HHS Public Access: Autoimmune Encephalopathies

HHS Public Access
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Ann N Y Acad Sci. Author manuscript; available in PMC 2016 March 01.
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Published in final edited form as:

Ann N Y Acad Sci. 2015 March ; 1338(1): 94–114. doi:10.1111/nyas.12553.
Autoimmune encephalopathies
Frank Leypoldt1,2, Thaís Armangue1, and Josep Dalmau1,3,4
1August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital
Clinic, University of Barcelona, Spain
2Institute
of Clinical Chemistry, Neuroimmunology Unit and Department of Neurology, University
Medical Center Schleswig-Holstein Campus, Kiel, Germany
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3Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
4Department of Neurology, University of Pennsylvania, Pennsylvania
Abstract
Over the last 10 years the continual discovery of novel forms of encephalitis associated with
antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and
treating disorders that were previously unknown or mischaracterized. We review here the process
of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders,
grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis,
several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune
encephalitides that result in psychosis, seizures, or abnormal movements are described in detail.
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We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing
link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the
caveats of limited serum testing are outlined. In addition, we review the underlying cellular and
synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The
multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery
that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some
patients may develop overlapping syndromes, including anti-NMDAR encephalitis and
neuromyelitis optica or other demyelinating diseases.
Keywords
autoimmune encephalitis; limbic encephalitis; anti-NMDAR antibodies; psychosis; treatment
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Corresponding author: Josep Dalmau, MD, PhD, IDIBAPS-Hospital Clínic, Universitat de Barcelona, Department of Neurology, c/
Villarroel 170, Barcelona, 08036 (Spain), and Department of Neurology, University of Pennsylvania Philadelphia, PA, USA,
[email protected].
Conflicts of interests
Dr. Dalmau holds patents for the use of Ma2, NMDAR, and GABAbR as autoantibody tests, and has patent applications for DPPX,
GABAaR, and IgLON5 as autoantibody tests; he receives royalties for Ma2, NMDAR, and GABAbR diagnostic tests. Dr. Dalmau has
a research grant from Euroimmun.
Leypoldt et al. Page 2
Introduction
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The encephalitides associated with antibodies against cell-surface or synaptic proteins are a
new category of diseases that occur with focal or widespread involvement of the nervous
system in association with antibodies against extracellular epitopes of neuronal cell-surface
or synaptic proteins.1 The discovery of this group of disorders—referred in this review as
autoimmune encephalitis—has affected many fields of medicine, resulted in changed
paradigms for the diagnostic and treatment approaches to some neuropsychiatric disorders,
and reclassified syndromes previously defined as idiopathic or with descriptive terms.1 In
addition, the study of these disorders has revealed novel mechanisms of how antibodies
might alter memory, behavior, and cognition or cause psychosis, seizures, or abnormal
movements (Fig. 1).2,3
The concept that autoimmunity mediated by antibodies or cytotoxic T-cell mechanisms can
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cause neurological symptoms is not new. The myasthenic syndromes are good examples of
how autoantibodies can cause neurological symptoms; in myasthenic syndromes
autoantibodies against acetylcholine receptor or voltage-gated calcium channels cause
reversible muscle weakness by altering the normal function of the neuromuscular
junction.4,5 As another example, some paraneoplastic syndromes such as cerebellar
degeneration or limbic encephalitis are associated with highly specific antibodies against
intracellular neuronal proteins and aggressive cytotoxic T cell responses that usually lead to
irreversible deficits.6
In contrast to classical paraneoplastic syndromes, the novelty of the autoimmune

encephalitides reviewed here is that they can affect patients of all ages, some of them
preferentially occurring in children and young adults;7-9 they can develop with or without an
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underlying tumor; they are associated with antibodies that target extracellular epitopes of
cell-surface or synaptic proteins; and for the disorders which underlying mechanisms have
been investigated, the antibodies alter the structure or function of the target antigen.2,10 In
addition, the associated syndromes often respond to immunotherapy, resulting in substantial
or complete recovery in 70–80% of the patients.11 Owing to the severity and duration of
symptoms, before these disorders were known the clinical recovery of similar patients was
not expected, thus changing our concepts about supportive therapy today in cases that would
have been considered futile in the past.12,13
Antibodies and target antigens

In 2005, the description of six patients with different forms of encephalitis, with antibodies
against neuronal cell surface proteins, marks the beginning of the molecular identification
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and understanding of these disorders.14 Until then, the only cell-surface antibodies
associated with autoimmune encephalitis (specifically, limbic encephalitis and Morvan’s
syndrome) were attributed to antibodies specific for the Kv1.1 and Kv1.2 subunits of the
Shaker family of voltage-gated potassium channels (VGKCs).15,16 (This was later shown to
be incorrect; discussed below). One of the six patients had been diagnosed with the Kv1.1-
and Kv1.2-specific antibodies, but in the other five cases the neuronal targets were
unknown. Remarkably, all of the patients improved substantially with immunotherapy and,
when appropriate, removal of the associated tumors (two had teratomas and two had tumors
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of the thymus).14 This improvement, when compared with the limited treatment response of
classic paraneoplastic syndromes17-20 led investigators to distinguish a new category of
autoimmune encephalitis. In subsequent studies, the unknown cell surface antigens were
immunoprecipitated and found to be synaptic receptors, including the N-methyl-D-aspartate
receptor (NMDAR),21 the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor
(AMPAR),22 or the γ-amino-butyric acid B-receptor (GABAbR).23 Similar strategies
showed that the antibodies originally attributed to the Shaker family of VGKCs were in fact
directed against other proteins, including leucine-rich, glioma-inactivated 1 (LGI1)24 and
contactin-associated protein-like 2 (Caspr2).25,26 Since 2005, the frequency of discovery of
novel syndromes and their associated autoantigens has been 1–2 per year (Table 1).
Many patients with autoimmune encephalitis have a propensity to autoimmunity, including

multiple serum antibodies that are unrelated to patients’ symptoms (e.g., thyroid peroxidase
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(TPO) antibody or antinuclear antibodies (ANA)).22,27 These encephalitis-irrelevant

antibodies are usually absent in in the cerebrospinal fluid (CSF), which provides a clean
source of disease-relevant antibodies for preliminary antigen characterization. Detection of
CSF reactivity with the neuropil of brain along with immunolabeling of the cell surface of
cultured neurons strongly suggests a pathogenic link between the antibodies and patients’
symptoms. The techniques more frequently used to eventually characterize antigens include
immunoprecipitation (nine of eleven antigens shown in Table 1, Fig. 1) 1,22 and screening of
candidate antigens according either to patients’ symptoms or the investigator’s hypothesis
(four of eleven; two of them, LGI1 and Caspr2, also identified by precipitation).8,28
General clinical features of autoimmune encephalitis

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At disease onset, there is substantial overlap of symptoms among the different types of
autoimmune encephalitis. The rapid development of symptoms in a few days or weeks,
sometimes with headache or mild hyperthermia, and frequent CSF pleocytosis often lead to
empiric antiviral or bacterial treatments while CSF and blood work for infectious, metabolic,
and toxic causes are processed.29,30 Alteration of mood, behavior, and memory, decreased
level of consciousness, and seizures occur in most types of autoimmune encephalitis;
however, the severity and predominance of some symptoms over others, and the presence of
other features (e.g., dyskinesias, severe psychiatric manifestations, facio-brachial dystonic
seizures, hyponatremia, diarrhea) along with demographic information (sex, gender, race),
brain MRI findings, and presence or absence of a tumor can suggest a specific disorder.
Sleep dysfunction, nearly constant in all forms of encephalitis, has been studied in detail in
only two disorders, anti-LGI1 encephalitis31 and the recently reported encephalopathy with
IgLON5-specific antibodies32 (discussed below).
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The electroencephalogram (EEG) is almost always abnormal in all types of autoimmune

encephalitis, showing focal or diffuse slow activity frequently associated with one or several
foci of epileptic activity. Except for a pattern referred to as extreme delta brush that may
occur in patients with anti-NMDAR encephalitis, there are no pathognomonic EEG
abnormalities for any other forms of autoimmune encephalitis.33,34 Magnetic resonance
imaging (MRI) of the brain is very useful in patients with limbic encephalitis (see below),
usually showing increased FLAIR/T2 signal involving one or both temporal lobes, without
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contrast enhancement (Fig. 2). Similar findings can occur in patients with herpes simplex
encephalitis (HSE) or medial temporal lobe seizures, but the pattern of highly selective
medial temporal lobe involvement is limited to a few other disorders (e.g., paraneoplastic
limbic encephalitis,35 rare cases of lupus,36 neurosyphilis,37 Sjogren’s syndrome,38 or
HHV6 infection39).
At symptom presentation, about 80% of patients with autoimmune encephalitis have mild-
to-moderate CSF lymphocytic pleocytosis (usually <100 white blood cells/μl), 30% have
mild-to-moderate increase of protein concentration, and 50–60% have oligoclonal bands.
These bands can be present even when routine CSF studies are normal. In contrast to most
autoimmune encephalitis, the limbic encephalitis associated with LGI1-specific antibodies
frequently occurs with normal or minimal CSF findings.40
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Specific syndromes
Anti-NMDAR encephalitis
The encephalitis associated with NMDAR-specific antibodies has been described in large
series of patients41-44 and a recent review.45 This disorder is characterized by CSF IgG
antibodies against the GluN1 subunit of the NMDAR. The disease usually occurs in young
adults and children, predominantly women, although it can affect patients of all ages. In a
population-based study in England examining causes of autoimmune encephalitis, anti-
NMDAR encephalitis was second only to acute demyelinating encephalomyelitis
(ADEM).46 In a referral center focused in the study of encephalitis of unclear etiology, the
incidence of anti-NMDAR encephalitis was higher than any individual viral encephalitis.30
One percent of young patients (18–35 years) admitted to the intensive care unit of a large
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German center for encephalitis of unknown origin were in retrospect found to have
NMDAR-specific antibodies.47
In a series of 577 patients (81% female), the median age was 21 years, 37% were younger
than 18 years and 5% older than 45.42 The frequency of males was higher in age groups
below 12 years (39%) and above 45 (43%). Thirty eight percent of the patients (representing
46% of all women) had an underlying neoplasm. The presence of a tumor predominated in
patients between 12 and 45 years. Only 6% of females younger than 12 years and 6% of
males (all adults) had a tumor. Ninety four percent of the tumors were ovarian teratomas,
2% extraovarian teratomas, and 4% other tumors.
The syndrome was established in 2008 in a series of 100 patients,41 and since then the
spectrum of symptoms has not changed substantially (Fig. 3).42,43 Approximately 70% of
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the patients develop prodromal symptoms, such as headache or fever, that are usually
followed by rapid change of behavior that may include anxiety, agitation, insomnia,
aggression, visual or auditory hallucinations, paranoia, grandiose delusions, hyper-
religiosity, sexual disinhibition, mania, psychosis, or catatonia. The prominence of the
psychiatric symptoms contributed to the initial identification of this disorder48 and has
recently led to a surge of interest in psychiatry49,50 (discussed below in the section
“Psychiatry”). These symptoms are usually followed by a wide range of abnormal
movements that may include orofacial dyskinesias, chorea, athetosis, ballismus,

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myorhythmia, stereotyped movements, rigidity, or opisthotonus.7,51-53 As the symptoms

progress there is decreased consciousness, stupor, coma, periods of agitation alternating with
catatonia, autonomic dysregulation such as fluctuation of blood pressure, hyperthermia,
sialorrhea, tachycardia, hypoventilation, and, less frequently, bradycardia, cardiac pauses, or
ictal asystole that may require transient use of a pacemaker.54-56 Seizures and complex
status epilepticus may occur at any stage of the disease,57 but almost always resolve after
other symptoms improve, not requiring chronic antiepileptic therapy.13 Seizures, as initial
presenting symptom, are more frequent in adult male patients than in women.43,58
Brain MRI is normal in 66% of NMDAR encephalitis patients;42 the other 34% have
nonspecific cortical or subcortical FLAIR/T2 abnormalities, sometimes involving posterior
fossa or medial temporal regions, often with small areas of demyelination, and in a few
cases with extensive demyelinating abnormalities59 (discussed in the section below
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“Overlapping syndromes”).
The average hospital admission is 3 months, but many patients require longer admissions in
rehabilitation centers.60 During recovery and after the acute symptoms have resolved
patients continue with deficits of memory and attention, impulsivity, behavioral
disinhibition, and executive dysfunction that usually improve over many months. In a
prolonged follow up of 501 patients, 81% had a modified Rankin scale score of 0–2 at 24
months, and some continued to improve thereafter.42 The mortality rate is approximately
7%, with most deaths occurring during the stage of intensive care support.
The presentation of NMDAR encephalitis in children with behavioral abnormalities may

initially suggest autistic regression, early onset schizophrenia, or childhood disintegrative
disorder.61,62 Compared with adults, children more often present initially with abnormal
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movements or seizures, and then in the ensuing days or weeks progress to develop a
syndrome similar to that of the adults.7,34,63 In patients older than 45 years, the clinical
picture is similar to that of younger patients, but the outcome is less favorable. In this age
group, 23% of patients had an underlying tumor (carcinomas instead of teratomas), and
delays in diagnosis and treatment were more frequent than in younger patients.64 For any
age group, monosymptomatic cases such as isolated abnormal movements,65,66 psychosis,67
or seizures are extremely rare.68
Owing to the protracted clinical course, complexity of symptoms and complications, and
loss of weight and deconditioning, many different specialists are involved in the care of
these patients. Approximately 50% of patients respond to first line immunotherapies
(intravenous immunoglobulins (IVIg), steroids, or plasma exchange) and the other 50%
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require second line therapies, such as rituximab or a combination of rituximab and

cyclophosphamide.42 Relapses occur in 12–20% of cases (12% during the first 24 months of
the disease),often presenting as fragments of the syndrome (perhaps due to prompt
diagnosis), and respond to immunotherapy.69 Overall, these data, and the fact that patients
that receive second line immunotherapies have fewer relapses, is leading many physicians to
use rituximab initially. Patients who do not respond to treatment, or who have relapses,
should be reassessed for the presence of an underlying12,13 contralateral or recurrent

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teratoma.70
Limbic encephalitis
Three neuronal cell–surface antibodies are associated with limbic encephalitis, anti-
LGI1,24,25 anti-GABAbR,23 and anti-AMPAR.22
The encephalitis associated with LGI1 antibodies—This limbic encephalitis

predominantly affects middle age or elderly patients, males more frequently than females
(2:1), and presents with prominent short-term memory deficits, confusion, and frequent
seizures.24,25 About 60% of the patients have hyponatremia and some patients have
preceding or concomitant myoclonic-like jerks in the face, arm, or leg—described as facio-
brachial dystonic or tonic seizures.71,72 Recognition and treatment of these seizures with
immunotherapy may prevent development of the encephalitis and cognitive dysfunction.73
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A study showed that five of six patients with limbic encephalitis and LGI1-specific
antibodies had rapid eye movement (REM) sleep behavior disorder; in three patients these
symptoms improved along with those of limbic encephalitis after immunotherapy, while in
two the sleep disorder persisted.31 Some patients with LGI1-specific antibodies develop
confusion and cognitive decline over a few months, suggesting more a rapidly progressive
dementia than subacute encephalitis. Creutzfeldt-Jakob disease (CJD) has been suspected in
some of these patients,74 although CJD patients do not have LGI1-specific antibodies (see
below).
The presence of LGI1 rarely associates with systemic tumors; when it does there is usually
an associated thymoma.24,25 Recent studies indicate the importance of differentiating LGI1
antibodies, as well as Caspr2 antibodies (both previously considered VGKC antibodies),
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from other antibodies referred to under the term VGKC-complex antibodies. While LGI1 and
Caspr2 antibodies (discussed below) specifically associate with limited subsets of
syndromes, the identity of other VGKC-complex antibodies is unknown (it is also unknown
if the antigens are on the cell surface); the VGKC-complex antibodies also have limited
specificity and may be found in non-autoimmune diseases, including Creutzfeldt-Jakob
disease (CJD), among others.75,76 In contrast, a study of CSF from 49 patients with
pathologically confirmed CJD showed that none had anti-LGI1, anti-Caspr2 or other well-
defined cell-surface antibodies.77 The same study found that among 346 patients with
suspected CJD, 6 (1.7%) had autoimmune disorders that responded well to immunotherapy.
The encephalitis associated with GABAbR antibodies—This limbic encephalitis

usually develops as limbic encephalitis.23 Two recent series,78,79 including a total of 37
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patients, showed in the majority of cases typical clinical and MRI involvement of the limbic
region along with early and frequent seizures. This autoimmunity is the most frequent cause
of limbic encephalitis in patients with small cell lung cancer (SCLC) and who are negative
for Hu antibodies.80 About 50% of patients with GABAbR antibodies have SCLC or
neuroendocrine tumors; the other 50% do not have an underlying cancer. Among patients
with SCLC and limbic encephalitis, those with GABAbR antibodies have a much better
outcome than those with Hu antibodies,81 reflecting the better response to immunotherapy
of patients with syndromes pathogenically associated with auto-reactive antibodies rather

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than cytotoxic T cell mechanisms.78,82 There are only a few cases of patients with GABAbR
antibodies and symptoms different from limbic encephalitis, including cerebellar ataxia83
and brainstem encephalopathy;84 and one child with overlapping GABAaR antibodies
developed confusion, chorea, opsoclonus, and ataxia.85
The encephalitis associated with AMPAR antibodies—Anti-AMPAR limbic

encephalitis was initially described in 2009.22 Patients develop symptoms and MRI features
of limbic encephalitis, but in some cases the presentation is purely psychiatric, with
confusion, agitation, and aggressive behavior. In two patients with isolated psychiatric
symptoms, the CSF and MRI were normal, but the EEG was abnormal.86 In a series of 10
patients (9 women), 7 had thymoma or cancer of the lung or breast. Additional antibodies,
such as anti-ANA, anti-TPO, anti-GAD65, or other autoimmune disorders (e.g.,
hypothyroidism) co-occur frequently.22 Symptoms usually respond to immunotherapy,
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although relapses are frequent. The severe memory deficits and confabulations complicate
the management of these patients, who may gradually develop cumulative deficits after each
relapse.
Other syndromes and autoantibodies to cell surface antigens or synaptic receptors

Morvan’s syndrome—This is a disorder that includes symptoms of encephalitis, such as
amnesia, confusion, hallucinations, sleep and autonomic dysregulation, in association with
peripheral nerve hyperexcitability, or neuromyotonia. Morvan’s syndrome and
neuromyotonia were previously considered associated with antibodies against the Shaker
family of VGKCs,15 but the serum and CSF of these patients do not react with Kv1.1 or
Kv1.2 subunits of the these channels. Instead, many patients with Morvan’s syndrome,87,26
and only a few with neuromyotonia,88 have antibodies against Caspr2, a protein expressed
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in the CNS and at the juxtaparanodal region of myelinated nerves where it is associated with
potassium channels. Patients with Caspr2 antibodies may also develop neuropathic pain,
encephalitis without symptoms of peripheral neuropathy, or, rarely, limbic encephalitis.26,87
The frequency of an underlying tumor (thymoma) varies substantially (0–40%) among
series, likely reflecting referral bias, and appears to depend more on the syndrome than the
antibody. For example, among patients with Caspr2 antibodies, those with Morvan’s
syndrome appear to more frequently have thymomas87 compared to those with
encephalitis.26 Immunotherapy is usually effective.
The Ophelia syndrome—This is a form of autoimmune encephalitis that occurs in

patients with Hodgkin’s lymphoma.89 The syndrome is often described as limbic
encephalitis, but in fact the clinical picture and MRI studies suggest a more diffuse
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encephalitis. Symptoms include depression, agitation, hallucinations, memory deficits,

delusions, and bizarre behavior. The disorder is extremely rare, and all cases studied
recently had antibodies against the metabotropic glutamate receptor 5 (mGluR5), which is
highly expressed in the hippocampus.90,91 A similar syndrome can occur without Hodgkin’s
lymphoma. The importance of recognizing this disorder is that patients have complete
recoveries after treatment of the tumor or immunotherapy. Patients with Hodgkin’s
lymphoma can also develop cerebellar degeneration, in which case the antibodies are against
mGluR1, which is highly expressed in cerebellum.92,93 It is unclear why these two mGluRs
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that belong to the same group of mGluR (group 1), and none of the six receptors that belong
to other groups (group 2 and 3), associate with CNS autoimmune disorders and Hodgkin’s
lymphoma.
Progressive encephalomyelitis with rigidity and myoclonus (PERM)—PERM is

a disorder that results from predominant brainstem and spinal cord dysfunction as a result of
immune-mediated disruption of inhibitory pathways. Recent studies showed that patients
with PERM often have antibodies to the α1 subunit of the glycine receptor (GlyR).28,94 A
few patients have been found to have thymoma or other tumors, but most patients do not
have cancer. Different from patients with stiff-person syndrome who rarely have
encephalopathy or prominent brainstem symptoms, 40–50% of patients with PERM have
ocular movement deficits, cranial nerve paresis, brainstem dysfunction, and encephalopathy,
and 30% have autonomic dysregulation. Hyperekplexia is also a frequent symptom of this
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disorder. In a retrospective study of 52 patients, the median age was 50 years, and four were
younger than 15 years of age. After a median follow-up of 3 years most patients had
substantially improved with immunotherapy, but four (9%) died during the course of the
disease.95 The authors concluded that GlyR antibodies strongly associate with spinal and
brainstem dysfunction. However, studies with a large number of disease control groups
show that these antibodies occur in a variety of disorders, including stiff-person syndrome,
limbic encephalitis, cerebellar degeneration, or optic neuritis.96 GlyR antibodies can overlap
with GAD65 antibodies.97,98
The most recent neuronal cell–surface autoantigen associated with PERM is dipeptidyl-
peptidase-like protein-6 (DPPX).99 Patients with antibodies to DPPX more frequently
develop a syndrome of CNS hyperexcitability (discussed below).100 The three cases
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reported with PERM, all younger than 30 years of age, developed prominent hyperekplexia,
a wide range of cerebellar-ocular movement abnormalities, ataxia, and muscle stiffness and
spasms (triggered by acoustic and tactile stimuli sometimes as mild as a gentle breeze). Two
of the patients had prominent gastrointestinal symptoms, a common feature of DPPX
autoimmunity. Two patients responded to immunotherapy; the third patient was diagnosed
retrospectively, developed spastic tetraparesis, and died of pneumonia that was a
complication of severe dysphagia. PERM-like symptoms may occur in some patients with
antibodies against the intracellular proteins Nova 1 and 2 (anti-Ri or ANNA2 antibodies).101
These antibodies associate with brainstem encephalitis or encephalomyelitis frequently
accompanied by opsoclonus, other ocular movement disorders,102 and sometimes life
threatening laryngeal spasms.103 In contrast to GlyR and DPPX antibody-associated
syndromes, anti-Ri associated encephalitis is likely mediated by cytotoxic T cells.
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Stiff-person syndrome—This syndrome comprises a clinical picture characterized by

muscle rigidity and spasms that may occur spontaneously or are triggered by several types
of stimuli (e.g., tactile, auditory, emotional upset). The disorder predominantly affects axial,
low back, and proximal muscles of the extremities. Electromyography (EMG) of the
involved muscles shows continuous motor unit activity as a result of dysfunction of the
inhibitory GABAergic system; symptoms and EMG findings improve with diazepam. Most
patients have high titers of GAD65 antibodies and may develop overlapping cerebellar
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symptoms in association with endocrinopathy (diabetes, thyroid dysfunction).104 The reason

why antibodies against GAD65 (an intracellular protein) associate with different symptoms,
including seizures or limbic encephalitis, is unknown.105,106 Patients with GAD65
antibodies usually do not have underlying tumors.
In addition to GAD65 antibodies, some patients with stiff-person syndrome develop GlyR
antibodies.98 In children the disorder is frequently misdiagnosed.97 Another study identified
four patients with stiff-person syndrome and low titer serum antibodies to GABAaR; three
of the patients had been previously considered seronegative and one had coexisting GAD65
antibodies.27 High CSF or serum GABAaR antibody titers associate with prominent seizures
and status epilepticus (discussed below).
About 5% of patients with stiff-person syndrome have SCLC or breast cancer; these patients
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usually develop amphiphysin antibodies instead of GAD65 or GlyR antibodies.107,108

Amphiphysin is a vesicular synaptic protein involved in endocytosis; although the protein is
not expressed on the neuronal cell surface, it has been suggested that during the process of
synaptic vesicle uptake amphiphysin is exposed on the cell surface and can be accessed by
antibodies. Amphiphysin antibodies also occur with paraneoplastic myelitis or
encephalomyelitis.109
Encephalitis associated with DPPX antibodies—Anti-DPPX encephalitis results in

symptoms of CNS hyperexcitability, including agitation, hallucinations, paranoid delusions,
tremor, myoclonus, nystagmus, seizures, and, sometimes, hyperekplexia.100 The disorder
was initially reported in four patients (45–76 years old, 2 males), three of whom had
prodromal diarrhea that led to substantial loss of weight. The target antigen, DPPX, is a cell
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surface auxiliary subunit of the Kv4.2 Shal potassium channel family. DPPX increases the
function of Kv4.2 channels, which are involved in somatodendritic signal integration and
attenuation of dendritic back propagation of action potentials. Although the encephalopathy
of patients with DPPX antibodies does not conform to a specific syndrome, the symptoms of
CNS hyperexcitability are consistent with the increased excitability noted in
electrophysiological studies of Dppx-deficient (Dpp6−/−) mice.110 The cause of the diarrhea
and other gastrointestinal symptoms is unknown, but DPPX is expressed in neurons of the
myentheric plexus that strongly react with patients’ antibodies. Overall, the disorder is
severe, resulting in lengthy hospitalization or multiple relapses that usually occur while
immunotherapy is decreased.
Encephalitis with antibodies to γ-amino-butyric acid A-receptor (GABAaR)—

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Anti-GABAaR encephalitis associated with prominent seizures and status epilepticus with
extensive cortical and subcortical FLAIR/T2 signal abnormalities that may appear, while
other abnormalities resolve (Fig. 2D).27 These MRI findings are rarely encountered in the
other autoimmune encephalitis mentioned above. In a recent study of 18 patients, six with
high CSF or serum antibody titers (ages 3–63 years, median 22, five males) developed
refractory seizures, status epilepticus, or epilepsia partialis continua, four of them required
pharmacological coma. Patients responded to immunotherapy, but two died of sepsis during
intensive care management of the seizures. The 12 patients without CSF antibodies (all with
low serum titers) developed a broader spectrum of symptoms likely indicative of coexisting
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autoimmune disorders; six patients had encephalitis with seizures, two opsoclonus, and four
stiff-person syndrome (discussed above).27
Basal ganglia encephalitis and antibodies to dopamine (D2) receptor—This

encephalitis and anti-D2 antibodies were recently reported in 12 children who developed
several types of movement disorders sometimes co-existing in the same patient, including
dystonia, tremor, oculogyric crises, parkinsonism, and/or chorea.8 Agitation, anxiety,
psychosis, and sleep dysfunction were frequent accompaniments. The brain MRI was
normal in 50% of the patients; when abnormal, the findings were localized to the basal
ganglia. Responses to immunotherapy were observed, but residual motor, cognitive, and
psychiatric deficits were common. Antibodies to the D2 receptor were also identified in a
subset of patients with Sydenham chorea, as reported by other investigators.111 The
frequency of these antibodies in patients with encephalitis associated with abnormal
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movements is low; in our experience with 120 patients, mostly children, with encephalitis
and abnormal movements or basal ganglia MRI abnormalities all were negative for D2
receptor antibodies (Armangue et al., data unpublished).
A novel link between autoimmunity and neurodegenerative disorders: encephalopathy and

IgLON5 antibodies
This disorder differs in many ways from the autoimmune encephalitides described above. In
contrast to the subacute presentation of most encephalitis, the clinical picture of patients
with IgLON5 antibodies may evolve over years.32 The syndrome was recently described in
eight patients (age 52–76 years of age, median 59 years; 5 women) and includes abnormal
sleep movements and behaviors, with obstructive sleep apnea, and stridor. Accompanying
symptoms preceding or developing after the core syndrome included dysarthria, dysphagia,
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ataxia, or chorea. In six patients, the median duration of the disease was 5 years (2–12
years); the other two patients had a subacute presentation and died within 6 months of
symptom onset. In all cases studied, polysomnography revealed abnormal sleep architecture,
undifferentiated non-REM sleep or poorly structured stage N2, simple movements and
finalistic behaviors, normalization of non-REM sleep by the end of the night, and REM
sleep behavior disorder. All patients had antibodies (IgG4) against IgLON5, a neuronal
specific cell adhesion molecule with unknown function. Four of four Spanish patients had
the HLA-DQB1*0501 and HLA-DRB*1001 alleles that are very uncommon among the
Spanish population. Symptoms did not respond to immunotherapy, and six patients had died
by the time of publication. Two patients had autopsy that showed an atypical neuronal
tauopathy with predominant involvement of the hypothalamus and tegmentum of the
brainstem, without signs of inflammation. Moreover, no inflammatory changes were
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identified in the patients’ CSF, leaving it unclear at whether there is an inflammatory

response that is subtle and transient or there is no inflammatory process at all. This disorder
suggests an intriguing link between autoimmunity and neurodegeneration.
Mechanisms of disease
For anti-NMDAR encephalitis the pathogenic role of GluN1 IgG antibodies has been
established in cultures of neurons and after hippocampal and cerebroventricular infusion into
rodents of patients’ antibodies (Fig. 4).41,112 Using cultured neurons, patients’ antibodies
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caused crosslinking and selective internalization of NMDARs that correlated with the
antibody titers; these effects were reversible after removing the antibodies.113,114 In contrast
to the intense effects on NMDAR, patients’ antibodies did not alter the localization or
expression of other synaptic proteins, number of synapses, dendritic spines, dendritic
complexity, or cell survival. In other experiments, the density of NMDAR was also
significantly reduced in the hippocampus of rats infused with patients’ antibodies, a finding
similar to that observed in the hippocampus of autopsied patients.113 More recently,
Mannara and colleagues developed a murine model of passive transfer of memory and
behavioral deficits using continuous ventricular infusion (14 days via osmotic pumps) of
CSF from patients with anti-NMDAR encephalitis. Analyses of hippocampus from the mice
showed progressive antibody binding over time and a decrease of total and synaptic
NMDARs, without affecting PSD95 or AMPAR. These effects gradually improved after
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stopping the antibody infusion, with reversibility of symptoms accompanied by restoration

of NMDAR levels, establishing the pathogenicity of the antibodies (Fig. 4H).115
For the disorders associated with AMPAR or GABAaR antibodies, studies on pathogenicity
have been conducted with cultured neurons, each antibody producing selective
internalization of the corresponding receptor. Patients’ AMPAR antibodies caused a
decrease of the receptors at synaptic and extrasynaptic sites, along with reduction of
AMPAR-mediated miniature excitatory postsynaptic currents using whole-cell patch
recordings.22,116 On the other hand, patients’ GABAaR antibodies selectively eliminated the
receptors from synapses but did not alter the number of extrasynaptic receptors.27
Different from the above cell membrane and synaptic receptors, LGI1 is a secreted protein
that interacts with the presynaptic receptor ADAM23 and the postsynaptic receptor
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ADAM22, organizing a trans-synaptic complex that includes presynaptic Kv1.1 potassium

channels and postsynaptic AMPAR (Fig. 5).24 Lgi1-deficient (Lgi−/−) mice develop a lethal
epileptic phenotype characterized by myoclonic seizures.117 In these mice, the increase of
neuronal excitability has been attributed to a decrease in AMPAR function in inhibitory
neurons, and to an increase in glutamate release.117,118 Although it is unknown how LGI1
antibodies result in limbic encephalitis, a recent study using cultured neurons showed that
patients’ antibodies interfered with the LGI1–ADAM interaction and decreased the levels of
postsynaptic AMPARs.119
The effects of patients’ GlyR and dopamine D2 receptor antibodies have been examined in
vitro in HEK cells expressing these receptors; the studies showed antibody-mediated
internalization of the corresponding receptors.8,95 It is not currently known if similar effects
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apply to neurons in vivo.
Autoimmune encephalitis in other disciplines

Information on autoimmune encephalitis in other disciplines is summarized in Figure 6.
Psychiatry
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That patients with anti-NMDAR encephalitis and other autoimmune encephalitis frequently
present with psychosis, affective dysregulation, and other behavioral abnormalities has
fueled interest in autoimmunity as potential cause of some psychiatric illness.49,50,120 One
study reported finding NMDAR antibodies in serum of 3 of 46 (6%) patients with first onset
of schizophrenia; the target subunit (e.g., GluN2 versus GluN1) was not determined and
only one of the patients appeared to improve after immunotherapy.121 Another study
included serum obtained at symptom presentation by 80 patients with first onset psychosis
who, one year later, met the DSM-IV-TR criteria for schizophrenia-spectrum illness. GluN1
IgG antibodies were not detected in any of the 80 cryopreserved sera;122 these findings were
consistent with those of another smaller study of patients with schizophrenia.123
Another study examined the prevalence of NMDAR antibodies in the sera from 121 patients
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with an initial diagnosis of schizophrenia, 108 with other psychiatric disorders, and 230
healthy subjects.124 Two patients had GluN1 IgG antibodies, and retrospectively both were
diagnosed with anti-NMDAR encephalitis (both had prominent dyskinesias, abnormal
movements, autonomic dysfunction, and EEG abnormalities). None of the other patients had
IgG GluN1 antibodies, though they did have other antibodies, mostly IgA or IgM against
GluN1 identified in 8% of patients with schizophrenia and 3% with major depression. In a
subsequent study, the same investigators found IgA or IgM antibodies in 16% of patients
with several types of dementia and 7% of normal subjects.125 More recently, Hammer and
colleagues examined 2817 subjects, including 1325 healthy subjects and 1492 patients with
schizophrenia, Parkinson disease, or affective-disorders, for the presence of serum
antibodies against GluN1 subunit of the NMDAR.126 In this study, 10.5% of all subjects
(patients and healthy controls) were seropositive for IgA or IgM antibodies; only 0.6% had
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IgG antibodies. The authors hypothesized that schizophrenic individuals with history of
blood–brain barrier (BBB) disturbance (e.g., neurotrauma at birth or thereafter) were more
likely to have more pronounced neurological symptoms when NMDAR antibody positive;
however, the authors did not show evidence of BBB disruption or the presence of antibodies
in the CSF.127
Overall, these studies demonstrate limited clinical significance of serum IgA or IgM
NMDAR antibodies in patients with psychiatric illness, given that a similar proportion of
healthy subjects or disease controls had the same antibodies. In contrast, the absence or rare
detection of GluN1 IgG antibodies suggests the specificity of these antibodies for anti-
NMDAR encephalitis. Future investigations should include CSF analysis, comprehensive
autoantigen characterization, and determination of antibody isotypes and subunit targets
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(e.g., GluN1 versus GluN2). The importance of antigen specification is shown in patients
with antibodies attributed to VGKC-complex proteins but whose target antigens are in fact
unknown. Antibodies to these unknown antigens have been detected in a few patients with
schizophrenia,121 though they were also found in a number of non-autoimmune disorders,
raising the question of significance.75
Herpes simplex encephalitis (HSE) as trigger of synaptic autoimmunity

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The clinical course of HSE is usually monophasic, but 14–26% of patients develop relapsing
symptoms a few weeks after the infection has resolved.128,129 These relapsing symptoms
have been attributed to (1) viral relapse characterized by the demonstration of HSV by
polymerase chain reaction (HSV-PCR) in the CSF, MRI findings of new necrotic lesions,
and response to acyclovir or (2) a disorder of unclear etiology without evidence of HSV
reactivation, absence of new necrotic lesions, and no response to acyclovir.130 This
complication occurs more frequently in children than in adults, and the clinical picture is
usually different from that related to the initial episode of viral encephalitis. In fact, most
children develop chorea, orofacial dyskinesias, dystonia, or ballismus, accompanied by
agitation, aggression, sleep dysfunction, seizures, or decrease of level of consciousness.131
This constellation of symptoms led physicians to coin the term choreoathetosis post-HSVE
to describe this complication.2,132 A similar disorder occurs in adults, but abnormal
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movements are infrequent.132 The observation that some patients with HSE developed IgG
antibodies against the GluN1 subunit of NMDAR,133 and subsequent studies of children
with choreoathetosis post-HSVE,34 revealed that this complication is in fact anti-NMDAR
encephalitis.134 A recent study showed that patients who developed this complication were
NMDAR antibody negative at the time HSE was diagnosed and then developed serum and
CSF antibodies in the ensuing 2–6 weeks, leading to anti-NMDAR encephalitis.135 The
same study demonstrated that HSE is a robust trigger of autoimmunity to other cell surface
or synaptic proteins (antigens still unknown), and another study showed antibodies to
dopamine D2 receptor in two patients.136 The identification of HSE as trigger of anti-
NMDAR encephalitis has been confirmed by multiple investigators over a short period of
time,137-140 suggesting this complication may be more common than previously reported as
choreoathetosis post-HSVE. Diagnosing anti-NMDAR encephalitis post-HSE is important
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because patients usually respond to immunotherapy.
Reclassification of disorders
In addition to choreoathetosis post-HSE, other disorders such as encephalitis lethargica with
dyskinesias or abnormal movements141 or encephalitis of unclear etiology with abnormal
movements29 are now identified as anti-NMDAR encephalitis. Archived serum or CSF
samples of these patients confirm the presence of IgG antibodies to these receptors and
retrospective assessment of the clinical picture is consistent with anti-NMDAR encephalitis.
Hashimoto’s encephalitis is a term that continues to be in use even though the disorder was
renamed steroid-responsive encephalopathy associated with autoimmune thyroiditis
(SREAT). The diagnosis is considered in patients who develop any type of encephalopathy
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of unclear etiology, with TPO antibodies, and response to steroids.142 However, TPO
antibodies are present in ~10% of healthy subjects143,144 and they are also frequently
encountered in patients with well-defined autoimmune encephalitis (e.g., NMDAR,
GABAbR, and GABAaR, among others).7,23,27,145 In our experience, patients with
autoimmune encephalitis and relevant cell surface or synaptic antibodies are frequently
misdiagnosed as Hashimoto’s encephalitis, while patients without relevant autoantibodies
that fulfill criteria of SREAT do not have antibodies reacting with the cell surface of neurons
(J. Dalmau, personal observation). This indicates that Hashimoto’s encephalitis or SREAT
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should be a diagnosis of exclusion.
Overlapping syndromes: anti-NMDAR encephalitis and demyelinating

disorders
Many patients with anti-NMDAR encephalitis have normal MRI scans (see anti-NMDAR
encephalitis). A study of 691 patients with the disorder identified 23 (range 4–62 years of
age, median 27; nine cases younger than 18 years of age), with clinical or MRI features
suggesting a demyelinating disorder.59 Twelve of these 23 patients developed anti-NMDAR
encephalitis preceded or followed by one or more episodes of demyelination, and the other
11 developed both disorders simultaneously. Among the 12 patients with sequential
development of syndromes, the demyelinating episode of five patients fulfilled criteria of
neuromyelitis optica spectrum disorder (NMOSD) or NMO (four with aquaporin 4
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antibodies); the other seven patients developed a a brainstem syndrome or multifocal

demyelinating features (all with myelin-oligodendrocyte (MOG) antibodies). Among the 11
patients with concurrent anti-NMDAR encephalitis and demyelinating symptoms, five had
aquaporin 4 antibodies (3 with features of NMOSD), and two had MOG antibodies, both
with infratentorial abnormalities.
Most patients improved with immunotherapy, but compared with the episodes of anti-
NMDAR encephalitis, the episodes of demyelination required more intensive therapy and
resulted in more residual deficits.59 Similar overlapping syndromes or autoantibodies have
been identified by other investigators.146-148
Caveats in the diagnosis and treatment of autoimmune encephalitis

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Autoantibodies to cell surface and synaptic proteins should be examined in both serum and
CSF. A recent study showed that 14% of patients with anti-NMDAR encephalitis did not
have detectable antibodies in serum using two different techniques, while all had antibodies
in the CSF. For other disorders, the proportion of cases that are CSF positive and serum
negative is unknown. In our experience, patients with encephalitis related to antibodies
against NMDAR, AMPAR, GABAbR, DPPX, mGluR1, or mGluR5 always have antibodies
in the CSF.
Other antibodies, such as anti-LGI1, anti-Caspr2, anti-GlyR, anti-GABAaR, may in rare

instances be identified only in serum. In these cases the disease relevance of the serum
antibodies is unclear, and sometimes the findings are not reproducible,149 suggesting false
positive results. Indeed, most of the atypical clinical associations of antibodies to neuronal
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cell surface antigens (e.g., NMDAR in patients with CJD or schizophrenia)121,150 have been
reported in patients who underwent limited serum testing using only cell-based assays
without examining CSF, or whose CSF was negative. Although some investigators argue for
a higher sensitivity of serum testing with the indicated cell-based assay, there is no data
supporting this (e.g., CSF not tested, or comparison with other techniques not performed). In
contrast, a study of Gresa-Arribas and colleagues151 examining paired serum and CSF of
250 patients with anti-NMDAR encephalitis and 100 controls with three different assays,
showed that serum testing with any type of cell-based assay (live or fixed cells) leads to
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false negative results in at least 14% of the patients. We recently saw a patient that had been
treated elsewhere for one year for anti-NMDAR encephalitis; the diagnosis had been based
in a serum live cell-based assay without CSF analysis. The syndrome was surprisingly
atypical for anti-NMDAR encephalitis; instead, the patient had narcolepsy-cataplexy that
was confirmed by a compatible HLA and undetectable hypocretin in CSF. Comprehensive
studies of the patient’s serum sample (considered NMDAR-antibody positive elsewhere)
and CSF (which had not been previously tested) were both antibody negative. In this case,
the serum assay was not more sensitive than the CSF and it provided a false positive result
(J. Dalmau, unpublished observation). In our experience, the problems that result from
assessing autoimmune encephalitis by serum testing only can be avoided by including CSF
testing. Moreover, the CSF findings show specific antibody–syndrome associations, and the
results are comparable among different series and laboratories.58
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There are no standard immunotherapy protocols for autoimmune encephalitis. Approaches

to decrease the antibody levels (with plasma exchange or IVIg) are less effective than in
antibody-mediated diseases of the peripheral nervous system such as myasthenia gravis or
the Lambert-Eaton syndrome. The intrathecal production of antibodies that occurs in many
types of autoimmune encephalitis, and the presence of CNS inflammatory infiltrates along
with plasma cells,21,152 likely explains the less frequent response to these immunotherapies.
Interestingly, patients with anti-LGI1 associated symptoms (a disorder with infrequent
intrathecal antibody synthesis) respond faster to steroids, plasma exchange, or IVIg than do
patients with anti-NMDAR encephalitis (a disorder that associates with intrathecal antibody
synthesis). However, the faster treatment response of patients with LGI1 antibodies does not
lead to better long-term outcome; in fact, patients with anti-NMDAR encephalitis have full
recoveries more frequently than do those with LGI1 antibodies (measured as ability to return
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to work or their original activities; Dalmau, personal observation).42,153
Experience with 501 patients with anti-NMDAR encephalitis demonstrated that rituximab
and cyclophosphamide are usually effective in patients who do not respond to first-line
immunotherapies.42 Although this approach is increasingly being used for other
autoimmune encephalitis, it is unclear whether it has the same effects.
Follow-up of serum antibody titers is an unreliable biomarker of disease activity in many

types of autoimmune encephalitis. A recent study showed that in patients with anti-NMDAR
encephalitis, the CSF antibody titers associate better with the course of the disease and
relapses than do serum titers.151 In our experience, serum antibody titers (or even CSF titers)
should not be used as the main guide for treatment decisions, instead they should be
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predominantly based on clinical assessment. As examples, patients with anti-NMDAR

encephalitis may be comatose for several months and have low or undetectable serum
antibody titers, while their CSF titers are persistently elevated.151 Conversely, patients may
have recovered, sometimes for several years, and still have antibodies in serum or
CSF.154,155 The limited usefulness of antibody titers is not surprising if one considers that
the same problem applies to other well-established antibody-mediated disorders such as
myasthenia gravis.
Future directions
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The discovery of autoimmune encephalitis has changed paradigms in the diagnosis and
treatment of disorders that were previously unknown or mischaracterized. The increasing
interest and number of studies in the field are raising interesting questions on multiple
fronts. For example, it is unclear whether the clinical and basic mechanisms of anti-
NMDAR encephalitis (the best studied of this group of disorders) are applicable to the other
disorders. There are important differences among them, not only clinical but also in the
function and structure of the target antigens (some are ion channels, others metabotropic
receptors, and one is a secreted protein). A critical question is how and where the
immunological response is initiated, and which mechanisms are involved in the activation
and expansion of the immune response within the CNS. It is unclear why some disorders
appear to be consistently associated with intrathecal synthesis of antibodies, while others
less so. What is the mechanism of action of rituximab in these CNS disorders? Despite the
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limited ability to cross the BBB, this drug can eliminate plasmablasts (which express CD20)
or interfere with the process of B cell expansion and maturation into plasma cells (which are
not directly affected by rituximab). These postulated mechanisms may explain why patients
with anti-NMDAR encephalitis who receive early and aggressive immunotherapy have
faster improvement and better outcome than those with delayed or less aggressive therapies
(perhaps allowing development of more extensive infiltrates of plasma cells in patient’s
brain; Fig. 7). Other prognostic factors, such as severity of symptoms42 or, perhaps,
compensatory mechanisms of synaptic function,156 should be investigated and may explain
differences in patients’ outcomes.
Most neuronal cell–surface or synaptic autoantibodies are IgG1 or IgG3 subtypes that
potentially fix complement; but in the disorders thus far studied (mainly anti-NMDAR
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encephalitis) there is no evidence of complement-mediated mechanisms of cell

injury.21,152,157 This is different from NMO and aquaporin 4 antibodies, where symptoms
are less reversible and complement-mediated brain injury is more visible in MRI.158 On the
other hand, IgLON5 antibodies are IgG4, which do not fix complement; but in general,
disorders associated with IgG4 antibodies appear to respond frequently to rituximab (an
observation to consider in future studies).32,159,160
The underlying mechanisms involved in antibody-mediated changes in the structure and

function of the target antigen have been elucidated in some autoimmune encephalitis, but the
effects at the circuit level are unknown. Upcoming animal models/studies will provide
strategies on how to neutralize the antibody effects, not only using immunotherapy but
perhaps optimizing compensatory synaptic mechanisms. In line with potentially novel
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therapeutic strategies, a study showed that Ephrin-B2 ligand prevents the destabilizing
NMDAR crosslinking effects of patients’ antibodies.114
The disorders discussed here provide natural models of human disease along with unique
tools (patients’ antibodies) to understand the link between selective alteration of specific cell
surface proteins or receptors and plasticity, memory, learning, and behavior.
Acknowledgments
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The National Institute of Health, the McKnight Neuroscience of Brain Disorders award, the Fondo de
Investigaciones Sanitarias, and Fundació la Marató de TV3.
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Figure 1.
Process of discovery, antigen immunoprecipitation, and development of a diagnostic test.
Dissociated rat hippocampal neurons maintained in vitro and incubated (live, non-
permeabilized) with CSF of a patient. Note the intense reactivity of patient’s antibodies with
cell surface antigens (A); scale bar = 10 μm. Confocal microscopy suggests that the antigens
are concentrated in clusters along dendrites (B); scale bar = 5 μm. Precipitation of these
antigens using two patients’ CSF antibodies is shown in a gel in which proteins are
visualized with EZBlue (C). Note that patients’ antibodies (P1, P2) precipitated a single
band at ~100 kDa; this band is not seen in the precipitate of a control individual (N).
Analysis of the 100 kDa band by mass spectrometry demonstrated sequences derived from
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GluR1/GluR2 subunits of the AMPAR. The ~50 kDa band across all samples corresponds to
IgG. Transfer of the proteins to nitro-cellulose and Western blot with GluR1 and GluR2
antibodies confirmed that the 100 kDa band contained both GluR1 and GluR2 subunits
(panels in D). Further validation of the antigen was done in heterologous cells expressing
GluR1/2, showing reactivity with patient’s antibodies (green), a monoclonal antibody (red),
and the merged reactivities (yellow). Adapted from Lai and colleagues22 with permission.
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Figure 2.
Comparison of MRIs of patients with limbic encephalitis and different cell surface
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autoantibodies with the MRI of a patient with multifocal encephalitis and GABAaR receptor
antibodies. The MRIs of the three cases with limbic encephalitis correspond to a patient with
LGI1 antibodies (A), a patient with AMPAR antibodies (B), and a patient with GABAb-R
antibodies (C). In contrast, note that the MRI of the patient with GABAaR antibodies shows
multifocal cortical-subcortical FLAIR abnormalities (D). Panels A–C, from Lancaster and
colleagues,11 with permission; panel D from Petit-Pedrol and colleagues27 with permission.
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Figure 3.
Sequence of syndrome development in patients with anti-NMDAR encephalitis. During the
first month of the disease most patients with anti-NMDAR encephalitis progressively
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develop the sequence of symptoms shown in the graph.42 Adapted from Dalmau and
colleagues.45
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Figure 4.
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Synaptic and behavioral effects of antibodies from patients with anti-NMDAR encephalitis.
(A–C) AMPA and NMDA receptors are localized in the postsynaptic membrane and are
clustered at the postsynaptic density A. Patient antibodies in the CNS bind selectively to
NMDA receptors at the synapse as well as extrasynaptic receptors. This binding leads to
receptor cross-linking B. NMDA receptors that have been bound and cross-linked by
antibodies are internalized, resulting in a decrease of surface, synaptically localized NMDA
receptors. Other synaptic components, such as postsynaptic AMPA receptor clusters,
PSD-95, as well as presynaptic terminals, dendrite branches, dendritic spines and cell
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viability, are unaffected C. Thus patient anti-NMDA receptor antibodies lead to a rapid,
selective excision of NMDA receptors from neuronal membranes. This effect is titer-
dependent and reverses after antibody titers are reduced (not shown). (D–E) Rodent cultured
neurons treated with control CSF or patient’s CSF for 3 days, and subsequently stained for
postsynaptic GluN1 to label NMDA receptor clusters, VGlut to label presynaptic sites, and
PSD-95 as a postsynaptic marker. Note that patient’s CSF cause a decrease in dendritic
GluN1 cluster density, while VGlut and PSD-95 cluster density remain unchanged. (F–G)
Whole-cell patch recordings of miniature excitatory postsynaptic currents (mEPSCs) that
consist of a fast AMPA receptor–mediated component and a slower later component
mediated by NMDA receptors and is APV sensitive. Compared with neurons incubated with
CFS control F, those treated with CSF from a patient with NMDA receptor antibodies show
a loss of the APV-sensitive NMDA receptor component E. H: Progressive memory deficit
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assessed by standard object recognition test, in a group of 5 mice treated with

cerebroventricular infusion of CSF from patients with anti-NMDAR encephalitis (grey
circles) compared with a group of 5 mice treated with CSF from control subjects without
NMDAR antibodies (white circles). Antibodies were continuously infused for 14 days; the
peak of memory deficit was on day 18, followed by progressive clinical recovery. Panels
(A–G) obtained from Moscato and colleagues,2 with permission. Panel H provide by
Planaguma and colleagues (unpublished data).
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Figure 5.
Interaction of LGI1 with synaptic proteins. Secreted LGI1 interacts at the presynapse with
ADAM23 and at the postsynapse with ADAM22. The figure is based on studies indicating
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that LGI1 co-precipitates with other proteins including the presynaptic Kv1 potassium
channels and a variety of pre- and post-synaptic scaffolding proteins. Adapted from
Lancaster and colleagues,11 with permision.
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Figure 6.
Associations, trigers, and common symptoms of autoimmune encephalitis: impact on
multiple disciplines
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Figure 7.
Plasma cell infiltrates in the brain of a patient with anti-NMDAR encephalitis. Paraffin
embedded sections of brain biopsy of a patient with anti-NMDAR encephalitis. CD138+
cells (plasma cells/plasmablasts) are present in perivascular, Virchow-Robin (A), and
interstitial spaces (B). In Virchow-Robin spaces (A) the CD138+ cells are in perivascular
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regions (arrows) and along the tissue surface (arrow heads) that delineates spaces containing
CSF and small vessels (v). The plasma cells/plasmablasts indicated with arrows are
amplified in the inset in A. Scales = 20 μm. Adapted from Martinez-Hernandez and
colleagues,152 with permision.
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Table 1
Autoimmune encephalitis with antibodies against cell surface and synaptic proteins
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Antigen Clinical syndrome Tumor

Anti-NMDAR encephalitis: prodromal symptoms, Age-dependent 10–45% ovarian
NMDAR (GluN1) psychiatric, seizures, amnesia, movement teratomas, infrequently
disorders, catatonia, autonomic instability, coma carcinomas
AMPAR Limbic encephalitis, psychiatric symptoms 70% (lung, breast, thymoma)
GABAbR Limbic encephalitis, prominent seizures 50% lung, neuroendocrine
Limbic encephalitis, 60% hyponatremia, occasional

LGI1 <10% (lung, thymoma)
focal faciobrachial seizures prior to encephalitis
CASPR2 Encephalitis, Morvan syndrome, neuromyotonia 0–40% thymoma
Limbic encephalitis
mGluR5 Frequently, Hodgkin lymphoma
(reported in less than 10 patients)
D2R Basal ganglia encephalitis, Sydenham chorea. Infrequent
Diarrhea, encephalitis with CNS hyperexcitability:

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confusion, psychiatric symptoms, tremor,

DPPX No tumor association
myoclonus, nystagmus, hyperekplexia, PERM-like
symptoms, ataxia.
Refractory seizures, status epilepticus, or epilepsia

GABAaR Infrequent
partialis continua, stiff-person, opsoclonus
Stiff-person, PERM, limbic encephalitis, cerebellar

GlyR Infrequent
degeneration, optic neuritis
Abnormal sleep movements and

behaviors,obstructive sleep apnea, stridor,
IgLON5 No tumor association
dysarthria, dysphagia, ataxia, chorea
(reported in less than 10 patients)
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In contrast to classical paraneoplastic syndromes, the novelty of the autoimmune

Antibodies and target antigens

Many patients with autoimmune encephalitis have a propensity to autoimmunity, including

(TPO) antibody or antinuclear antibodies (ANA)).22,27 These encephalitis-irrelevant

General clinical features of autoimmune encephalitis

The electroencephalogram (EEG) is almost always abnormal in all types of autoimmune

movements that may include orofacial dyskinesias, chorea, athetosis, ballismus,

myorhythmia, stereotyped movements, rigidity, or opisthotonus.7,51-53 As the symptoms

The presentation of NMDAR encephalitis in children with behavioral abnormalities may

require second line therapies, such as rituximab or a combination of rituximab and

should be reassessed for the presence of an underlying12,13 contralateral or recurrent

The encephalitis associated with LGI1 antibodies—This limbic encephalitis

The encephalitis associated with GABAbR antibodies—This limbic encephalitis

of patients with syndromes pathogenically associated with auto-reactive antibodies rather

The encephalitis associated with AMPAR antibodies—Anti-AMPAR limbic

Other syndromes and autoantibodies to cell surface antigens or synaptic receptors

The Ophelia syndrome—This is a form of autoimmune encephalitis that occurs in

encephalitis. Symptoms include depression, agitation, hallucinations, memory deficits,

Progressive encephalomyelitis with rigidity and myoclonus (PERM)—PERM is

Stiff-person syndrome—This syndrome comprises a clinical picture characterized by

symptoms in association with endocrinopathy (diabetes, thyroid dysfunction).104 The reason

usually develop amphiphysin antibodies instead of GAD65 or GlyR antibodies.107,108

Encephalitis associated with DPPX antibodies—Anti-DPPX encephalitis results in

Encephalitis with antibodies to γ-amino-butyric acid A-receptor (GABAaR)—

Basal ganglia encephalitis and antibodies to dopamine (D2) receptor—This

A novel link between autoimmunity and neurodegenerative disorders: encephalopathy and

identified in the patients’ CSF, leaving it unclear at whether there is an inflammatory

stopping the antibody infusion, with reversibility of symptoms accompanied by restoration

ADAM22, organizing a trans-synaptic complex that includes presynaptic Kv1.1 potassium

apply to neurons in vivo.

Autoimmune encephalitis in other disciplines

Herpes simplex encephalitis (HSE) as trigger of synaptic autoimmunity

because patients usually respond to immunotherapy.

should be a diagnosis of exclusion.

Overlapping syndromes: anti-NMDAR encephalitis and demyelinating

antibodies); the other seven patients developed a a brainstem syndrome or multifocal

Caveats in the diagnosis and treatment of autoimmune encephalitis

Other antibodies, such as anti-LGI1, anti-Caspr2, anti-GlyR, anti-GABAaR, may in rare

There are no standard immunotherapy protocols for autoimmune encephalitis. Approaches

to work or their original activities; Dalmau, personal observation).42,153

Follow-up of serum antibody titers is an unreliable biomarker of disease activity in many

predominantly based on clinical assessment. As examples, patients with anti-NMDAR

encephalitis) there is no evidence of complement-mediated mechanisms of cell

The underlying mechanisms involved in antibody-mediated changes in the structure and

Neurosci. 2012; 32:11082–11094. [PubMed: 22875940]

17. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:

21. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis

channel antibody-associated limbic encephalitis. Ann. Neurol. 2006; 59:178–181. [PubMed:

63. Goldberg EM, Titulaer M, de Blank PM, et al. Anti-N-methyl-D-aspartate receptor-mediated

mimicking creutzfeldt-jakob disease. Arch. Neurol. 2008; 65:1341–1346. [PubMed: 18852349]

autoimmunity. JAMA Neurol. 2014; 71:620–623. [PubMed: 24590315]

against a glutamate receptor. N. Engl. J. Med. 2000; 342:21–27. [PubMed: 10620645]

2013; 70:1531–1536. [PubMed: 24100349]

2223. [PubMed: 8245793]

receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet. J. Rare.

neuronal hyperexcitability. Hum. Mol. Genet. 2010; 19:1702–1711. [PubMed: 20130004]