Handbook of Clinical Neurology, Vol.

133 (3rd series)

Autoimmune Neurology
S.J. Pittock and A. Vincent, Editors
© 2016 Elsevier B.V. All rights reserved

Chapter 13

Autoimmune epilepsy
JEFFREY BRITTON*
Department of Neurology, Mayo Clinic, Rochester, MN, USA

Abstract
Seizures are a common manifestation of autoimmune limbic encephalitis and multifocal paraneoplastic
disorders. Accumulating evidence supports an autoimmune basis for seizures in the absence of syndromic
manifestations of encephalitis. The autoimmune epilepsies are immunologically mediated disorders in
which recurrent seizures are a primary and persistent clinical feature. When other etiologies have been
excluded, an autoimmune etiology is suggested in a patient with epilepsy upon detection of neural auto-
antibodies and/or the presence of inflammatory changes on cerebrospinal fluid (CSF) or magnetic reso-
nance imaging. In such patients, immunotherapy may be highly effective, depending on the particular
autoimmune epilepsy syndrome present. In this chapter, several autoimmune epilepsy syndromes are dis-
cussed. First, epilepsies secondary to other primary autoimmune disorders will be discussed, and then
those associated with antibodies that are likely to be pathogenic, such as voltage-gated potassium chan-
nel–complex and N-methyl-D-aspartate receptor, gamma-aminobutyric acid A and B receptor antibodies.
For each syndrome, the typical clinical, imaging, electroencephaloram, CSF, and serologic features, and
pathophysiology and treatment are described. Finally, suggested guidelines for the recognition, evalua-
tion, and treatment of autoimmune epilepsy syndromes are provided.

2014), and the fact that certain forms of epilepsy, such as

INTRODUCTION
Epilepsy affects 65 million people worldwide, of whom
30% remain inadequately controlled despite best available
therapy (England et al., 2012). Identification of a treatable
etiology, such as a surgically remediable lesion, may be the
only chance to achieve a significant seizure reduction in
such patients. Similarly, the diagnosis of an autoimmune
etiology in a patient with medically intractable epilepsy
opens up the possibility of immunotherapy, which would
otherwise not usually be considered.
The role of autoimmunity in certain subgroups of
epilepsy has been recognized for decades, from the dis-
covery of the inflammatory pathogenesis of Rasmussen’s
encephalitis (Rasmussen et al., 1958), to the observation
of the occurrence of seizures as a relatively common
central nervous system (CNS) manifestation of systemic
autoimmune diseases such as lupus (Mikdashi et al., 2005;
González-Duarte et al., 2008; Hanly et al., 2012; Tsai et al.,
infantile spasms and Landau–Kleffner syndrome, may
respond dramatically to immunotherapy (Sinclair and
Snyder, 2005; Arts et al., 2009; Go et al., 2012). Further
evidence for the potential role of immune mechanisms
in the pathogenesis of seizures was established by the
discovery of paraneoplastic limbic encephalitis in the
1960s (Brierley et al., 1960; Corsellis et al., 1968). The sub-
sequent identification of circulating neural antigen-
targeting antibodies in these patients provided further
insight as to the potential pathogenesis of these disorders
(Graus et al., 1986; Dalmau et al., 1992). And most
recently, the favorable response to therapy in certain non-
paraneoplastic encephalitides with detectable neuronal
surface antibodies has led to an increasing interest in iden-
tifying such disorders (Graus and Saiz, 2008).
Antibodies to an expanding number of neural anti-
gens are now recognized, and significant improvements
have been achieved in the commercialization of tests

*Correspondence to: Jeffrey Britton, MD, Associate Professor, Neurology, Mayo Clinic, 200 1st St SW, Rochester MN 55905, USA.
Tel: +1-507-538-1036, Fax: +1-407-266-4419, E-mail: britton.jeffrey@mayo.edu
220 J. BRITTON
and availability of testing. As a result, increasing numbers
of patients are being diagnosed with autoimmune epilepsy
syndromes (Peltola et al., 2000; Tüzün and Dalmau, 2007;
Graus and Saiz, 2008; Graus et al., 2008; Liimatainen et al.,
2010; Quek et al., 2012). In addition, correlations between
epilepsy and several other autoimmune diseases are being
identified, suggesting that autoimmune mechanisms may
play a broader role in the pathogenesis of epilepsy (Ong
et al., 2014).
In this chapter, the clinical features of several autoim-
mune epilepsy syndromes are presented. Current ther-
apy will also be discussed. A list of the autoimmune
epilepsy syndromes is shown in Table 13.1. A more
detailed discussion of these syndromes follows.
RASMUSSEN’S ENCEPHALITIS
Rasmussen’s encephalitis is an asymmetric encephalitis
that presents with intractable focal seizures, progressive
hemiparesis, and unilateral hemispheric atrophy. It was
first reported in the literature in 1958 (Rasmussen et al.,
1958). The cause of Rasmussen’s encephalitis is unknown,
but an autoimmune etiology is suspected. The condition is
poorly responsive to anticonvulsant therapy.
Table 13.1
Autoimmune epilepsy syndromes
Primary autoimmune epilepsies
Rasmussen’s encephalitis
Immunotherapy-responsive epilepsies
Epileptic spasms (West syndrome)
Landau–Kleffner syndrome
Systemic autoimmune disorders associated with epilepsy
Systemic lupus erythematosus
Celiac disease
Sj€
ogren’s syndrome
Linear scleroderma (Perry–Romberg)
Other
Antibody-mediated epilepsy syndromes
Antibodies targeting cell surface antigens
Voltage-gated potassium channel (VGKC)
N-methyl-D-aspartate (NMDA)
Glutamic acid decarboxylase 65 kD isoform (GAD-65; this is an
intracellular target but can be associated with other cell
surface antibodies)
Gamma-aminobutyric acid-B (GABA-B)
Gamma-aminobutyric acid-A (GABA-A)
a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA)
Acetylcholine receptor (AChR) ganglionic
Antibodies targeting intracellular antigens
Type 1 antineuronal nuclear antibody (ANNA-1) (Hu)
Ma1/Ma2
Collapsin response mediator protein-5 (CRMP-5)
Seronegative autoimmune limbic encephalitis
Epidemiology
Rasmussen’s encephalitis is uncommon, with an incidence
of 2.4 per 107 persons under age 18 years per year (Bien
et al., 2013). Rasmussen’s encephalitis typically affects
children, although late-onset cases have been described.
Clinical presentation, course, and prognosis
Rasmussen’s encephalitis presents with focal seizures
involving one side of the body. The seizures are typically
focal motor clonic in nature, and can involve the face,
the extremities, trunk, or abdomen. A low-grade fever
may be present at its inception. The seizures typically pro-
gress over time, often evolving to focal status epilepticus
(epilepsy partialis continua). A spastic hemiparesis typi-
cally develops, and this can become severe. Neurologic
decline typically develops as seizures continue. Antiepi-
leptic drug therapy is usually modestly effective, and sei-
zures typically continue despite treatment. Progression
of the disease usually occurs over months but can
“burn itself out” after a period of time, leaving the
patient with a static hemiplegia and residual focal motor
seizures. Such patients may live for many years after ces-
sation of the “active” phase of the disease. However, if
seizures continue and neurologic deterioration con-
tinues, the disease can prove fatal. Figure 13.1 illustrates
the typical clinical course of Rasmussen’s encephalitis.
Diagnostic evaluation
SEROLOGY
There is no serologic testing specific for the diagnosis of
Rasmussen’s encephalitis.
CEREBROSPINAL FLUID
Although the inflammatory nature of Rasmussen’s is
clear, cerebrospinal fluid (CSF) examination is normal
in over 50% of cases at time of evaluation.
NEUROIMAGING
Magnetic resonance imaging (MRI) and computed
tomography (CT) imaging of the brain typically shows
unilateral hemispheric atrophy (Fig. 13.2). Serial imaging
may show progression of atrophy over time. In addition
to hemispheric atrophy, MRI may show increased T2
signal and swelling of the cortical gray matter over the
affected hemisphere (Bien et al., 2002b). Despite
the presence of inflammation, contrast enhancement is
typically absent (Bien et al., 2005). Fluorodeoxyglucose
positron emission tomography (FDG-PET) may show
hypermetabolic abnormalities if seizures occur during
FDG administration (Bien et al., 2005).
 AUTOIMMUNE EPILEPSY 221
Immunotherapy
Hemisphere volume EPC

Motor function
Inflammation

Seizures

Prodromal stage Acute stage (8-12 months) Residual stage

Fig. 13.1. Natural clinical course and expected effect of immunotherapy. The natural clinical course of Rasmussen’s encephalitis
was characterized in the past century. The disease might have a preceding prodromal stage with infrequent seizures, and presents
with an acute stage of drug-resistant epilepsy. The epilepsy is characterized by very frequent seizures of different semiologies in the
same patient, often epilepsia partialis continua, with the emergence of a fluctuating, then permanent, hemiplegia (motor function)
and concurrent progressive hemispheric volume loss on neuroimaging. With the advent of immunotherapy, the natural clinical
course seems to be changing. The rate of motor function and hemispheric volume loss is slowed, and seizures decrease in frequency
and plateau. Cognitive deterioration is not shown because it is more variable, although usually becomes manifest during the acute
phase. EPC, epilepsia partialis continua. (Reproduced from Varadkar et al., 2014, with permission.)

EEG brain, cerebral infarctions, and porencephalic cysts, all

Electroencephalogram (EEG) usually shows interictal
epileptiform abnormalities and intermittent or continu-
ous focal seizure activity over the affected hemisphere
(Longaretti et al., 2012). Asymmetric delta slowing
may also be present. Although the EEG may show focal
or asymmetric abnormalities commensurate with the
unilateral nature of the underlying encephalitis, EEG
abnormalities may also be present over the unaffected
hemisphere due to secondary bilateral synchrony.
It should be noted that EEG will not always show a
confirmatory discharge during clinical seizures if the
seizure focus in question involves a small cortical region
localized remote from the scalp surface (Fattouch
et al., 2008).
CANCER EVALUATION
Rasmussen’s encephalitis does not occur as paraneoplas-
tic syndrome and cancer evaluation is not warranted in
typical cases.
DIFFERENTIAL DIAGNOSIS
Rasmussen’s encephalitis is very difficult to diagnose
at onset but, over time, the clinical presentation is char-
acteristic. Early in the illness, other causes of focal
seizures and status epilepticus need to be considered,
including focal or lateralized malformations of cortical
development, neoplasms, vascular malformations of the
of which may cause focal seizures in childhood. Acutely,
infectious causes of meningoencephalitis need to be
considered. Mitochondrial disorders may also present
with focal seizures and status epilepticus. Neuroimaging
is an important step in the evaluation of these patients to
help exclude many of the aforementioned diagnoses.
Pathophysiology
The inflammatory nature of Rasmussen’s is indisput-
able. Pathology from autopsy and surgical specimens
shows microglial nodules and perivascular mononuclear
cell infiltration. Although the pathologic changes are sim-
ilar to those seen in viral encephalitis, a specific infectious
agent has never been implicated, and Rasmussen’s
encephalitis is currently considered an autoimmune dis-
order of unknown etiology and mechanisms (Varadkar
et al., 2014). Elevations of interleukin-6 (IL-6) have been
identified in CSF in Rasmussen’s encephalitis patients
(Tekgul et al., 2005). Inflammatory cytokine abnormali-
ties have been described in the cortex of Rasmussen’s
encephalitis cases as well, with IL-1beta, IL-8, IL-12p70,
and macrophage inflammatory protein (MIP)-1beta
elevations identified in surgical specimens (Choi
et al., 2009).
At one time, antibodies to GluR3 receptors were
thought to play a causative or pathogenic role in Rasmus-
sen’s encephalitis, when induction of antibodies targeting
GluR3 antigens were shown to reproduce a Rasmussen’s
encephalitis illness in rabbits, and GluR3 antibodies were
222 J. BRITTON

Fig. 13.2. (A, B) Neuroimaging in Rasmussen’s encephalitis. Magnetic resonance imaging brain scans of children with Rasmus-
sen’s encephalitis, showing contrasting cases of radiologic progression. (A) Progressive right-hemisphere atrophy, high signal, and
basal ganglia loss over 1 year (from left to right) in a child with Rasmussen’s encephalitis. The disease was mostly centered near the
right Sylvian fissure (arrow). (B) Slowly progressive disease with more subtle right-hemisphere atrophy in a child on immuno-
suppressant treatment at 6 months (left), 18 months (center), and 30 months (right) of disease course. (C) Computed tomography of
the head in a 58-year-old patient with a history of Rasmussen’s encephalitis as a child, showing severe left-hemispheric atrophy. He
continues to have daily, fleeting focal motor seizures on his right, one to two major hemiconvulsive seizures per year, and a spastic
right hemiplegia. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

reported in serum of affected patients (Rogers et al.,
1994). However, subsequent evaluation, mainly using pep-
tide enzyme-linked immunosorbent assays, showed
GluR3 antibodies to be present in other chronic epilepsies,
and absent in some or all cases of Rasmussen’s, eliminat-
ing them from being considered causative (Wiendl et al.,
2001; Mantegazza et al., 2002). Also, GluR3 antibodies
were not observed in a large cohort using a range of assays
(Watson et al., 2004). Furthermore, analysis of the epi-
topes of antibodies recognizing GluR episolon2 subunit
(another name for the N-methyl-D-aspartate receptor
(NMDAR) NR2B subunit) on Western blots was found
 AUTOIMMUNE EPILEPSY
to be broad and with expansion as disease progressed, sug-
gesting that these autoantibodies may occur secondary to
cytotoxic T-cell-mediated neuronal damage, rather than
being a primary causative factor (Takahashi et al., 2005).
The inflammatory response in Rasmussen’s enceph-
alitis is currently considered to be T-cell-mediated.
Inspection of the inflammatory infiltrates in surgical
specimens shows a mixed infiltrate of dendritic cells
and cytotoxic CD3+/CD8 + T lymphocytes (Bauer
et al., 2002; Bien et al., 2002a; Rhodes et al., 2007). Li
et al. (1997) reported that PCR analysis of T-cell receptor
BV gene transcripts in surgical specimens suggested that
the local immune responses in Rasmussen’s syndrome
includes restricted T-cell populations responding to
discrete antigenic epitopes.
Treatment
Despite the clear involvement of inflammation in its
pathogenesis, the response to immunosuppressive ther-
apy is often disappointing. Several reports in the litera-
ture attest to individuals or small groups of patients
responding to a variety of immunotherapy regimens,
including corticosteroids and cyclophosphamide (Hart
et al., 1994; Krauss et al., 1996; Kashihara et al., 2010),
intravenous immunoglobulin (IVIG) (Hart et al., 1994;
Leach et al., 1999; Villani et al., 2001; Buenz and
Howe, 2007), adrenocorticotropic hormone (Granata
et al., 2003), selective immunoglobulin G (IgG) immu-
noadsorption by protein A (Antozzi et al., 1998), and
plasmapheresis (Andrews et al., 2001). A randomized
trial of tacrolimus and IVIG showed lengthening of sur-
vival with either treatment, but disappointingly, no consis-
tent improvement in seizures (Bien et al., 2013). Finally,
there remains uncertainty as to whether Rasmussen’s
encephalitis is a primary autoimmune disease. In one
report, significant improvement was seen following the
administration of the antiviral ganciclovir in 2 of 3
patients treated within 3 months of disease onset. Five
additional patients treated 6 months or longer after dis-
ease onset did not respond. This raises the question as
to whether Rasmussen’s encephalitis is triggered by a viral
etiology, which transforms into a chronic progressive pre-
dominantly immune-mediated disease following resolu-
tion of the active infection (McLachlan et al., 2011).
In most cases, however, immunotherapy is temporiz-
ing. In refractory cases, hemispherectomy or hemispher-
otomy remains the most effective option for attaining
seizure control and in arresting the neurologic deteriora-
tion that otherwise typically occurs in this disease (Vining
et al., 1997; Marras et al., 2010). In the largest published
series of hemispherectomies in children, 89% of patients
with Rasmussen’s encephalitis experienced an excellent
seizure outcome, being either seizure-free or reduced to
223
having nondisabling seizures (Vining et al., 1997). Most
patients remain ambulatory despite variable severities
of hemiparesis.
SEIZURES OCCURRING IN SYSTEMIC
AUTOIMMUNE DISEASES
Seizures are not uncommon in the setting of systemic
autoimmune diseases (Vincent and Crino, 2011).
Although the mechanisms leading to seizures in these dis-
orders are likely multifactorial, antibodies targeting neu-
ral antigens may play a role (Vincent et al., 2010). Seizures
are more characteristic in some autoimmune disorders
than others; however, a study utilizing insurance claims
data from over 2.5 million beneficiaries showed the risk
of epilepsy to be 3.8 times higher among patients with a
variety of autoimmune diseases (Ong et al., 2014). These
associations were not only found in autoimmune diseases
in which a link with seizures was already established (e.g.,
systemic lupus erythematosus (SLE)), but also in diseases
in which a correlation had not previously been appreci-
ated, such as myasthenia gravis, psoriasis, and Graves
disease.
Systemic lupus erythematosus (SLE)
Neurologic symptoms, including seizures, are common in
SLE. The seizures associated with SLE can be disabling.
EPIDEMIOLOGY
Seizures are relatively common in SLE. In a study using
insurance claims data, the adjusted hazard ratio for epi-
lepsy in the SLE versus non-SLE population was 2.33
(95% confidence interval (CI) ¼ 1.89–2.88) (Tsai et al.,
2014). The incidence was much higher in younger SLE
patients: the hazard ratio for those aged 20 years
was 8.05 (95% CI ¼ 4.30–15.0).
CLINICAL PRESENTATION
Seizures are one of 19 clinical features comprising
what is referred to as neuropsychiatric SLE (NPSLE)
(ACR, 1999). Other CNS manifestations of NPSLE
include headache, neurocognitive deficits, depression,
and psychosis. Seizures may be the presenting symptom
of SLE. The most common seizure types seen in NPSLE
are generalized tonic-clonic and complex partial sei-
zures. Affected patients may also present in status
epilepticus. In one cohort, 14% of patients with SLE
had a history of seizures, which became chronic and
recurrent in 43% (Mikdashi et al., 2005). As in epilepsy
from other causes, other neuropsychiatric symptoms are
more prevalent in SLE patients with seizures than
without.
224 J. BRITTON
DIAGNOSTIC EVALUATION
Clinical
There is no characteristic seizure type or presentation
specific to NPSLE. Patients with seizures who have an
existing diagnosis of SLE should undergo evaluation
to exclude non-SLE causes. However, seizures may be
the presenting symptom in SLE.
Serology
Antinuclear antibody (ANA) testing is highly sensitive
for the diagnosis of SLE, but not specific. In a study
of normal subjects, the prevalence of ANA positivity
ranged from 31.7% of individuals when a titer criterion
of 1:40 was used and 3.3% at a titer of 1:320 (Tan et al.,
1997). Anti-ds-DNA antibody testing, by contrast, is
highly specific for the diagnosis of SLE, but has a limited
sensitivity of 70%. Anticardiolipin and anti-Smith anti-
bodies are characteristically present in NPSLE.
Cerebrospinal fluid
The CSF may show an inflammatory profile, with mildly
elevated mononuclear cell concentration and CSF
protein. However it may be normal.
Differential diagnosis
The differential diagnosis of seizures presenting in a
patient with SLE is broad. For patients treated with
chronic immunosuppressive therapy, opportunistic infec-
tious and neoplastic diseases of the CNS need to be con-
sidered. For patients with SLE nephritis, electrolyte
disturbances should be excluded. Opiates, tramadol,
selective serotonin reuptake inhibitor and serotonin and
norepinephrine reuptake inhibitor medications, com-
monly used for pain management and mood disorders
in SLE and other chronic illnesses, all lower the seizure
threshold. Thromboembolism and cerebral venous throm-
bosis secondary to SLE-associated valvular abnormalities
and presence of lupus anticoagulant need to be consid-
ered as well. Other secondary causes of seizures unrelated
to SLE also need to be considered, such as neoplasms, vas-
cular malformations, other structural abnormalities,
trauma, and genetic etiologies.
PATHOPHYSIOLOGY
The causes of seizures in patients with SLE are many.
Seizures may result from cerebral infarction due to
Libman–Sacks endocarditis and thromboembolism due
to presence of lupus anticoagulant. In fatal cases of
NPSLE with seizures, autopsy has been reported to show
evidence of thrombotic thrombocytopenic purpura
(Devinsky et al., 1988). Vasculitis is not a typical patho-
logic finding in NPSLE, and should not be assumed to be
present in SLE patients presenting with seizures. Other
potential causes of seizures in SLE include medication
side effects, electrolyte disturbances related to renal fail-
ure, and opportunistic infections.
Primary autoimmune mechanisms are also thought to
play a role in seizures associated with SLE. Moderate to
high titers of anticardiolipin and anti-Smith antibodies,
and high titers of antiribosomal P protein antibodies in
CSF have been correlated with an increased risk of sei-
zures in SLE (Liou et al., 1996; Mikdashi et al., 2005;
Yoshio et al., 2005). The prevalence of antineuronal anti-
bodies has also been identified in SLE patients, and
found more commonly in those with NPSLE than in
those without CNS manifestations (Kang et al., 2008).
Antibodies binding to peptides of the anti-NMDA recep-
tor subunit NR2- were identified in CSF and serum
(DeGiorgio et al., 2001) of patients with SLE, which cor-
related with the presence of NPSLE symptoms (Arinuma
et al., 2008). These antibodies are reported to interact
in vitro with NMDA receptors, leading to calcium
influx, suggesting antibody-mediated neuroexcitation
as a possible seizure mechanism in NPSLE (Gono
et al., 2011). In addition, anti-intermediate neurofilament
alpha-internexin antibodies have been identified in 50%
of patients with NPSLE symptoms in the CSF and serum.
Administration of this antibody to murine models pro-
duced an encephalopathy, suggesting they could play a
pathogenic role in NPSLE (Lu et al., 2010). These data
should be interpreted with caution, as the pathophysio-
logic relevance of such antibodies remains unproven.
Furthermore, discovery of clinically pertinent antibodies
in sera of lupus patients is confounded by the presence
of “sticky” immunoglobulins/immune complexes that
result in a high frequency of false positivity in immuno-
assays, if adequate controls for patient-specific sticki-
ness are not included.
THERAPEUTIC APPROACH
The management of NPSLE varies depending on sever-
ity. Hydroxychloroquine may be tried in milder cases.
Corticosteroids are commonly used in more severe
cases (Muscal and Brey, 2010). High-dose (2 g/kg)
IVIG therapy has been proposed as an option in treat-
ing several manifestations of SLE, including NPSLE
(Zandman-Goddard et al., 2009). Finally, nonmyeloa-
blative hematopoietic stem cell transplant following
administration of high-dose cyclophosphamide has
been used in severe SLE cases, including those with
NPSLE, with a reported 50% disease-free survival rate
(Burt et al., 2006).
 AUTOIMMUNE EPILEPSY
Other autoimmune connective tissue diseases
While Sj€ogren’s may present with predominantly sali-
vary and lacrimal gland dysfunction, it may also present
with more systemic manifestations, including those
involving the CNS in which seizures may result. Seizures
are a prominent feature in an unusual form of sclero-
derma referred to as linear scleroderma (also referred
to as Perry–Romberg syndrome, morphea, and “coup
de sabre”) (Amaral et al., 2012). This disorder is clinically
manifested by a localized sclerodermal lesion affecting
the face as well as the brain, localized to the region
underlying the facial lesion. The seizures in linear sclero-
derma are typically refractory to antiepileptic medica-
tion, and unfortunately usually do not improve with
systemic immunotherapy.
Seizures do not typically complicate rheumatoid
arthritis or the inflammatory myopathies. Primary
CNS vasculitis can present with seizures in 16% of cases
(Salvarani et al., 2007). Opportunistic infections or neo-
plastic conditions are also a concern in patients with any
autoimmune disorder requiring chronic immunosup-
pressive therapy and need to be considered in the event
of a seizure.
Celiac disease
Celiac disease is an autoimmune disorder of the gastro-
intestinal tract due to hypersensitivity to gliadin, a gluten
protein in wheat, rye, and barley. Celiac disease has
received increasing public awareness in recent years.
A number of neurologic presentations have been associ-
ated with celiac disease, including seizures (Chapman
et al., 1978), although the nature of any causal relation-
ship between these diseases and celiac disease is still
not clear.
EPIDEMIOLOGY AND GENETICS
In a population-based study, patients with celiac disease
were determined to be at 1.42 higher risk of epilepsy, sug-
gesting a modest association (Ludvigsson et al., 2012).
Celiac disease characteristically occurs in patients carry-
ing alleles for HLA-DQ2 and/or HLA-DQ8. Absence
of these alleles confers a protective effect against the
development of celiac disease.
CLINICAL PRESENTATION, COURSE, AND PROGNOSIS
The nonneurologic symptoms characteristic of celiac dis-
ease include diarrhea, weight loss, bloating, abdominal
distension, iron deficiency, fatigue, aphthous stomatitis,
dermatitis herpetiformis, and osteopenia. In a clinical
series of 71 patients with celiac disease, a variety of neu-
rologic symptoms occurred in 22.5%, including
225
headache, depression, entrapment syndromes, periph-
eral neuropathy, and epilepsy (Briani et al., 2008). Ataxia
is a characteristic nonepileptic neurologic manifestation.
Seizures have been reported in 2–6% of patients with
celiac disease (Tengah et al., 2004; Bürk et al., 2009).
A history of exacerbation of neurologic symptoms
concurrent with dietary exposure to gluten-containing
foods can sometimes be elicited. A unique syndrome
referred to as CEC (celiac disease, epilepsy, and cerebral
calcifications), has been recognized for several years
(Bouquet et al., 1992; Fois et al., 1994). In this syndrome,
CT imaging shows calcifications in the parietal-occipital
cortical regions (Bouquet et al., 1992; Cury and Hobi
Moreira, 2014). Such patients may have partial seizures
manifested by transient episodes of blindness correlating
with the occipital calcifications. This syndrome accounts
for only a proportion of celiac patients with seizures.
There is little information as to the long-term progno-
sis of seizures occurring in the setting of celiac disease.
In general, treatment success hinges on adherence to the
gluten-free diet.
DIAGNOSTIC EVALUATION
Serologic testing
Testing for celiac disease typically begins with testing for
antitissue tranasglutaminase (anti-TTG) IgA antibodies,
which is 94% sensitive and 97% specific for celiac disease
(Fasano and Catassi, 2012). IgG anti-TTG testing is advis-
able in IgA-deficient patients. Antiendomysial IgA anti-
bodies are highly specific (>98%), but are expensive
and operator-dependent. IgA antigliadin antibody testing
has fallen out of favor due to a 15–20% false-positive
rate. However, testing for IgG antibodies targeting
deaminated gliadin peptides has >90% sensitivity and
specificity and is useful in IgA-deficient patients. The
sensitivity of antibody testing in celiac disease is signifi-
cantly reduced in patients on the gluten-free diet. In such
cases, testing for the presence of HLA-DQ2 and HLA-
DQ8 alleles is advised, as their absence makes the diag-
nosis highly unlikely.
Small-bowel biopsy
Endoscopy with small intestinal villous biopsy is the
definitive diagnostic procedure in celiac disease. The char-
acteristic pathologic findings in celiac disease include
lymphocytic infiltration of the endothelium, crypt hyper-
plasia, and villous atrophy.
Neuroimaging
In celiac patients with seizures, CT or MRI should be con-
sidered. The presence of parietal-occipital calcifications
in such cases would suggest the CEC syndrome.
226 J. BRITTON
Similarly, celiac disease testing is recommended in
patients with seizures and occipital calcifications
(Bouquet et al., 1992).
Cancer investigation
Celiac disease does not usually occur as a paraneoplastic
syndrome. An evaluation for cancer is not warranted in
typical cases.
PATHOPHYSIOLOGY
The neurologic manifestations of celiac disease are
thought most likely to be immune in origin. Antigliadin
antibodies, which are ubiquitously present in celiac dis-
ease, have been shown to cross-react with a neural anti-
gen, synapsin 1 (Alaedini et al., 2007). This suggests a
potential pathogenic link between celiac disease and its
neurologic manifestations. However, other investigators
have found no clear association between the presence of
antineural antibodies and neurologic symptoms in celiac
patients (Briani et al., 2008). The etiology of the cerebral
calcifications in the CEC syndrome is unknown, but
thought to be related to folate or vitamin D deficiency
resulting from malabsorption (Bouquet et al., 1992).
THERAPEUTIC APPROACH
Treatment of the CNS manifestations of celiac disease
primarily involves institution of a gluten-free diet. If
the diet is adhered to, anticonvulsant therapy alone is
usually ineffective. A role for immunosuppressant ther-
apy has not been established. Folate replacement therapy
should be considered to help prevent neurologic compli-
cations in celiac disease. Iron and vitamin deficiency
may occur as well in celiac disease and replacement ther-
apy should be considered.
SEIZURES DUE TO ANTIBODY-
MEDIATED NEUROLOGIC AUTOIMMUNE
DISORDERS
Hashimoto’s encephalopathy, better termed
autoimmune encephalopathy associated with
thyroid antibodies
Hashimoto’s encephalopathy, first described by Lord
Brain in 1966, is an inflammatory CNS disorder charac-
terized by waxing and waning mental status changes,
seizures, and stroke-like episodes, that is associated with
thyroid autoantibodies (Brain et al., 1966). It has been
increasingly recognized over the last several years as
an important treatable cause of encephalopathy,
although the lack of a clear definition of the syndrome,
and overlap with the newer neuronal antibody-associated
syndromes, raises questions about its frequency (Tüzün
et al., 2011). Patients characteristically have high titers of
antithyroperoxidase (anti-TPO) antibodies and typically
respond to corticosteroid therapy. These features have
led to use of the acronym SREAT (steroid-responsive
encephalopathy associated with autoimmune thyroiditis)
in place of Hashimoto’s encephalopathy (Mahad et al.,
2005; Castillo et al., 2006). Another term used for this
syndrome is the less-specific acronym NAIM (nonvascu-
litic autoimmune inflammatory meningoencephalitis),
which was coined based on the absence of frank vascu-
litis seen on brain biopsy in affected cases (Caselli
et al., 1999).
EPIDEMIOLOGY
Awareness of Hashimoto’s encephalopathy has
increased over the last several years but it is still rela-
tively uncommon, with an estimated prevalence of
2.1/100 000 (Ferracci et al., 2003). It is significantly more
common in women. The wide availability of antiTPO
antibody testing has made identification of potential
cases readily accessible, likely leading to an increase in
recognition of this entity.
CLINICAL PRESENTATION, COURSE, AND PROGNOSIS
Seizures are present in up to 66% of cases (Chong et al.,
2003; Castillo et al., 2006). Other clinical presentations
include chronic cognitive decline, dementia, depression,
irritability, psychosis, ataxia, myoclonus, tremors, and
chorea. Hashimoto’s encephalopathy may also present
as an acute disseminated encephalomyelitis-like illness,
transverse myelitis, a syndrome mimicking Creutzfeldt–
Jakob disease, and coma. Epilepsy presentations include
progressive myoclonic epilepsy of childhood, a syndrome
identical to limbic encephalitis, and new-onset status epi-
lepticus (Arya et al., 2013; Chaigne et al., 2013). Despite
the presence of antithyroid antibodies, patients with
Hashimoto’s encephalopathy are typically euthyroid.
The encephalopathy and seizures in Hashimoto’s
encephalopathy are amenable to immunotherapy. The
prognosis is generally good, but depends in part on the
severity at presentation. Recurrences can occur, and in
some cases maintenance immunotherapy proves neces-
sary. The prognosis in patients presenting in status
epilepticus and limbic encephalitis is more guarded,
but good responses are still possible.
DIAGNOSTIC EVALUATION
Serology
The serologic hallmark of Hashimoto’s encephalopathy
is the presence of anti-TPO antibodies. Antithyroglobu-
lin and antithyroid microsomal antibodies are also
 AUTOIMMUNE EPILEPSY 227
elevated. Patients with Hashimoto’s encephalopathy may
also have a positive ANA, potentially causing confusion
with NPSLE. CSF may show an inflammatory profile but
may not, and the lack of inflammatory CSF abnormali-
ties does not exclude the diagnosis. In one large series, an
inflammatory profile was seen in 25% (Castillo et al.,
2006). However, none of these antibodies, which are rel-
atively common in the most susceptible age groups,
should exclude the diagnosis of a more specific autoim-
mune form of encephalitis, such as those associated with
NMDA receptor or voltage-gated potassium channel
(VGKC)–complex antibodies (Tüzün et al., 2011).

Neuroimaging
MRI may be normal. In one series, MRI was normal in
74% of cases (Castillo et al., 2006). Abnormal T2 signal
hyperintensity in the hippocampi may be seen in some
cases (Song et al., 2004; Tang et al., 2012). FDG-PET
may show multifocal hypometabolism during active
encephalopathy, with resolution to normal following
treatment (Seo et al., 2003).

EEG Fig. 13.3. Electroencephalograms (EEGs) from patient with

The EEG usually shows moderately severe abnormalities
during the encephalopathy, which may improve signifi-
cantly in parallel with clinical response following treat-
ment (Fig. 13.3). The EEG abnormalities seen in
Hashimoto’s encephalopathy include interictal epilepti-
form discharges, seizures, and generalized triphasic
waves. None of these findings is specific to Hashimoto’s
and can be seen in encephalopathies resulting from other
causes.
Differential diagnosis
The differential diagnosis of Hashimoto’s encephalopa-
thy is broad due to its protean manifestations, and
includes encephalopathies due to diffuse toxic-
metabolic, infectious, vascular, and other inflammatory
etiologies. Hashimoto’s encephalopathy should also be
on the differential diagnosis of patients presenting with
unexplained subacute dementia, de novo status epilepti-
cus, and limbic encephalitis.
PATHOPHYSIOLOGY
Anti-TPO antibodies are considered markers of autoim-
munity rather than playing a direct role in the pathophys-
iology of Hashimoto’s encephalopathy. Antibodies to
antigens expressed in neural tissue have been identified
in Hashimoto’s encephalopathy, including antibodies
targeting the amino-terminal of alpha-enolase (Fujii
et al., 2005; Matsunaga et al., 2013). Serum and CSF
antibodies targeting dimethylargininase-I and aldehyde
autoimmune encephalopathy associated with thyroid anti-
bodies. (A) EEG prior to treatment shows generalized triphasic
waves and anterior predominant delta-frequency slowing. (B)
EEG performed 2 years posttreatment is normal. (Reproduced
from Schauble et al., 2003, with permission.)
reductase-I antigens have also been identified, and are
located in endothelial and neuronal tissue, potentially
accounting for the neurologic features of this condition
(Beatrice et al., 2008). The pathologic relevance of the
immune response to these targets remains to be
determined.
Few autopsies of Hashimoto’s encephalopathy have
been reported given most respond to therapy and are
not acutely fatal. Perivenular inflammatory changes
have been described in the few autopsy and biopsy cases
in the literature, but frank vasculitis is typically not pre-
sent (Caselli et al., 1999; Striano et al., 2006).
THERAPEUTIC APPROACH
One of the striking features of this presumed autoim-
mune encephalopathy is the marked and relatively
quick response to steroids (Olmez et al., 2013). Cortico-
steroid therapy dosage strategies have not been formal-
ized, but typically consist of 1 gram methylprednisolone
IV daily for 3–5 days, followed by weekly administra-
tion. Alternatively, 60 mg oral prednisone daily has
been advocated, with a gradual reduction afterwards
if allowed by the clinical course. IVIG has been
used for those who do not tolerate corticosteroid
228 J. BRITTON
treatment. Plasmapheresis has also been reported to be
efficacious in refractory cases (Bektas et al., 2012; Pari
et al., 2014). Hashimoto’s encephalopathy may relapse
over time, prompting some authorities to recommend
chronic maintenance therapy in some cases. No supe-
rior maintenance treatment has been identified. Ritux-
imab, IVIG, azathioprine, and mycophenolate have
all been reportedly used for this purpose (Olmez
et al., 2013).
Glutamic acid decarboxylase 65 kD isoform
(GAD-65) antibody-associated encephalitis
and seizures
GAD-65 antibody is classically associated with stiff-man
syndrome (McKeon et al., 2012). However, over time it
has become apparent that GAD-65 antibodies are associ-
ated with a variety of neurologic features, including
ataxia, vertigo, brainstem dysfunction, limbic encepha-
lopathy, extrapyramidal signs, myelopathy, and seizures
(Pittock et al., 2006; Saiz et al., 2008). Seizures and epi-
lepsy may be a prominent neurologic feature in affected
patients.
EPIDEMIOLOGY
GAD-65 antibodies are prevalent in diabetes mellitus
type 1, occurring in over 70% of patients (Petersen
et al., 1994). It is important to note that GAD-65 anti-
bodies are also present in the normal population. In
one study comparing the prevalence of GAD-65 in the
type 1 diabetes and nondiabetes populations, GAD-65
antibody was found in 4% of normal subjects.
While GAD-65 antibodies can occur in association
with an acute or subacute limbic encephalitis syndrome
(Malter et al., 2010), they may also be present in patients
with chronic epilepsy. In a case-control study comparing
253 patients from an epilepsy clinic with 250 nonepilepsy
controls, GAD-65 positivity was found in 15 (5.9%) of
epilepsy patients and 3 (1.5%) controls ( p ¼ 0.026)
(Liimatainen et al., 2010). High titers (>1000 relative
units/mL) were found in 7 patients with epilepsy and
none of the controls. In another study in which serum
from two large epilepsy cohorts was screened for neuro-
pil antibodies, a lower prevalence of GAD-65 antibodies
was observed (1.7%) (Brenner et al., 2013). The majority
of GAD-65-positive epilepsy patients have temporal-
lobe seizures. In a study comparing 51 patients with
partial epilepsy, 49 patients with generalized epilepsy,
38 patients with other neurologic conditions, and 48 nor-
mal controls, GAD-65 positivity was found in 8 (16%)
partial epilepsy patients and in none of the other groups
(Peltola et al., 2000).
CLINICAL PRESENTATION, COURSE, AND PROGNOSIS
The seizures seen in association with GAD-65 antibody
consist of simple partial, complex partial, and secondary
generalized tonic-clonic seizures. Affected patients may
also present with the limbic encephalitis syndrome and
nonconvulsive status epilepticus. It should be noted that,
while seizures clearly occur in the setting of GAD-65
positivity, they are present in the minority of cases. In
one study evaluating the neurologic findings in patients
with high GAD-65 antibody titers, seizures or limbic
encephalopathy were collectively present in only 10%
(6 of 61) (Saiz et al., 2008).
The clinical course of epilepsy and seizures associ-
ated with GAD-65 antibodies is variable, and the progno-
sis is guarded. While some patients will respond to
immunotherapy, many do not, in which case seizures
remain disabling (Toledano et al., 2014).
DIAGNOSTIC EVALUATION
Clinical
Patients with seizures associated with GAD-65 antibodies
typically present with complex partial and secondary
generalized tonic-clonic seizures. The semiology of the
seizures occurring in the context of this antibody has
no distinguishing feature. Certain other clinical features,
however, suggest the possibility of GAD-65 antibody
positivity, such as the presence of diabetes type 1 and con-
current autoimmune thyroid disease. Diabetes type 1, for
example, is present in over 50% of patients with GAD-65-
associated neurologic syndromes, and concurrent thy-
roid disease and/or antithyroid antibody positivity are
present in 30–40% (Pittock et al., 2006; McKeon et al.,
2012). Finally, vitiligo is present in 15% of patients with
GAD-65-associated neurologic syndromes, and if pre-
sent should suggest the diagnosis (Pittock et al., 2006).
Serology and CSF
As indicated previously, antibodies targeting GAD-65 are
present in approximately 4% of the normal population
(>0.02 nmol/L or >0.5 U/mL), and in most patients with
type 1 diabetes, so cannot be considered specific for the
presence of an autoimmune etiology in a patient with epi-
lepsy. However, the antibody titers seen in autoimmune-
mediated neurologic disorders, including seizures, are
typically much higher, often 100-fold higher, than those
seen in the general and type 1 diabetes populations. Other
antibodies are commonly encountered. For example, in
one study, 50% of GAD-65 patients had antithyroid anti-
bodies, and many other antibodies were present, including
calcium channel, VGKC–complex, striated muscle,
amphiphysin, parietal cell, and islet cell antibodies in a
smaller proportion (Pittock et al., 2006).
 AUTOIMMUNE EPILEPSY
Neuroimaging
MRI may show mesial temporal T2 signal hyperintensi-
ties with or without gadolinium enhancement (Fig. 13.4).
These findings are not unique to GAD-65 antibody, and
may be seen in limbic encephalitis from other causes.
Indeed, there is a GAD antibody-associated form of lim-
bic encephalitis (Malter et al., 2010). Over time, atrophy
of the hippocampal structures may develop. Imaging in
patients lacking the full features of limbic encephalopa-
thy may be normal.
EEG
The EEG in GAD-65 patients with epilepsy may show
epileptiform abnormalities involving the frontotemporal
regions (Fig. 13.5). There are no unique EEG features
seen in association with this antibody.
Cancer investigation
GAD-65 antibodies are not generally considered a sign
of paraneoplastic disease. In one series, underlying neo-
plasms were found in 7% (4 of 61) of patients, three of
which were neuroendocrine tumors (Saiz et al., 2008).
Differential diagnosis
For patients presenting chiefly with temporal-lobe
seizures and a low-titer anti-GAD-65 antibody, other
229
etiologies of temporal-lobe seizures should still be
considered, such as structural lesions of the temporal
lobe and others. For patients presenting with limbic
encephalitis and nonconvulsive status epilepticus, other
etiologies of these syndromes need to be considered.
Hashimoto’s encephalopathy presents a particular prob-
lem in assigning a diagnosis, as antithyroid antibodies,
which are a key diagnostic feature in Hashimoto’s
encephalopathy, may also be present in GAD-65
patients. In such cases, high titers of GAD-65 would typ-
ically suggest a GAD-65-associated syndrome. This dis-
tinction may be relevant for counseling purposes, as the
response to immunotherapy is generally regarded as
being more satisfactory in Hashimoto’s encephalopathy
than in GAD-65 antibody-associated encephalitis.
PATHOPHYSIOLOGY
It has not been established whether GAD-65 antibodies
play a pathogenic role or are mainly present as a marker
of autoimmune-mediated neuronal injury. GAD plays a
critical role in the glutamate-gamma-aminobutyric acid
A (GABA) cycle, catalyzing the conversion of glutamic
acid to GABA, the major inhibitory neurotransmitter in
the brain. GAD exists as two major isoforms, 67 kD
(GAD-67) and 65 kD (GAD-65). The GAD-65 isoform
is transiently activated in response to demands for

Fig. 13.4. Imaging from a 62-year-old woman with limbic encephalitis and frequent subclinical frontotemporal seizures associ-
ated with glutamic acid decarboxylase 65 kD isoform (GAD-65) antibody. (A) Coronal fluid-attenuated inversion recovery
(FLAIR)-weighted imaging shows hyperintensity involving the bilateral orbitofrontal (bracket), right hypothalamic (arrow),
and bilateral hippocampal regions (star). (B) 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) showing hyper-
metabolic abnormalities in the bilateral hippocampal regions (arrows) and striatum (star). Used with permission of Mayo Foun-
dation for Medical Education and Research. All rights reserved.
230 J. BRITTON

Fig. 13.5. Electroencephalogram in patient with glutamic acid decarboxylase 65 kD isoform (GAD-65)-associated limbic enceph-
alitis, showing a right frontotemporal seizure manifested as a rhythmic discharge arising first in the F8 derivation (arrow). Used
with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

temporary boosts in GABAergic neurotransmission
(Fenalti et al., 2007). It is therefore conceivable that an
antibody directed against GAD-65 could disrupt the
glutamate-GABA balance to one favoring an accumula-
tion of glutamate and reduction in GABA, leading to
increased neuronal excitation and seizures. In the
stiff-person syndrome this is thought to take place
mainly in the spinal cord and brainstem (see
Chapter 17). There is evidence that GAD-65 antibodies
may affect GABA activity. In a study of 4 patients with
epilepsy and high serum GAD antibody levels, cortical
GABA levels as measured on MR spectroscopy were
reduced compared to 10 controls (Stagg et al., 2010).
In another study, application of GAD-65 sera to a net-
work of hippocampal neurons in culture led to suppres-
sion of recorded inhibitory postsynaptic potentials
(Vianello et al., 2008). These findings suggest that
GAD-65 antibodies may lead to a reduction in
GABAergic-mediated inhibition, which could hypotheti-
cally lead to increased seizure propensity, but does not
address the question of how antibodies to an intracellular
protein cause the disease.
THERAPEUTIC APPROACH
A trial of immunotherapy is justified in GAD-65-positive
patients with medically unresponsive seizures; however
the results are often disappointing, unfortunately. In our
autoimmune epilepsy cohort, only 2 of 6 GAD-65
antibody-positive patients improved with immunotherapy
(Fig. 13.6) (Toledano et al., 2014). Corticosteroid therapy
needs to be used with caution in GAD-65 patients with
diabetes due to the effects of the former on serum glucose
concentrations. In such cases, IVIG may be a consideration.
The responder rates to corticosteroid and IVIG ther-
apy are generally higher for seizures related to other neu-
ral antibody-mediated syndromes, as illustrated by the
poor responses of patients with GAD antibodies and lim-
bic encephalitis (Malter et al., 2010). The reasons why sei-
zures in association with this antibody do not respond are
not completely clear. One theory holds that GAD-65 anti-
bodies may arise after irreparable neuronal injury or
apoptosis has already occurred, which exposes intracel-
lular enzymes like GAD-65 to circulating self-
antibodies, in which case immunotherapy is too late. In
contrast, antibodies targeting membrane surface anti-
gens may be more prone to causing functional changes
in neurons due to interaction at receptor targets, as
opposed to causing cellular destruction, thereby present-
ing at a stage where neuronal salvage is still possible.
In patients unresponsive to corticosteroid or IVIG
therapy, there is little guidance from the literature. Plas-
mapheresis, rituximab, mycophenolate, and azathio-
prine are options, but the efficacy of these therapies in
this setting has not been established.
Voltage-gated potassium channel–complex
antibody-associated encephalitis
VGKC–complex antibodies are an important cause of
limbic encephalitis and temporal-lobe seizures
(Buckley et al., 2001; Pozo-Rosich et al., 2003; Thieben
et al., 2004; Irani et al., 2010). These antibodies are
 AUTOIMMUNE EPILEPSY 231
Immunotherapy Response: Flow Chart Response to Immunotherapy According to Antibody Type
Patients with suspected autoimmune epilepsy
n = 29
PMA Ab positive PMA Ab negative
n = 16 n = 13

Abs to plasma
Onco-neural Abs
membranes gAChR Ab CC P/Q; CC N GAD 65 Abs No neuronal Abs
n=1
n = 12 n=3 n=1 n=6 n=6
Ma1/Ma2
VGKC-complex

Responders Responders Nonresponders Nonresponders Responders Nonresponders Responders Nonresponders

Nonresponders
n = 12 n=2 n=1 n=1 n=2 n=4 n=2 n=4

100
Responders

Responders (%)
n = 13 80
IVMP Responders
60
n = 23 n=2
Nonresponders IVIg
40
n = 10 n=5
Nonresponders 20
n=3
0
VGKC gAChr GAD65 Ma1/Ma2 No neural
abs
C PMA Abs Ab to intracellular
proteins

60
Responders Responders (%)
50
n=2
IVIg Responders 40
n=6 n=1 30
Nonresponders IVMP
n=4 n=2 20
Nonresponders
10
B
n=1
0
IVMP as IVIg as IVMP as IVIg as
D 1st agent 1st agent 2nd agent 2nd agent

Fig. 13.6. Immunotherapy trial response in autoimmune epilepsy. (A) Flow chart of response to immunotherapy trial according to
antibody type. (B) Flow chart of response to immunotherapy trial according to immunotherapeutic agent tried. (C) Percent of
responders by antibody type. (D) Percent of responders to first and second immunotherapeutic agent tried. Abs, antibodies;
CC N and CC P/Q, voltage-gated calcium channel N-type and P/Q-type; gAChR, neuronal ganglionic nicotinic acetylcholine
receptor antibody; GAD65, glutamic acid decarboxylase 65; IVIg, IV immune globulin; IVMP, IV methylprednisolone; PMA
Ab, plasma membrane antigen antibodies; VGKC, voltage-gated potassium channel. (Reproduced from Toledano et al., 2014,
with permission.)

associated with a number of neurologic presentations
other than seizures, including Morvan’s syndrome, neu-
romytonia, gastrointestinal dysmotility, and a chronic
pain syndrome thought to be mediated by hyperexcitabil-
ity of nociceptive pathways (Klein et al., 2012, 2013).
EPIDEMIOLOGY
The prevalence of VGKC–complex antibodies in the epi-
lepsy and limbic encephalitis population is not definitively
known, as discovery of this antibody and its association
with seizures is relatively recent. In a study of serum from
106 women with epilepsy, VGKC–complex antibodies
were found in 6 (7%) (Majoie et al., 2006). In another study
screening for neuropil antibodies in serum from two large
epilepsy center cohorts, VGKC–complex antibodies were
found in 5% (Brenner et al., 2013). The prevalence of
VGKC–complex antibodies in the limbic encephalitis pop-
ulation is higher. In a study evaluating the prevalence of
neuronal surface antigen antibodies in 45 patients with
limbic encephalitis, VGKC–complex antibodies were
found in 13 (29%) (Graus et al., 2008).
CLINICAL PRESENTATION, COURSE, AND PROGNOSIS
Patients with seizures related to VGKC–complex anti-
bodies may experience a number of seizure semiologies.
Early descriptions described hypersalivation as a charac-
teristic feature of seizures in these patients (Buckley
et al., 2001). Since these earliest case reports, other seizure
semiologies have been associated with VGKC–complex
antibody.
The most characteristic seizure type seen in VGKC–
complex antibody encephalitis are called faciobrachial
dystonic seizures, which are manifested by the sudden
onset of flexion contraction of one upper extremity or
the other, accompanied by contraction of the face and
head and neck ipsilateral to the affected upper extremity
232 J. BRITTON
(Irani et al., 2011). These seizures typically last a second
or so, and occur multiple times per day. The trunk, lower
extremity, and abdomen may be involved, in addition to
the face and upper extremity, and they are sometimes
accompanied by a brief vocalization. This seizure type
is present in approximately a fourth of VGKC–complex
antibody epilepsy patients (Toledano et al., 2014).
Patients with VGKC–complex antibodies may also
experience simple partial autonomic seizures manifested
by unilateral piloerection or palpitations. Others describe
their seizures as being manifested by a brief ascending
or descending “wave” passing through their body. The
above-described seizures typically last a second or so
and occur multiple times a day in affected patients, similar
to faciobrachial dystonic seizures. These may be accompa-
nied by brief periods of amnesia. Patients with VGKC–
complex antibodies may also present with complex partial
seizures and in complex partial status epilepticus.
The other neurologic presentations of VGKC–
complex antibodies are further reviewed in Chapter 10.
Hyponatremia is a relatively common laboratory finding
and can provide a helpful clue to the antibody.
The prognosis of VGKC–complex antibody-mediated
seizures is relatively favorable. Unlike NMDA encephali-
tis, patients with VGKC–complex-associated seizure dis-
orders are usually manageable in the outpatient setting.
The seizures in the setting of VGKC–complex encephali-
tis are typically highly responsive to immunotherapy.
Some patients demonstrate hippocampal edema at onset.
Atrophy may develop subsequently, in which case deficits
in short-term memory may become evident (Fig. 13.7). The
recovery of memory deficits occurring in association
with VGKC–complex encephalitis is unfortunately less
dependable compared to the prognosis for seizures.
DIAGNOSTIC EVALUATION
Clinical
VGKC–complex antibody-associated epilepsy should
be considered in patients with a history of new onset
of seizures, confusion, and memory deficits. The sei-
zures are often brief and occur at high frequency.
The presence of faciobrachial dystonic seizures and
other focal seizures occurring at a frequency of several
per day is also highly suggestive.
Serology and CSF
VGKC–complex antibodies were originally thought to tar-
get antigens residing directly on the voltage-gated potas-
sium channel subunits. However, it was subsequently
discovered that these antibodies actually target proteins
that remain complexed with potassium channels in the rab-
bit brain extracts used in the assay, as opposed to the potas-
sium channel itself (Irani et al., 2010). Three other protein
targets were identified as the actual targets: (1) leucine-rich
glioma inactivated 1 protein (LGI1), which is extensively
represented in the hippocampus comprising the majority
of the samples; (2) contactin-associated protein-2
(CASPR-2), which is localized primarily in the juxtanodal
region of myelinated axons; and (3) Tag1/contactin-2, a
protein associated with CASPR-2 (Irani et al., 2010). In

Fig. 13.7. Serial head magnetic resonance imaging scans in a patient with voltage-gated potassium channel–complex antibody
encephalitis. Comparison of the hippocampi over an 8-month period (arrows) shows the development of significant atrophy. Used
with permission of Mayo Foundation for Medical Education and Research. All rights reserved.
 AUTOIMMUNE EPILEPSY
18 of 96 cases, the precise antigenic target within the
VGKC–complex was undefined.
CSF examination in VGKC–complex antibody
patients showed mild elevations in mononuclear cell
count in 41% and mild elevations in CSF protein in
47% (Jarius et al., 2008). In this series, there was no evi-
dence of intrathecal immunoglobulin production.
Neuroimaging
MRI may show swelling and hyperintensity in the hippo-
campi on fluid-attenuated inversion recovery (FLAIR)
and T2-weighted sequences. These findings were present
in 33/42 (78.6%) of cases in one series (Kotsenas et al.,
2014). Gadolinium enhancement and restricted diffusion
may be present in addition in the early phases. Serial
imaging often shows resolution of hippocampal edema,
and may show progression to hippocampal atrophy over
time (Fig. 13.7).
A unique MRI finding described in the setting of
VGKC–complex antibody positivity is FLAIR hyperin-
tensity abnormalities involving the striatum (Hiraga
et al., 2006; Plantone et al., 2013; Kotsenas et al.,
2014). FDG-PET hypermetabolism of the striatum has
also been described in association with VGKC–complex
antibody (Rey et al., 2012).
FDG-PET may show hypermetabolic abnormalities in
the hippocampal regions in VGKC–complex antibody
encephalitis (Fauser et al., 2005; Kotsenas et al., 2014).
This may reflect the high seizure frequency sometimes
seen in this population. However, it may also reflect
excess glucose utilization secondary to inflammation
in these regions. These FDG-PET findings are not unique
to VGKC–complex and can be seen in limbic encephalitis
from other etiologies (Fig. 13.4).
EEG
The EEG typically shows interictal abnormalities local-
ized in the temporal regions. In patients with a high sei-
zure frequency, electrographic temporal-lobe seizure
discharges may also be present. Such findings are not
specific for VGKC–complex and are common to limbic
encephalitis of all causes (Fig. 13.3). Importantly, the
faciobrachial seizures in VGKC–complex antibody
encephalitis are often brief and not associated with loss
of awareness, suggesting that a small cortical regional
area may be involved during the seizure, which may ren-
der the seizure undetectable on scalp EEG. This can lead
to a misdiagnosis that the recorded events are functional
if the EEG reader does not take this into account when
interpreting the recording (Tao et al., 2007). The absence
of confirmatory ictal EEG findings is the rule rather than
the exception for faciobrachial dystonic seizures, and
for simple partial seizures and auras without impaired
reactivity, which are not uncommon in this population.
233
Cancer investigation
The identification of VGKC–complex antibodies alone
does not strongly suggest the presence of an underlying
neoplasm. In a large series of 96 VGKC–complex-
positive patients comprising epilepsy and nonepilepsy
clinical presentations, 6 were diagnosed with an underly-
ing tumor (5 thymoma, 1 endometrial carcinoma) (Irani
et al., 2010). This rate is far lower, for example, than the
rate of cancer seen in association with paraneoplastic
antibodies such as anti-Hu (ANNA-1) or anti-Ma1 or
Ma2. Indeed, when antibodies targeting intraneuronal
targets are present in combination with VGKC–complex
antibodies, the potential for an underlying cancer is
higher (Graus and Saiz, 2008). In the latter situation, a
cancer evaluation is clearly warranted. However, the
value of pursuing an extensive cancer evaluation in
the setting of isolated VGKC–complex antibody positiv-
ity is arguable.
Differential diagnosis
For patients presenting with the syndrome of limbic
encephalitis, the differential diagnosis is extensive and
includes consideration of other autoimmune causes dis-
cussed in this chapter. In the acute setting, infectious lim-
bic encephalitis due to human herpes viruses 1 and 6 needs
to be considered. Other diseases affecting the limbic sys-
tem also need to be excluded, including vascular diseases,
neoplasms, or other structural lesions. In patients pre-
senting with an acute amnestic syndrome in the absence
of seizures, Wernicke’s encephalopathy would be
included in the differential diagnosis. Affective symp-
toms and anxiety are common in these patients, and this
can cause misdiagnosis of a primary psychiatric disorder.
PATHOPHYSIOLOGY
LGI1 is highly represented in the hippocampi, and is the
predominant VGKC–complex antibody type in patients
presenting with limbic encephalitis and seizures. LGI1
is weakly expressed in the peripheral nervous system
and can be present in patients with peripheral nervous
system disease (Irani et al., 2010; Klein et al., 2013).
CASPR-2 is primarily localized to the juxtanodal region
in myelinated nerve fibers and most often presents with
neuromyotonia and other peripheral nervous system
manifestations, although it is also expressed widely in
the brain, and CASPR-2 antibodies have been identified
in patients with CNS presentations. The mechanism by
which these antibodies lead to seizures is not definitively
established. However, as potassium channels allow
potassium efflux resulting in neural inhibition, any
impairment of their function could favor neural excita-
tion, which could theoretically result in seizures and
peripheral hyperexcitability phenomena such as
234 J. BRITTON
neuromyotonia. IgG from one patient with LGI1 anti- recent years, a syndrome associated with antibodies tar-
bodies caused epileptogenic effects on rodent hippocam- geting the NMDA receptor has been identified (Dalmau
pal slices (Lalic et al., 2011). et al., 2007). NMDA receptor antibody encephalopathy
Data on the neuropathology of VGKC–complex anti- has many characteristic clinical features, and is poten-
body encephalitis is limited. In one report of an autopsy in tially fatal. However, it is also highly amenable to immu-
a VGKC–complex antibody patient, the hippocampi con- nosuppressant therapy, and the chances for a good
tained activated microglia and occasional B lymphocytes, neurologic recovery are realistic in many cases.
with sparing of other limbic structures, including the cin-
gulate gyrus and insular cortex (Khan et al., 2009).
Immunoglobulin staining showed a nonspecific pattern, EPIDEMIOLOGY
and did not show specific deposits near neurons or blood
The prevalence and incidence of this disorder are not
vessels. These findings generally support a predominant
precisely known. In a study evaluating the prevalence
B-cell-mediated inflammatory mechanism in this disor-
of neural antibody positivity in a large epilepsy cohort,
der, with some complement-mediated damage (see
NMDA receptor antibodies were identified in 1.7%.
Chapter 7 for further details).
Therefore, it is an unlikely cause of epilepsy outside
of its occurrence in association with the NMDA receptor
Therapeutic approach
antibody encephalopathy syndrome.
Most patients respond favorably to corticosteroid ther-
apy. If corticosteroids are contraindicated or inadvis-
able, IVIG can be considered. There have been no CLINICAL PRESENTATION, COURSE, AND PROGNOSIS
randomized clinical trials establishing the efficacy supe-
Seizures are often present at the onset of NMDA recep-
riority of one over the other in this condition. If the
tor antibody encephalopathy, and consist of complex
patient does not respond to one first-line treatment,
partial and secondary generalized tonic-clonic seizures.
the other is generally tried next.
These can occur at a high frequency at onset, and
The responder rate to either first-line immunotherapy
patients may present in status epilepticus. However,
treatment is generally excellent in terms of seizure
nonepileptic symptoms are also very prominent at onset
response. In our series of patients treated with IV meth-
as well, and in some cases may overshadow the seizures.
ylprednisolone and/or IVIG, 100% of 10 patients with
Affected patients often have a prominent psychosis at
seizures associated with VGKC–complex antibodies
presentation, for example, with delusions and auditory
improved substantially in terms of seizure rate (Irani
and visual hallucinations (Titulaer et al., 2013a, b).
et al., 2010; Quek et al., 2012; Toledano et al., 2014).
Affected patients are also prone to respiratory failure
Within days of initiation of treatment with IV methyl-
and the need for ventilatory support is not uncommon.
prednisolone, the seizure frequency may decrease from
Dyskinesias are another characteristic feature of this
multiple daily simple partial seizures to zero or a few per
disorder, and affect the limbs, digits, head and neck,
day. In the event of failure of first-line therapy, plasma-
and face (Stamelou et al., 2012). The dyskinesias may
pheresis can be considered. Finally, rituximab was found
occur continuously, and can last for days and weeks.
to be efficacious in a series of 5 patients (Irani et al.,
Affected patients may develop catatonia in addition.
2014). Despite the good seizure response, the recovery
Patients with NMDA receptor antibody-associated
of memory functions is seldom complete, and hippo-
encephalopathy can be critically ill and often require
campal atrophy is common with LGI1 antibodies
ICU care.
(Butler et al., 2014; Malter et al., 2014).
This disorder can affect all age groups. Of impor-
In responders, a decision must then be made as to
tance, this syndrome is highly correlated with the pres-
whether to initiate chronic maintenance treatment. For
ence of ovarian teratoma. In young women, adequate
this important question, there are unfortunately no avail-
evaluation for an underlying teratoma is essential.
able data. More natural history studies need to be done in
Although patients with NMDA receptor encephalop-
order to inform treatment decisions like this in these
athy may be gravely ill, the potential for recovery follow-
disorders.
ing immunotherapy with corticosteroids, IVIG, and
rituximab is relatively high (Titulaer et al., 2013a).
NMDA receptor antibody-associated
Recovery may take weeks or even months, but the pos-
encephalopathy
sibility of a good outcome is realistic. Interestingly,
NMDA receptors are excitatory receptors that mediate spontaneous remission without immunotherapy may
several critical neurologic functions, such as long-term also occur, although the reported recovery in these cases
potentiation and synaptic plasticity. Excessive activation took several months (Iizuka et al., 2008). This topic is
of NMDA receptors, however, may lead to seizures. In covered in much more detail in Chapter 12.
 AUTOIMMUNE EPILEPSY
DIAGNOSTIC EVALUATION
Clinical
The prominent psychotic symptoms, dyskinesias, and
propensity for respiratory failure are relatively unique
to this disorder, in comparison to the other autoimmune
encephalopathies, although psychosis can complicate
limbic encephalitis of other causes. The presence of a ter-
atoma in this setting would be a surprising feature in a
patient with a seizure syndrome, and would strongly sug-
gest an NMDA receptor antibody etiology.
Serology and CSF
NMDA receptor antibodies can be found in serum, but
are sometimes only present in the CSF. NMDA receptor
antibodies have been reported in schizophrenia and nar-
colepsy populations as well, raising some questions as to
their specificity (Tsutsui et al., 2012). It is important to
note that these antibodies may continue to be present
long after resolution of the acute illness; therefore their
mere presence does not always correlate with active dis-
ease (Hansen et al., 2013). A recent interesting observa-
tion is the presence of NMDA receptor antibodies
arising during or after herpes simplex encephalitis, often
with a relapse of encephalopathy symptoms following
initial response to antiviral therapy (Armangue et al.,
2014). In children the association of NMDAR antibodies
with postherpes simplex virus encephalitis is particularly
striking (see Chapter 26).
Imaging
Standard structural MRI of the brain is often normal in
NMDA receptor antibody encephalopathy. However,
nonstandard MRI modalities may be more revealing.
In one study, functional MRI showed reduced func-
tional connectivity of the left and right hippocampus
with the anterior default-mode network. In this same
study, diffusion tensor imaging showed evidence of
extensive white-matter changes most prominent in the
cingulum (Finke et al., 2013).
EEG
The EEG characteristically shows diffuse moderate ampli-
tude rhythmic delta-frequency activity (Kirkpatrick et al.,
2011). This diffuse delta pattern is sometimes associated
with superimposed intermittent bursts of low-amplitude,
high-frequency activity. Given the resemblance of these
waveforms to delta brushes seen in premature infant
EEG recordings, this has been referred to as the “excess
delta brush” pattern (Schmitt et al., 2012) (Fig. 13.8).
235
Cancer investigation
NMDA receptor antibody encephalopathy is associated
with the presence of teratomas. Given this association,
evaluation for teratoma is indicated in women with this
disorder. Teratomas are typically localized to the ovaries;
however, teratomas have also been identified in the medi-
astinum in this population. It may rarely be associated with
other tumor types (breast, lung, testicular, pancreatic, and
thymic have been reported) (Titulaer et al., 2013a).
Differential diagnosis
Other causes of autoimmune and paraneoplastic encepha-
litis should be considered, as well as herpes simplex viral
encephalitis and other infectious meningoencephalitides
during the acute setting. The presence of the antibodies
in herpes simplex virus encephalitis cases suggests that,
in some cases, NMDA receptor antibodies may form as
a parainfectious response in this disease (Pruss et al.,
2012a; Armangue et al., 2014), although there is no evidence
for molecular mimicry. Other causes of encephalopathy,
such as those stemming from vascular, neoplastic, and
toxic-metabolic etiologies, should also be considered.
PATHOPHYSIOLOGY
NMDA receptor antibodies in vitro target the GluN1 sub-
unit, leading to a selective decrease in surface density
and synaptic localization in neuronal cultures secondary
to antibody-mediated capping and internalization of
NMDA receptors (Hughes et al., 2010; Moscato et al.,
2014). This results in decrease in the synaptic localization
and function of NMDA receptors, and decreased
NMDR-mediated currents, but this is reversible and
NMDAR recovery takes place when the antibody is
removed from the cell culture. In mice infused with
CSF positive for the antibody, there is also a loss of
NMDA receptor with prominent changes in NMDA
receptor-mediated currents (Pruss et al., 2012b). In addi-
tion, the application of CSF from patients with NMDA
receptor antibody encephalopathy to murine hippocam-
pal slices leads to suppression in long-term potentiation
(Zhang et al., 2012). Importantly, autoimmune neuronal
destruction does not typically occur, and this is likely the
reason underlying the potential for recovery in this ill-
ness and why neuroimaging is often unremarkable in
these patients, even in the acute phase (for further
details, see Chapters 5 and 12).
THERAPEUTIC APPROACH
In female patients, it is important to evaluate for a ter-
atoma. A large retrospective series demonstrated that
immunosuppressive therapy was efficacious in NMDA
receptor encephalopathy (Titulaer et al., 2013a). Of 472
236 J. BRITTON

Fig. 13.8. Electroencephalogram patterns in N-methyl-D-aspartate receptor antibody encephalopathy. (A) Synchronous, rhythmic
generalized delta in a 48-year-old comatose woman on ventilatory support. She walked out of the hospital 3 weeks later. (B) Rhyth-
mic generalized delta with delta brush-like waveforms in a 2-year-old patient with severe encephalopathy, continuous dyskinesias
of face and limbs, and respiratory depression on ventilatory support. Used with permission of Mayo Foundation for Medical Edu-
cation and Research. All rights reserved.

patients receiving first-line therapy, 251 (53%) were
improved within 4 weeks, although some patients
required 18 months to improve. First-line immunother-
apy usually consists of steroids, IVIG, or plasma
exchange in these patients. Of 221 nonresponders, those
who received second-line therapy had a better outcome
than those who did not. Second-line immunotherapy
included rituximab or cyclophosphamide. At 2 years,
81% had a good outcome, but 30 died. Predictors of good
outcome were early treatment and lack of need for ICU-
level care. There was a 12% risk of relapse within 2 years
in the series, with relapses typically being milder than the
original attack.
Other neural antibodies associated with
autoimmune epilepsy
GABA-B RECEPTOR ANTIBODY
Antibodies directed at GABA-B receptor antigens may
cause limbic encephalitis (Lancaster et al., 2010;
Boronat et al., 2013). GABA-B receptor antibodies may
also present with ataxia, brainstem encephalitis, and
opsoclonus-myoclonus syndrome (Hoftberger et al.,
2013; Mundiyanapurath et al., 2013). These antibodies
accounted for 14% of cases of limbic encephalitis in
one series (Boronat et al., 2013) and 10% of limbic enceph-
alitis cases previously deemed seronegative prior to
 AUTOIMMUNE EPILEPSY
discovery of this antibody in another (Jeffery et al., 2013).
EEG and MRI usually show features typical of limbic
encephalitis. There is a significant association of
GABA-B receptor antibodies and small-cell lung carci-
noma (33–70% of cases in published series) (Lancaster
et al., 2010; Boronat et al., 2011; Hoftberger et al.,
2013), so a proper evaluation for small-cell lung cancer
is indicated in these patients. Despite their association
with small-cell lung cancer, GABA-B antibodies were
only found in 1.7% of sera from patients positive for other
paraneoplastic antibodies predictive of small-cell lung
cancer in one study (Jeffery et al., 2013). Improvement
was seen in response to immunosuppressant treatment
with corticosteroids or IVIG in these patients in
75–90% (Lancaster et al., 2010; Hoftberger et al., 2013).
GABA-A RECEPTOR ANTIBODY
GABA-A receptor antibodies have been recently reported.
In this series, high titers of antibodies were found in CSF
from 6 patients with status epilepticus or epilepsy partialis
continua: 4 of them required pharmacologic coma (Petit-
Pedrol et al., 2014). Seizures were also common in a UK
study (Pettingill et al., 2015), but in both studies low titers
of GABA-A receptor antibodies were found in 3% of
patients presenting with a variety of neurologic syn-
dromes, some associated with GAD-65 antibodies.
AMPA RECEPTOR ANTIBODY
a-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic
acid (AMPA) receptor antibodies have been reported.
They usually present with limbic encephalitis. However,
2 patients in one series presented with psychosis, similar
to patients with NMDA receptor antibody positivity
(Graus et al., 2010). Seven of 10 reported in one series
occurred in association with a tumor; tumor types
included lung, breast, and thymus (Lai et al., 2009). In
this report, 90% responded to immunotherapy. Similar
to NMDA receptor antibodies, AMPA receptor anti-
bodies have been determined in vitro to cause a reduc-
tion in the number of AMPA receptor clusters on the
cell surface (Lai et al., 2009). Mesial temporal
Fig. 13.9. Clinical factors suggesting the diagnosis of an autoimmune epilepsy syndrome. Used with permission of Mayo Foun-
dation for Medical Education and Research. All rights reserved.
237
hypermetabolic abnormalities were described in FDG-
PET in 1 patient, and improved corresponding with clin-
ical improvement (Spatola et al., 2014).
GLYCINE RECEPTOR ANTIBODY
Glycine receptor antibodies typically present with a clinical
syndrome referred to as the progressive encephalomyeli-
tis, rigidity, and myoclonus (PERM) syndrome In the larg-
est published series of glycine receptor antibodies, 73%
presented with PERM (Carvajal-Gonzalez et al., 2014),
but seizures were present in around 10% and status epilep-
ticus has been reported in 2 patients (Zuliani et al., 2014).
Most treated patients responded to immunotherapy.
AUTOIMMUNE EPILEPSY: DIAGNOSTIC
AND THERAPEUTIC APPROACH
One-third of patients with epilepsy will not respond to
antiepileptic drug therapy. Of these, some may be candi-
dates for surgery, and some may benefit from other
treatments, such as ketogenic diet or stimulation
devices. For those who are not candidates for such treat-
ments, however, options are limited and the outlook can
be bleak. A primary goal in the evaluation of patients
with intractable epilepsy is to clarify the underlying eti-
ology and to treat that etiology if feasible in order to gain
control of the patient’s seizures. Identification of an
autoimmune etiology opens another avenue of therapy
for such patients, specifically immunotherapy, which
in some cases may be highly effective.
When to suspect an autoimmune epilepsy
syndrome
Clinical features that should suggest the possibility of an
autoimmune epilepsy syndrome are summarized in
Figure 13.9 and Table 13.2. Autoimmune epilepsy syn-
dromes often begin in an acute or subacute manner,
as opposed to gradual. Fever may be present at the onset
in some cases. A history of other autoimmune conditions
may also be present. Patients with autoimmune epilepsy
may also concurrently show signs of cognitive
238
Table 13.2
Clinical features suggestive of autoimmune epilepsy
Acute to subacute onset (maximal seizure frequency
3 months)
Multiple seizure types in same patient
Faciobrachial dystonic seizures
Antiepileptic drug resistance
Personal or family history (first-degree relative) of
autoimmunity
History of recent or past neoplasia
Viral prodrome
Evidence of central nervous system inflammation
● CSF (elevated protein, pleocytosis, oligloclonal bands, + CSF
index)
● MRI (mesial temporal or parenchymal T2 hyperintensity)
● Hypermetabolism on functional imaging (PET)
Detection of neural autoantibody
CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET,
positron emission tomography.
impairment, encephalopathy, significant psychiatric and
behavioral changes, movement disorder symptoms
(myoclonus, tremor, dyskinesia), and new uncharacteris-
tic headaches since onset of seizures. Seizure rates tend
to be significantly higher in autoimmune epilepsy syn-
dromes than in epilepsy due to other etiologies, often
occurring several times per day. In our series, 81% of
patients were experiencing daily seizures (Quek et al.,
2012). The seizures usually have features suggesting
involvement of the limbic regions, although extralimbic
seizures may also be present (Rudzinski et al., 2011).
The seizures in some patients may be brief and not
associated with loss of awareness. In such seizures, the
symptoms may consist primarily of aura-like phenomena
with rising and descending sensations, accompanied by
features suggesting autonomic involvement. Manifesta-
tions consistent with faciobrachial dystonic seizures
should prompt testing for VGKC–complex antibodies.
The EEG may be notably unremarkable during these
and other focal, brief seizures that may occur in associ-
ation with autoimmune epilepsy syndromes. This is even
true in cases of epilepsy partialis continua. Clearly,
however, more typical complex partial seizures, secondary
generalized tonic-clonic seizures, and nonconvulsive
complex partial status epilepticus also occur in these
patients, in which case ictal EEG abnormalities will
usually be present. Autoimmune epilepsy syndromes
may present with accompanying neurologic and nonneur-
ologic features that suggest a particular syndrome. For
example, the presence of features such as psychosis, agi-
tation, limb and oral dyskinesias, autonomic disturbances,
catatonia and respiratory failure, should suggest NMDA
receptor antibody-associated encephalitis. Similarly, the
J. BRITTON
presence of diabetes and vitiligo may suggest GAD-65
antibody positivity; hyponatremia may suggest VGKC–
complex antibodies; gastrointestinal dysmotility may
suggest ganglionic acetylcholine receptor antibodies;
occipital calcifications may suggest celiac disease, and
diffuse rhythmic delta on EEG should suggest NMDA
receptor antibodies. Similarly, the presence of bilateral
hippocampal swelling and increased FLAIR or T2 signal
hyperintensity in a patient with seizures suggests limbic
encephalitis, which should prompt evaluation for auto-
immune and, in some cases, paraneoplastic causes. Sim-
ilar signal changes in the basal ganglia may prompt
consideration of VGKC–complex encephalitis more spe-
cifically (Kotsenas et al., 2014). Also, medial temporal
FDG-PET hypermetabolic abnormalities are a finding
that is relatively unique to limbic encephalitis and, if pre-
sent in a patient with seizures, should raise suspicion of
an antibody-mediated etiology.
Evaluation of patients with suspected
autoimmune epilepsy
EEG is useful in the evaluation of patients suspected of
having autoimmune epilepsy syndromes. The EEG is
abnormal in over 90% of patients (Quek et al., 2012).
These include focal or diffuse slowing of the back-
ground, encephalopathic abnormalities such as triphasic
waves, interictal epileptiform abnormalities, and sei-
zures (Rudzinski et al., 2011). Also, subclinical seizures
contributing to cognitive deficits may be present, and
can be detected on EEG. Continuous EEG monitoring
can help more clearly determine the seizure frequency
in patients with autoimmune epilepsy syndromes. The
EEG may also serve a role in helping to monitor the
effects of treatment (Fig. 13.3).
Neuroimaging is important in order to help exclude
other causes of seizures, such as mass lesions, vascular
disorders, and other disease processes. Despite the char-
acteristic findings that can be seen on MRI at least in lim-
bic encephalitis cases, it is important to realize that
structural MRI may be normal in the autoimmune epi-
lepsies. In our autoimmune epilepsy series, for example,
MRI was nondiagnostic in 47% of cases (Quek et al.,
2012). Negative MRI is more the rule than the exception
in NMDA receptor encephalitis. Finally, FDG-PET may
show hypermetabolic abnormalities in the limbic and
basal ganglia structures in autoimmune epilepsy syn-
dromes, which are not typical for epilepsy due to other
etiologies. However, it should be noted that FDG-PET
may be unremarkable in these patients, and may also
show hypometabolic abnormalities, even in active auto-
immune epilepsy cases.
Serologic testing is critical in patients suspected
of having an autoimmune epilepsy syndrome. The
 AUTOIMMUNE EPILEPSY
identification of certain neural antibodies can help treat-
ment decisions, as clinical response to immunotherapy is
relatively well known and favorable for certain anti-
bodies. Conversely, the presence of certain other anti-
bodies (such as those targeting intraneuronal antigens)
and the lack of an antibody in otherwise suspicious cases
have been shown to correlate with a less satisfactory
response to treatment, which may prompt a pause prior
to initiation of treatment (Toledano et al., 2014). Another
role of serologic testing is to help make a judgment as
to the likelihood of the presence of an underlying
neoplasm. For example, the presence of ANNA-1 (anti-
Hu) and anti-GABA-B antibodies alone or in combination
with other antibodies should prompt evaluation for small-
cell lung carcinoma or other underlying neoplasm.
CSF examination may be indicated in order to exclude
other etiologies, such as herpes encephalitis and other
infectious meningoencephalitides. CSF may be tested
for the presence and titer of neural antibodies as well,
as neural antibodies may be absent in serum but present
in CSF, as reported in a few cases with NMDA and
GABA-B receptor antibody encephalitis, although very
rare with VGKC–complex antibodies. It should be real-
ized that the CSF may be unremarkable in other respects
(cells, protein, oligoclonal bands) in up to 60% of cases,
including those who respond to immunotherapy (Quek
et al., 2012).
Treatment of autoimmune epilepsy
syndromes
The diagnosis of an autoimmune etiology opens up the
potential for immunotherapy in affected patients.
Several publications referenced previously attest to the
dramatic response that can be observed in patients with
certain antibody-mediated epilepsy syndromes. Unfor-
tunately, there are no consensus guidelines for treatment
of patients with autoimmune epilepsy (see Chapter 10).
Immunotherapy options include corticosteroid therapy,
IVIG, plasmapheresis, rituximab, cyclophosphamide,
mycophenolate, and other agents. The results seen in a
consecutive group of patients with autoimmune epilep-
sies of a variety of types seen in our Autoimmune Neu-
rology and Epilepsy clinics are shown in Figure 13.6. The
treatment strategy we use in patients with a newly diag-
nosed autoimmune epilepsy syndrome is shown in
Figure 13.10. This strategy is more effective for certain
antibody-mediated autoimmune epilepsy syndromes
than others. In our experience and in that of other inves-
tigators, patients with antibodies directed at cell surface
antigens generally fare better than those with antibodies
targeting intracellular antigens and those associated with
T-cell autoimmunity (Dalmau, 2008).
239
The initial first-line therapy typically used in treat-
ment of autoimmune epilepsy is corticosteroid therapy.
Parenteral methylprednisolone is most commonly used;
however, no trials have been performed in order to deter-
mine if IV therapy is superior to oral. A typical dosing
strategy is administration of 1 gram of methylpredniso-
lone daily for 3–5 days, then weekly for 6–12 weeks. The
potential side effects of corticosteroid therapy are well
known and include weight gain, hypertension, hypergly-
cemia, insomnia, mood changes, and susceptibility to
opportunistic infections. For this reason, sulfamethoxa-
zole with trimethoprim is usually considered to prevent
Pneumocystis pneumonia. With long-term corticoste-
roid use, osteopenia can develop. To prevent this,
calcium and vitamin D supplementation is usually
advised. Another complication of chronic corticosteroid
use is aseptic necrosis of the hips, which should be con-
sidered in the event of the development of hip or groin
pain during treatment.
Another commonly used first-line therapy is IVIG
(Gelfand, 2012). The cost and attendant approval
requirements often involved make treatment with IVIG
challenging. IVIG is typically given at our institution at a
dose of 0.4 g/kg IV daily for 3–5 days, then weekly for
6–12 weeks. IVIG side effects include headache, hives,
low-grade fever, aseptic meningitis, hemolytic anemia,
venous thrombosis, and acute renal injury. IgA-depleted
IVIG therapy should be considered in IgA-deficient
patients to prevent the hypersensitivity reaction to IgA
that may occur in association with IVIG administration.
Plasmapheresis is sometimes used in autoimmune
encephalitis. It tends to be used in critically ill patients
in order to reduce autoimmune antibody levels quickly,
although its superiority to other treatments in this setting
has not been demonstrated. Plasmapheresis usually neces-
sitates placement of a special intravenous cannula into the
subclavian or internal jugular vein, which runs risks of
embolism, pneumothorax, and infection. It is also very
costly. There is no evidence establishing superiority of
plasmapheresis over corticosteroid or IVIG treatment.
Treatment typically proceeds as follows (Fig. 13.10).
Initially, a single first-line agent is selected and treatment
response assessed during weeks #6–12 of therapy. If treat-
ment is ineffective or not tolerated, one of the other first-
line treatments is usually tried instead. Once a first-line
therapy is deemed successful, the patient is reassessed
during weeks 6–12 to judge whether there has been a
response. If there is evidence of response, the dosage
interval is gradually increased, and consideration is given
to the initiation of oral chronic immunosuppressant ther-
apy, such as mycophenolate mofetil or azathioprine.
Unfortunately, these disorders are uncommon, and at this
time, there is not enough evidence to make a determina-
tion as to the advisability of chronic immunosuppressive
240 J. BRITTON

Fig. 13.10. Treatment approach in autoimmune epilepsy and antibody-mediated encephalitis. These treatment options have not
been established with randomized control trials and are not approved by the US Food and Drug Administration for this indication.
ANNA-1, type 1 antineuronal nuclear antibody; CRMP5, collapsin response mediator protein-5; Abs, antibodies; AE, autoimmune
epilepsy; NMDAR, N-methyl-D-aspartate receptor; VGKC, voltage-gated potassium channel; LGI1, leucine-rich glioma inacti-
vated 1 protein; CASPR2, contactin-associated protein-2; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
GABA-B, gamma-aminobutyric acid B; mGluR, metabotropic glutamate receptor; VGCC, voltage-gated calcium channel;
gAChR, neuronal ganglionic nicotinic acetylcholine receptor antibody; DPPX, dipeptidyl-peptidase-like protein-6; GAD-65,
glutamic acid decarboxylase 65 kD isoform; IVIg, intravenous immunoglobulin. Used with permission of Mayo Foundation
for Medical Education and Research. All rights reserved.

treatment. However, relapses have been described in
some antibody-mediated autoimmune epilepsy syn-
dromes, providing a rationale for their use.
If first-line therapies fail, second-line therapies can be
considered. Second-line treatments typically used include
rituximab and cyclophosphamide. Cyclophosphamide is a
cytotoxic agent which lyses lymphocytes, but which may
also affect myeloid cells. Potential side effects of cyclo-
phosphamide include alopecia, leukopenia, thrombocyto-
penia, abdominal discomfort, hematuria, peripheral
neuropathy, cardiotoxicity, interstitial lung disease,
opportunistic infection, and hematologic and solid tumor
malignancy. Rituximab is a monoclonal antibody that tar-
gets CD20 antigens, which serve as a specific marker for
antibody-producing B cells. Elimination of CD20 cells
leads to a significant reduction in antibody production
(Maloney, 2012). In treated patients, CD19 or CD20 lym-
phocyte counts can be followed in order to ensure a full
response has been achieved. Initial doses of rituximab are
associated with infusion-related hypersensitivity reactions
in 50%, such as urticaria, fevers, and chills. Ten percent
experience more serious reactions, including hypotension,
rigors, bronchospasm, and angioedema. Other potential
reactions include cardiac arrhythmia, acute coronary
syndrome, interstitial lung disease, bowel perforation,
Stevens–Johnson syndrome, and infection. Fulminant
hepatitis B reactivation can occur, so screening for
chronic hepatitis should be performed prior to treatment.
Neutropenia may occur in 3–27% of patients, and most
often develops 3–4 weeks posttreatment. Progressive mul-
tifocal leukoencephalopathy has been described in associ-
ation with rituximab use as well.
 AUTOIMMUNE EPILEPSY
SUMMARY
The clinical spectrum and understanding of autoimmune
epilepsy syndromes are expanding. Many challenges
remain with respect to diagnosis and treatment. Treat-
ment is highly efficacious in some autoimmune epilepsy
syndromes due to certain antibody types; however, it is
frustratingly ineffective in others. Improvements in the
understanding of immune mechanisms underlying all
forms of autoimmune epilepsy are needed in order to
devise more uniformly effective therapies.
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