mechanism is the coexistence of
antibodies directed against neuronal sur-
face antigens in patients with an auto-
immune systemic disorder.24,28,29
Seizures happen in approximately
15% of cases of SLE and are part of the
primary diagnostic criteria. One-third of
the seizures occur at SLE onset and tend
to accompany disease flares. Children
and patients with antiphospholipid anti-
bodies are at higher risk.
Steroid-responsive encephalopathy
associated with autoimmune thyroiditis
(SREAT), previously called Hashimoto
encephalopathy, can manifest by various
combinations of subacute encephalopa-
thy (eg, rapid-onset dementia, delirium,
alteration of consciousness), movement
disorders (eg, myoclonus, ataxia, tremor),
and strokelike episodes.56,57 Seizures
occur in up to two-thirds of cases.56,57
Some patients have hypothyroidism or
hyperthyroidism, and all exhibit high
serum titers of antibodies directed
against thyroperoxydase (TPO) or thy-
roglobulin (TG). The patients response
to steroids is usually striking.58 The
mechanism of SREAT is unknown, but
some patients also have antibodies
against neuronal surface antigens.24,28
Seizures may also indicate CNS in-
volvement by Sjgren syndrome, sar-
coidosis, Beh0et disease, and Wegener
granulomatosis.59
A rare and peculiar form of occipital
epilepsy with occipital cerebral calcifi-
cation has been reported in patients
with celiac disease in southern Europe
and South America.60
ANTIBODIES IN PATIENTS WITH
ISOLATED CHRONIC EPILEPSY
In most of the conditions detailed
above, seizures occur in the setting of
acute or subacute encephalitis or in con-
junction with an active systemic auto-
immune disorder. While an immune
treatment is warranted, seizures them-
selves are considered to be acute symp-
tomatic and thus do not fulfill the
recently revised ILAE criteria for the
definition of epilepsy. Some patients
continue to have seizures in the after-
math of a treated episode of autoim-
mune encephalitis. In this case, seizures
are likely unprovoked and a diagnosis
of epilepsy is justified, but as they are
the manifestation of postencephalitic
irreversible brain injury, they do not re-
quire immune therapy and do not
strictly represent autoimmune epilepsy.
Anecdotal evidence suggests that au-
toimmune (paraneoplastic or not) lim-
bic encephalitis may present as temporal
lobe epilepsy with hippocampal sclero-
sis. Compared to patients with chronic
epilepsy associated with most other eti-
ologies, patients with limbic encephalitis
tend to have a higher seizure frequency,
more frequent memory impairment, and
bilateral hippocampal involvement.61
Various antibodies can be identified
in patients with newly diagnosed epi-
lepsy, including VGKC complex, GAD65,
NMDA receptor, and GlyR antibodies.62Y65
Their prevalence and significance are
unclear as available studies differed
widely in terms of inclusion and diagnos-
tic criteria. Seizure frequency in patients
with antibodies tends to be higher than
in patients without antibodies, and most
February 2016
 KEY POINTS
have pharmacoresistant epilepsy from tentially strong clinical implications. h A subgroup of patients
the onset. Some patients, usually with Suggested clues that should raise the with epilepsy have
high titers of GAD65 or VGKC complex possibility of an autoimmune origin to antibodies to neuronal
antibodies, have memory impairment epilepsy are summarized in Table 12-2. surface antigens, but
and behavioral changes and fulfill the the significance of this
criteria for limbic encephalitis.63,64 All INTERPRETATION OF finding needs to be
patients with newly diagnosed epilepsy ANTIBODY TESTING confirmed as many have
and NMDA receptor antibodies have In patients with suspected autoimmune low titers of antibodies
prominent neuropsychiatric symptoms encephalitis, the presence of antibodies directed toward
typical of anti-NMDA receptor enceph- should be investigated both in the se- uncharacterized antigens.
A small minority of
alitis.63 Many patients with GAD65 rum and the CSF, which may yield con-
patients with epilepsy
antibodies also exhibit multiple auto- flicting results. The combination of a
and voltage-gated
antibodies, including against TPO, TG, positive CSF with a negative serum sug- potassium channel
and antinuclear antibody (ANA).62 Some gests intrathecal synthesis, which is (VGKC) complex
have associated autoimmune diseases, not rare with antibodies directed and glutamic
such as thyroiditis, celiac disease, or against neuronal surface antigens, es- acid decarboxylase
type 1 diabetes mellitus. Many patients pecially NMDA receptor antibodies. A 65 (GAD65) antibodies
seem to improve upon immune treat- positive serum, especially if only low appear to have a
ment, and some become seizure free.65 levels are detected, with a negative CSF mild form of limbic
Overall, these studies suggest that usually indicates a false-positive result, encephalitis, in which
some patients with localization-related although this can be seen with LGI1 seizures predominate.
epilepsy, including patients with tem- and Caspr2 antibodies. It is also im- h Antibody testing should
poral lobe epilepsy and hippocampal portant to remember that because not be performed on both
sclerosis, may correspond to mild forms all antibodies have been described, and serum and CSF.
of limbic encephalitis. Their exact prev- because not all described antibodies False-negative cases
alence is difficult to ascertain since in- have commercially available testing, are possible if only
serum is tested, as
clusion criteria, diagnostic criteria, and negative results do not exclude an au-
intrathecal synthesis of
immunologic investigations vary greatly toimmune disorder.
antibodies occurs.
across studies. Nonetheless, given the
resistance of definite cases of limbic TREATMENT
encephalitis to antiseizure medications Currently, no evidence-based immuno-
and their good response to immune therapy guidelines exist for autoimmune
therapies, a positive diagnosis has po- encephalitis, but authors have suggested

TABLE 12-2 Clinical Clues to the Diagnosis of Autoimmune Epilepsy

b Onset with status epilepticus or flurry of seizures

b Early pharmacoresistance
b Cognitive impairment or rapid decline
b Onset after 30 years of age
b Known associated autoimmune disorder
b Mesial temporal inflammatory findings on brain MRI (eg, swelling,
T2 hypersignal)
b Bilateral mesial temporal findings on brain MRI
MRI = magnetic resonance imaging.

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 Autoimmune Epilepsy
KEY POINT
h First-line immune
therapies for autoimmune
encephalitis include
IV steroids, IVIg, and
plasma exchange. In case
of insufficient response,
cyclophosphamide and
rituximab are usually
considered appropriate
second-line treatments.
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
protocols based on personal experience
and published observational evidence.66
IV steroids, IVIg, and plasma exchange
are common first-line options. By con-
trast with patients with myasthenia
gravis or Lambert-Eaton myasthenic syn-
drome, those with autoimmune enceph-
alitis associated with autoantibodies
usually do not respond quickly to treat-
ment, and approaches that aim to de-
crease serum antibody levels (such as
plasma exchange and IVIg) seem less
effective. This is perhaps explained by
the intrathecal synthesis of antibodies
that occurs in several types of autoim-
mune encephalitis, by the presence of
an associated cellular immune response,
and by delayed recovery of the more
complex CNS. For instance, patients
with LGI1 encephalitis (characterized
by infrequent intrathecal antibody syn-
thesis) respond faster than patients with
NMDA receptor encephalitis (charac-
terized by very frequent intrathecal
antibody synthesis).
Rituximab, a B-cellYdepleting human-
ized antibody, and cyclophosphamide,
an alkylating agent with cytotoxic prop-
erties against T cells, are also used. In a
large cohort of patients with NMDA
receptor encephalitis, rituximab and
cyclophosphamide were usually effective
in patients who did not respond to first-
line medications.20 Although rituximab
and cyclophosphamide are increasingly
being used in other types of autoim-
mune encephalitis, the available evi-
dence is more limited.
In cases of paraneoplastic encephali-
tis, tumor removal is necessary for
oncologic reasons, but neurologic im-
provement is rare.
Currently, very little evidence exists
that patients with isolated chronic epi-
lepsy and autoantibodies should receive
immune treatment. Cases that meet
criteria for limbic encephalitis, have high
serum titers, or show intrathecal syn-
thesis should probably be treated.
FUTURE DIRECTIONS
Syndromes of paraneoplastic limbic en-
cephalitis with onconeural antibodies
and of encephalitis with antibodies di-
rected against neuronal surface antigens
NMDA receptor, LGI1, and Caspr2 are
now well characterized. Further studies
should aim to define the best treatment
courses for these syndromes. Some rare
or recently described clinical antibody
associations (eg, mGluR5, GlyR, GAD65,
AMPA receptor, GABA-A receptor, GABA-
B receptor) await further character-
ization. The mechanisms of other
syndromes (eg, Rasmussen encephali-
tis, NORSE, and FIRES) and seizures in
patients with systemic autoimmune dis-
orders are less clear and deserve more
attention. Finally, the role of antibodies
in patients with chronic epilepsy remains
to be clarified. This question is of major
importance since some patients who
have been described in recent studies
seemed to benefit from immune ther-
apies, in contrast with their resistance
to conventional antiseizure medications.
CONCLUSION
Seizures, and perhaps epilepsy, are com-
mon manifestations of autoimmune en-
cephalitis. The relation to malignancy
in paraneoplastic encephalitis and the
pathogenicity of antibodies directed
toward neuronal surface antigens, in
particular the most common NMDA
receptor and LGI1, are well established.
Other syndromes of encephalitis re-
quire further study for their mechanism
to be clarified and for new antibodies
to be discovered. Perhaps the greatest
challenges ahead are the identification
of autoimmune cases among the ever-
growing population of patients with
chronic epilepsy and the establishment
of the optimal therapeutic strategies.
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