Autoimmune REVIEW ARTICLE

Encephalitis

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
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ONLINE
By Sarosh R. Irani, BMBCh, MA, DPhil(Oxon), FRCP, FEAN
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ABSTRACT
OBJECTIVE: This article focuses on the clinical features and diagnostic
evaluations that accurately identify patients with ever-expanding forms of
antibody-defined encephalitis. Forms of autoimmune encephalitis are
more prevalent than infectious encephalitis and represent treatable
neurologic syndromes for which early immunotherapies lead to the best
outcomes.
CITE AS:
LATEST DEVELOPMENTS: A clinically driven approach to identifying many CONTINUUM (MINNEAP MINN)
2024;30(4, AUTOIMMUNE
autoimmune encephalitis syndromes is feasible, given the typically NEUROLOGY):995–1020.
distinctive features associated with each antibody. Patient demographics
alongside the presence and nature of seizures, cognitive impairment, Address correspondence to
psychiatric disturbances, movement disorders, and peripheral features Dr Sarosh Irani, Mayo Clinic,
4500 San Pablo Road,
provide a valuable set of clinical tools to guide the detection and Jacksonville, FL 32224, irani.
interpretation of highly specific antibodies. In turn, these clinical features sarosh@mayo.edu.
in combination with serologic findings and selective paraclinical testing,
RELATIONSHIP DISCLOSURE:
direct the rationale for the administration of immunotherapies. Dr Irani has received personal
Observational studies provide the mainstay of evidence guiding first- and compensation in the range of
$500 to $4999 for serving as an
second-line immunotherapy administration in autoimmune encephalitis editor, associate editor, or
and, whereas these typically result in some clinical improvements, almost editorial advisory board
all patients have residual neuropsychiatric deficits, and many experience member for Brain; in the range
of $5000 to $9999 for serving on
clinical relapses. An improved pathophysiologic understanding and a scientific advisory or data
ongoing clinical trials can help to address these unmet medical needs. safety monitoring board for F.
Hoffman-La Roche Ltd and
United BioSource LLC; in the
ESSENTIAL POINTS:Antibodies against central nervous system proteins range of $10,000 to $49,999 for
characterize various autoimmune encephalitis syndromes. The most serving as a consultant for
Cerebral Therapeutics, Inc, F.
common targets include leucine-rich glioma inactivated protein 1 (LGI1), Hoffman-La Roche Ltd, Janssen
N-methyl-D-aspartate (NMDA) receptors, contactin-associated Global Services, LLC, and United
proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each BioSource LLC; and in the range
of $100,000 to $499,999 for
antibody-associated autoimmune encephalitis typically presents with a serving as an expert witness for
recognizable blend of clinical and investigation features, which help Clarke-Wilmott and Moore
differentiate each from alternative diagnoses. The rapid expansion of Blatch. Dr Irani has received
intellectual property interests
recognized antibodies and some clinical overlaps support panel-based from a discovery or technology
antibody testing. The clinical-serologic picture guides the immunotherapy relating to health care.
regime and offers valuable prognostic information. Patient care should be
UNLABELED USE OF
delivered in conjunction with autoimmune encephalitis experts. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Irani reports no disclosure.

© 2024 American Academy

of Neurology.

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 AUTOIMMUNE ENCEPHALITIS

INTRODUCTION

D
uring the past 2 decades, there has been a dramatic expansion in the
number of recognized autoimmune neurologic diseases, none more
so than autoimmune encephalitis.1-3 In autoimmune encephalitis,
particularly given the brain was firmly considered an immune-
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privileged organ until very recently, the description of more than 20

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disease-associated and pathogenic antibodies is a major conceptual advance. This

gain in knowledge has had a remarkable clinical impact with the rapid uptake of
antibody testing into routine neurologic practice. This bench-to-bedside
translation has been predominantly driven by the potential for immunotherapy-
induced reversibility in patients with autoimmune encephalitis, which comprise a
group of “not to miss” neurologic diagnoses. Hence, contemporary neurologic care
requires consideration of autoimmune encephalitis in appropriate clinical settings.
Antibody testing is now commonplace in patients who present with a few days to
months of cognitive impairment, seizures, movement disorders, and prominent
psychiatric features. Although this varied symptomatology increases the risk of
overdiagnosis of autoimmune encephalitis, it emphasizes the need for judicious
antibody testing and close serologic correlations with clinical features. The
subsequent steps of immunotherapy administration and patient management
should be coordinated with autoimmune encephalitis specialists to incorporate
cutting-edge knowledge in this rapidly expanding field. Patients with these
complex conditions benefit from early and accurate diagnosis. This article focuses
on patient-centered observations, which form the foundation for accurate
diagnosis of autoimmune encephalitis. Included are a practical approach to
antibody testing and interpretation, the benefits of immunotherapies for patients,
and an outline of the unmet medical needs that persist despite current therapies.
By integrating aspects of autoimmune encephalitis pathogenesis and clinical trials,
this article highlights the ongoing and novel therapeutic approaches that may be
soon adopted into clinical practice.

EPIDEMIOLOGY
In a rapidly expanding field, it is perhaps unsurprising that newly described
conditions are originally considered rare. However, with greater availability of
widespread antibody testing and better clinician recognition of key clinical
features, it is increasingly clear that autoimmune encephalitis is at least as
common as infectious forms of encephalitis in high-income countries.4 As the
number of recognized antibodies grows and seronegative forms of autoimmune
encephalitis become better defined, the incidence of autoimmune encephalitis
will likely far exceed that of its infectious counterparts. Although the precise
figures vary somewhat between available autoimmune encephalitis studies, the
most common antibodies that target cell-surface epitopes include those against
leucine-rich glioma inactivated protein 1 (LGI1), the N-methyl-D-aspartate
(NMDA) receptor, contactin-associated proteinlike 2 (CASPR2), γ-aminobutyric
acid A (GABAA) or γ-aminobutyric acid B (GABAB) receptors, and myelin
oligodendrocyte glycoprotein (MOG). These antibodies are likely to be directly
causative of their respective clinical syndromes. LGI1 is the most common overall
(incidence of approximately 1 to 2 per one million per year) and almost
exclusively affects adults. NMDA receptor antibodies are the next most frequent,
typically affecting the younger population. In patients 35 years old or younger,

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 NMDA receptor encephalitis alone exceeds the incidence of herpes simplex KEY POINTS
encephalitis in developed countries.5 Further, the many emerging reports of
● During the past 2 decades
autoimmune encephalitis in low-to-middle-income countries suggest that this there has been dramatic
set of syndromes exists worldwide, despite a relative paucity of antibody growth in the recognition of
testing availability in some regions.6 Also, a variety of antibodies that target autoimmune encephalitis.
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intracellular epitopes are associated with autoimmune encephalitis, especially

● The most common
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those against glutamic acid decarboxylase 65 (GAD65), glial fibrillary acidic

autoimmune encephalitis
protein (GFAP), and a range of paraneoplastic antibodies, most commonly syndromes are associated
against antineuronal nuclear antibody type 1 (ANNA-1; also known as anti-Hu) with antibodies against
and collapsin response mediator protein-5 (CRMP-5; also known as anti-CV2) leucine-rich glioma
inactivated protein 1 (LGI1),
(TABLE 2-1 and TABLE 2-2).4 For more information, refer to the article
N-methyl-D-aspartate
“Paraneoplastic Neurologic Disorders” by Anastasia Zekeridou, MD, PhD,7 in this (NMDA) receptors,
issue of Continuum. contactin-associated
proteinlike 2 (CASPR2),
APPROACHES TO AUTOIMMUNE ENCEPHALITIS CATEGORIZATION γ-aminobutyric acid
(GABA)A or GABAB
It is of critical importance to recognize the key clinical features associated with receptors, and myelin
autoimmune encephalitis. The range of clinical features and investigation results oligodendrocyte
within the spectrum of autoimmune encephalitis syndromes is substantial and glycoprotein (MOG).
summarized in TABLE 2-1. One approach to organizing these diagnoses is to
● The clinical features of
“lump” them into clinical syndromes, and another is to “split” them into autoimmune encephalitis
categories based on their specific antibody. In this article, each syndrome is syndromes necessitate
defined (“split”) by its associated antibody, which provides an opportunity to diagnosis by either lumping
compare and contrast antibody-defined clinical features, paraclinical results, and or splitting. The former
approach directs patient
overall outcomes. By contrast, current diagnostic criteria “lump” clinical features
care according to their
and investigations to identify broader categories of possible autoimmune clinical features, and the
encephalitis (TABLE 2-2), after which individual antibody subtypes can be latter by knowledge
dissected. Both are reasonable clinical approaches to patient recognition, but the regarding the typical
patterns associated with a
latter approach may be more straightforward for routine clinical practice and
specific antibody. Although
augmented by panel-based antibody testing to better define the precise category. both are valuable, tailoring
Alternatively, the former approach may immediately direct the patient with a patient care according to
highly specific set of features toward the precise entity. The importance of the exact antibodies permits
eventually splitting these syndromes, where possible, is illustrated by the differing a more personalized
approach.
clinical features, tumor associations, and responses to treatment between the
antibody-defined categories. Therefore, the exact antibody-syndrome association ● LGI1 encephalitis was
allows for more tailored patient care and the delivery of more accurate previously misclassified as a
information to the patient and their family. In this article, the antibody is used as voltage-gated potassium
channel–antibody disease.
the starting point to define the associated syndrome characteristics, whereas in Correcting this
clinical practice these associations may be arrived at through direct or indirect misperception has allowed
routes; therefore, wider differential diagnoses are also considered. for improved assays and a
more specific diagnosis for
patients.
LGI1 ENCEPHALITIS
Antibodies against the synaptic protein LGI1 were first described in 2010.8 Most
patients with LGI1 antibodies were previously classified as having antibodies
against potassium channels; however, the multiple pitfalls and clinical dangers
associated with the potassium channel antibody assay mean clinicians now more
specifically refer to LGI1 antibodies.9,10 Patients with LGI1 antibodies are more
commonly male than female (2:1), and few patients younger than 50 years
present with these antibodies.8,11,12 The median age of onset is approximately
65 years, and some patients present in their nineties.8,11-13 Unlike many
autoimmune encephalitis syndromes, LGI1 antibodies are only occasionally

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 AUTOIMMUNE ENCEPHALITIS

TABLE 2-1 Demographic, Clinical, and Paraclinical Features of Neuronal Antibody

Syndromesa

Neuronal
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antibody Sex ratio

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(predominant Typical median age (male:

IgG subclass) in years (range) female) Clinical features MRI findings

NMDA 21 1:4 Encephalitis with prominent 70-80% normal or nonspecific, with

receptor (2 months-85 years) polysymptomatic limbic encephalitis in a minority
(IgG1) neuropsychiatric presentation,
polymorphic movement
disorder, language disorder,
autonomic dysfunction, coma,
and central apnea

LGI1b 64 2:1 Limbic encephalitis with Approximately 40% increased signal

(IgG4) (31-84) frequent focal seizures with swelling in mesial temporal
(including highly characteristic lobes (unilateral > bilateral)
faciobrachial dystonic seizures)

CASPR2b 66 9:1 Main syndromes: peripheral Approximately 30% increased signal

(IgG4) (25-77) nerve hyperexcitability, limbic in mesial temporal lobes
encephalitis, and Morvan
syndrome

GABAA 40 1:1 Encephalitis with frequent >80% cortical and subcortical fluid-
receptor (2 months-88 years) status epilepticus attenuated inversion recovery
(IgG1) (FLAIR) signal abnormalities
involving 2 or more brain regions

GABAB 61 1.5:1 Limbic encephalitis with Approximately 70% abnormal (45%

receptor (16-77) prominent seizures increased signal in mesial temporal
(IgG1) lobes)

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Immunotherapy response
CSF findings EEG findings Other investigations and outcomes

80% abnormal (lymphocytic 90% abnormal (slowing Ovarian teratoma in 60% Approximately 50% improve in 4 weeks
pleocytosis, unpaired most common, 20% of female patients aged with first-line immunotherapy
oligoclonal band [OCB] epileptiform 15-35 years
Approximately 60% of nonresponders
common) abnormalities, rarely
After herpes simplex improve with second-line immunotherapy
extreme delta brush
virus encephalitis,
pattern) Improvement up to 24 months, with 80%
particularly children
reaching a modified Rankin Scale (mRS)
can develop NMDA
score of 0-2
receptor (and other
neuronal surface) 10-15% relapse risk, reduced by
antibodies immunotherapy and tumor removal
Approximately 5% mortality

Approximately 25% Approximately 50% HLA-DRB1*07:01 At 2 years, 80% reach an mRS score of 0-2,
abnormal (mild pleocytosis abnormal but almost all show incomplete recovery
Hyponatremia
with elevated protein) (approximately 30%
common Relapses in approximately 40%
epileptiform
(approximately 50%)
abnormalities but
usually normal with
faciobrachial dystonic
seizures,
approximately 20%
focal slowing)

Approximately 30% Approximately 70% HLA-DRB1*11:01 50% with good response to tumor therapy
abnormal (pleocytosis, abnormal (40% and immunotherapy
Thymoma in
elevated protein +/- OCB) epileptiform
approximately 20% 45% with partial immunotherapy response
abnormalities)
(often with coexistent
Approximately 30% relapse
LGI1 antibodies)
EMG may demonstrate
hyperexcitability in
Morvan syndrome
(fasciculation potentials,
myokymic discharges)

25-50% lymphocytic >80% abnormal Thymoma in Responsive to immunotherapy, however,

pleocytosis with or without (encephalopathy with approximately 30% mortality due to status epilepticus or
OCB and elevated protein ictal abnormalities) related complications in approximately
10%

Approximately 80% 75% with ictal Tumors in 90% show response to immunotherapy;
lymphocytic pleocytosis abnormalities approximately 50% those with tumors have poorer prognoses
(mostly small cell lung
cancer)

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 AUTOIMMUNE ENCEPHALITIS

CONTINUED FROM PAGE 999

Neuronal
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antibody Sex ratio

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(predominant Typical median age (male:

IgG subclass) in years (range) female) Clinical features MRI findings

AMPA 53 2:1 Limbic encephalitis with Approximately 85% abnormal (67%

receptor (14-92) prominent confusion, amnesia, with bilateral mesial temporal
(IgG1) seizures, and psychiatric and involvement)
behavioral symptoms

DPPX 53 1.5:1 Multifocal encephalitis with Normal or nonspecific

(IgG4) (13-76) myoclonus, tremors and
hyperekplexia, prominent
diarrhea and weight loss
(median 20 kg [44 lb])

Glycine receptor 50 1:1 Three main syndromes: stiff Brain: temporal lobe inflammation
(IgG1/3) (1-75) person syndrome, progressive in 5%, abnormal in approximately
encephalopathy with rigidity 30%, mostly nonspecific
and myoclonus, and limbic
Spinal cord: approximately 20%
encephalitis
abnormal, mostly short and patchy
lesions, 5% longitudinally extensive
lesions

MOG 37 1:1 Optic neuritis, myelitis, Brain: approximately 75% abnormal

(IgG1) (1-74) brainstem encephalitis, (bilateral subcortical lesions or
encephalitis cortically limited swelling),
approximately 30% brainstem
involvement
Spinal cord and orbit involvement
are frequent

IgLON5 64 1:1 Sleep disorder (rapid eye Approximately 80% normal or

(IgG1/4) (46-83) movement [REM] and non-REM nonspecific
parasomnias sleep apnea),
Approximately 15% brainstem
bulbar syndrome, progressive
atrophy
supranuclear palsylike
syndrome, cognitive syndrome 5% bilateral hippocampal atrophy
with or without chorea

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CASPR2 = contactin-associated proteinlike 2; DPPX = dipeptidyl-peptidase–like

protein 6; GABA = γ-aminobutyric acid; GAD = glutamic acid decarboxylase; IgLON5 = Ig-like cell adhesion molecule 5; LGI1 = leucine-rich glioma
inactivated protein 1; MOG = myelin oligodendrocyte glycoprotein; NMDA = N-methyl-D-aspartate.
a
Modified with permission from Uy CE, et al, Pract Neurol.78 © 2023 BMJ Publishing Group, Ltd.
b
LGI1 and CASPR2 antibodies were historically classified as antibodies against the voltage-gated potassium channel.

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Immunotherapy response
CSF findings EEG findings Other investigations and outcomes

Approximately 45% abnormal Tumor identified in Most patients showed improvement from
70% abnormal approximately 70% peak of disease, median mRS score = 1 in
(thymoma, small cell survivors
lung cancer, breast
Approximately 15% of reported patients
cancer, ovarian
died (commonly due to complications
cancer)
from malignancy)

Approximately 30% Approximately 70% Approximately 10% 60-70% improve substantially with
abnormal (mild pleocytosis abnormal (focal or with B-cell neoplasm immunotherapy
and elevated protein) diffuse slowing) (gastrointestinal
follicular lymphoma,
chronic lymphocytic
leukemia)

Approximately 40% Approximately 70% EMG abnormalities in Approximately 10% mortality reported
pleocytosis, 20% OCB abnormal (55% diffuse 60% (continuous motor
Good outcomes in survivors with median
slowing, 15% focal unit activity,
mRS score = 1 at latest follow-up
epileptic abnormalities, spontaneous or
5% focal slowing) stimulus-induced Duration of follow-up 18 months to 7 years,
activity, neuromyotonia) 82% treated with immunotherapy
Coexisting GAD
antibodies in 10%
Thymoma in 15%

Approximately 60% Diffuse slowing Visual evoked Approximately 80% have good response to
lymphocytic pleocytosis; potentials or optical steroids
OCB uncommon coherence
Approximately 60% make a full or good
tomography may
recovery
demonstrate
evidence of previous Relapses are common
optic neuritis

Approximately 30% CSF Diffuse slowing HLA-DRB1*10:01 and Approximately 50% respond to initial
pleocytosis HLA-DQB*05:01 immunotherapy with less showing a
alleles in 87% sustained response
Approximately 50% elevated
protein
Approximately 10% OCB

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 AUTOIMMUNE ENCEPHALITIS

associated with tumors, mostly thymomas and small cell lung carcinomas,
meaning it would be unconventional to rescan these patients regularly, which is
common practice with more prototypical paraneoplastic conditions. Clinical
features usually appear over several weeks, although some patients can present
with a more abrupt onset, and in other patients it can take many months for these
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features to be recognized. Despite the clear benefits of immunotherapies,

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discussed later in this article, some case series studies suggest that up to 40% of
patients receiving these treatments can relapse.8,11,12

Seizures
The hallmark of LGI1 encephalitis is the nature of the seizures (CASE 2-1).
These patients have among the highest frequencies of seizures in neurology,
with some experiencing several hundred per day at their disease nadir. Their
symptomatology also makes them distinctive. Although these seizures can include
common mesial temporal lobe features such as automatisms and epigastric rising
sensations, there are more specific patterns, including piloerection, thermal
sensations and paroxysmal dizzy spells, and the pathognomonic description of
faciobrachial dystonic seizures.11-14 Piloerection attacks are seen in some other
conditions, but, in unbiased surveys, they are frequently associated with an
antibody, often LGI1.15 Paroxysmal dizzy spells are an unusual phenotype,
consisting of very brief and intense periods of dizziness without associated
physical signs.16 Although this is a nonspecific description in isolation, paroxysmal
dizzy spells can be a valuable clinical clue in the context of other features
associated with LGI1 antibodies. The term faciobrachial dystonic seizures was
coined to describe short-lived (typically <2 seconds) dystonic posturing of
the arm (approximately 100%), face (approximately 90%), and sometimes
leg (approximately 40%) that occurs tens to hundreds of times per day
(FIGURE 2-1).11-13,17 The phenomenology of the motor aspect is especially key to
recognize because it is slower and more dystonic than cortical myoclonus, and it is

TABLE 2-2 Diagnostic Criteria for Possible Autoimmune Encephalitisa

Diagnosis can be made when all three of the following criteria have been met
1 Subacute onset (rapid progression of less than 3 months) of working memory deficits
(short-term memory loss), altered mental status,b or psychiatric symptoms
2 At least one of the following
◆ New focal central nervous system findings
◆ Seizures not explained by a previously known seizure disorder
◆ CSF pleocytosis (white blood cell count of more than five cells per mm3)
◆ MRI features suggestive of encephalitisc
3 Reasonable exclusion of alternative causes

a
Reprinted with permission from Graus F, et al, Lancet Neurol.79 © 2016 Elsevier Ltd.
b
Altered mental status is defined as decreased or altered level of consciousness, lethargy, or personality
change.
c
Brain MRI hyperintense signal on T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences
highly restricted to one or both mesial temporal lobes (limbic encephalitis), or in multifocal areas involving
gray matter, white matter, or both compatible with demyelination or inflammation.

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 not associated with the pain of tonic spasms. Furthermore, in terms of specificity, KEY POINTS
the appearance of patients with classic faciobrachial dystonic seizures who do not
● Patients with LGI1
have LGI1 antibodies have not, to the author’s knowledge, been described; hence, antibody–mediated disease
faciobrachial dystonic seizures appear pathognomonic. Importantly, patients often are typically older males
show many of these semiologies in the acute phase. All are short-lived and who rarely have an
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stereotyped, consistent with their ictal etiology. Generalized seizures occur later in associated tumor. The
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hallmark of this condition is

the disease course and are typically isolated events. faciobrachial dystonic
In the early phases of the disease, seizures are typically the sole feature and seizures, which can occur
increase in frequency until patients develop cognitive and behavioral deficits. hundreds of times per day.
Hence, the seizure-predominant presentation before the development of These seizures can be the
sole feature of the disease.
cognitive impairment is especially valuable to recognize and should prompt very
early initiation of immunotherapies, which appear to mitigate the otherwise ● Cognitive impairment
incipient cognitive decline.11,17 from LGI1 encephalitis tends
to develop after seizure
Cognition presentation and may be
prevented by effective early
In addition to seizures, amnesia is another key feature associated with LGI1 immunotherapy.
encephalitis. Most patients develop a dense anterograde amnesia, consistent with
bilateral hippocampal involvement, and some retrograde gaps that do not follow a ● Most patients with LGI1
clear temporal gradient.18 Also, alterations in personality, elated or depressed encephalitis develop a
dense anterograde amnesia
mood, and heightened emotionality are observed in the acute phase. The latter is in addition to retrograde
another distinctive feature of this behavioral profile, almost always associated with gaps. Behavioral changes
marked tearfulness.19 These characteristics, in addition to the tempo of onset, help often occur and are
differentiate LGI1 encephalitis from other rapidly progressive dementias.20 associated with marked
tearfulness in these
patients.
Investigations
In patients with LGI1 encephalitis, investigations are often unremarkable. CSF ● Although current imaging
testing typically shows normal white blood cell counts and normal protein levels. modalities are often
MRI can show hippocampal-amygdala hyperintensity on T2-weighted imaging, unremarkable in patients
with LGI1 encephalitis, a low
and basal ganglia can be involved too, especially in patients with faciobrachial serum sodium (in
dystonic seizures. But increasingly, and perhaps because of earlier recognition of approximately 50% of
the associated clinical features, brain MRI is normal. In some patients with patients), and HLA-
normal MRI, positron emission tomography (PET) can show mesial temporal DRB1*07:01 (in
approximately 90% of
lobe abnormalities. EEG often shows clinical and subclinical seizure activity with patients), can be
mildly slowed background rhythms.12,14,21 Hence, this condition often presents diagnostically informative.
without MRI or CSF abnormalities that are conventional features of
inflammation. One additional feature of this condition is low serum sodium in
approximately one-half of patients, which can be a very helpful clue.
Additionally, HLA-DRB1*07:01 is strikingly found in approximately 90% of
patients with LGI1 encephalitis and can provide an adjunct diagnostic tool in
challenging cases.22,23

NMDA RECEPTOR ENCEPHALITIS

Antibodies against the excitatory NMDA receptor preferentially target
the NR1 subunit of this heteromeric channel. NMDA receptor encephalitis
presents with a diffuse encephalopathy that predominantly affects females
more than males (3:1) and approximately 50% of patients with this condition
are younger than 18 years, including some younger than 1 year.24-26
Approximately 30% of patients who are women, mainly those between 18 and
35 years old, have ovarian teratomas.24-26 By contrast, ovarian teratomas are far
less common in children and adolescents and in older adults in whom various

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 AUTOIMMUNE ENCEPHALITIS

malignant tumors are more prevalent.24-26 In addition, approximately 5% of

NMDA receptor encephalitis cases occur between a few weeks and months
after herpes simplex virus infection, representing a clear link between
infectious and autoimmune forms of encephalitis.27
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Psychiatric Features
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In addition to the contrasting demographics, a key difference between NMDA

receptor encephalitis and LGI1 encephalitis is the prominent psychiatric features
seen at onset in patients with NMDA receptor encephalitis, which can often lead
to patients initially presenting to psychiatric services and being misdiagnosed
with a primary psychiatric condition. However, the psychopathology of NMDA
receptor encephalitis appears discrete, incorporating a highly mixed phenotype
that appears over just a few days to weeks.28 The presentation includes core
features of agitation, aggression, hallucinations, delusions, anxiety, mutism, and
insomnia, with many patients exhibiting all or many of these features. Hence, the

CASE 2-1 An 81-year-old man presented to clinic after developing a tendency to

drop items for the past 8 weeks. In the prior 2 weeks, his wife had noticed
his forgetfulness about the places they had visited in the past decade and
the names of his children. On direct questioning, his wife recalled that he
had arm spasms occurring at least every hour and seemed to be the cause
of his dropping items. She also acknowledged that his face twitched,
probably on the same side as his arm. He said that with some of the
attacks, he experienced a vague, odd preceding feeling. In addition, he
had experienced other short, recurrent attacks of hot and cold
sensations running up and down his body for a few seconds. His MRI,
CSF, and EEG were all unremarkable, prompting consideration of a
functional basis for the attacks. There was no response to
carbamazepine. The neurologist observed four attacks in the clinic and
noticed similarities to faciobrachial dystonic seizures.

COMMENT This case exemplifies the high frequency of faciobrachial dystonic seizures
and the nature of these focal seizures, which typically affect the arm and
ipsilateral face (FIGURE 2-1). Their frequency is sufficiently high that,
particularly at presentation, they are visible in the outpatient setting during
an office visit. They can coexist with other seizure semiologies, in this case,
thermal seizures. In patients with leucine-rich glioma inactivated protein 1
(LGI1) antibodies, MRI, EEG, and CSF analysis may not reveal changes
suggestive of inflammation and can be normal. After a few weeks, most
patients with faciobrachial dystonic seizures alone progress to develop
memory and cognitive deficits. Immunotherapy is not only highly effective
for treating faciobrachial dystonic seizures but also in preventing patients
from manifesting with cognitive decline.

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 psychopathology of NMDA receptor encephalitis traverses multiple traditionally
segregated psychiatric features and can clinically present as a syndrome distinct
from primary psychiatric diagnoses such as those listed in the International
Classification of Diseases, Tenth Revision or the Diagnostic and Statistical Manual of
Mental Disorders (Fifth Edition).28
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Neurologic Features
In everyday clinical practice, it is usually the onset of more typical neurologic
features that signal the recognition of NMDA receptor encephalitis. In particular,
patients with this condition can develop seizures and cognitive dysfunction in
the early days of their disorder.25,29,30 Adults typically develop a movement
disorder after approximately 1 or 2 weeks. This is, akin to their psychopathology,
a highly complex movement disorder, often incorporating elements of chorea,
stereotypies, and dystonia in individual patients.31,32 Sometimes these
movements can be almost continuous, as in status dystonicus. Also, catatonia is a

FIGURE 2-1
Faciobrachial dystonic seizure characteristics and affected regions. A-E, Ictal stills show
ipsilateral face grimacing and arm posturing. F, The percentage of patients with dystonic
posturing of specified body part(s) during faciobrachial dystonic seizures (white bars) and
whether faciobrachial dystonic seizures remained strictly unilateral or sometimes
alternated in an individual patient (black bars).
Reprinted with permission from Irani SR, et al, Ann Neurol.13 © 2011 American Neurological Association.

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 AUTOIMMUNE ENCEPHALITIS

common feature that crosses the psychiatric-movement disorder boundary and

acts as another red flag for identifying the condition in these patients.28,29,33
In children, movement disorders can often be the heralding feature.30 For more
information on autoimmune movement disorders, refer to the article “Autoimmune
Movement Disorders” by Bettina Balint, MD,34 in this issue of Continuum. In
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addition, patients with NMDA receptor encephalitis can develop severe multiorgan
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dysautonomia and a hypoventilation syndrome, which may indicate a brainstem

localization.25,30 These two features may account for a substantial proportion of the
mortality associated with this condition.

Investigations
The routine MRI is typically and surprisingly normal in most patients with
NMDA receptor encephalitis, particularly given the severe clinical presentation.
However, functional imaging, including imaging of white matter tracts, shows
substantial deficits. CSF usually shows lymphocytic pleocytosis, and EEG
typically demonstrates slowing (CASE 2-2).

CASE 2-2 A 25-year-old woman with no psychiatric history was found unclothed,
running in the streets. Her family stated that in the preceding week, she
was elated, very energetic, and behaving oddly, claiming to be the
strongest woman in the world. She presented with disorientation and
agitation and appeared to see things in the corner of the examination
room. There was no thought withdrawal, insertion, or broadcasting, no
somatic hallucinations, and no delusional perception. Her CSF revealed a
white blood cell count of 20 cells/mm3 (lymphocyte predominant) with
negative polymerase chain reaction and cultures for infection organisms,
and metabolic and drug screens were unremarkable. A mental status
examination revealed disorientation to time, person, and place, with
flight of ideas and repetition that she possessed supernatural strength.
Her brain MRI was normal and EEG showed mild diffuse slowing without
electrographic seizures. Taken together with the disorientation,
autoimmune encephalitis was considered likely, and she was pulsed with
corticosteroids while receiving antipsychotic medications.
Subsequently, her CSF and serum N-methyl-D-aspartate (NMDA)
receptor antibodies were found to be positive, and she proceeded to
plasma exchange, with a marked improvement. No ovarian teratoma was
found, as is the case in most patients with this condition.

COMMENT This case shows features typical for the early stages of NMDA receptor
encephalitis, with a disturbance of mood and behavior plus overt psychotic
features but without the schneiderian first-rank symptoms usually observed
in patients with schizophrenia. A normal MRI is typical for most people with
NMDA receptor encephalitis. A broad differential includes forms of mania,
drug intoxication, metabolic disturbances, and infectious encephalitis.

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 Other Phenotypes KEY POINTS
NMDA receptor encephalitis is defined by the presence of NMDA receptor
● NMDA receptor
antibodies, particularly in the CSF. Despite reports to the contrary, these encephalitis predominantly
antibodies are not relevant to the majority of patients with neuropsychiatric affects females younger
forms of lupus.35 The same is true for primary forms of psychosis for which these than 35 years. Approximately
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antibodies are not detected in CSF, and only in the serum of a few cases.36,37 This 30% of patients between the
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ages of 18 and 35 years also

combination of serum positivity with negative CSF antibodies is typically of have ovarian teratomas.
limited clinical significance. A very small number of psychiatric presentations
may be accounted for by NMDA receptor antibodies.38 These patients may ● Patients with NMDA
present early with a psychiatric-limited syndrome but often develop many of the receptor encephalitis are
distinct from patients with
core features previously described within a few days.
other antibody-mediated
encephalitides because of
CASPR2 ANTIBODY DISEASE the prominent psychiatric
CASPR2 antibodies are associated with one of the more common forms of features at presentation,
autoimmune encephalitis. Patients with CASPR2 antibodies have two broad which can result in
misdiagnosis.
syndromes affecting the brain: (1) a limbic-predominant encephalopathy
and (2) Morvan syndrome. Both affect males far more than females (an ● The stages of NMDA
approximately 9:1 ratio has been reported), predominantly in their sixties receptor encephalitis often
and seventies.8,16,39 The tempo of onset is often over several months, partly progress from early
development of a complex
overlapping with conditions including more rapid forms of neurodegeneration psychiatric presentation to a
such as Creutzfeldt-Jakob disease. Morvan syndrome is characterized by the mixed movement disorder.
presence of severe autonomic dysfunction (especially hyperhidrosis and This disease can be lethal
cardiovascular instability); insomnia; peripheral nerve hyperexcitability (often because of brainstem-
associated features like
neuromyotonia); and a behavioral syndrome, with few seizures but prominent
dysautonomia and
psychiatric impairments including hallucinations, agitation, and delusions hypoventilation.
occurring at higher rates than in CASPR2 antibody–associated encephalopathy.39
Patients with Morvan syndrome often have coexistent LGI1 antibodies, and ● CASPR2 antibody disease
approximately 25% will have a thymoma, a common cause of death in this affects males far more than
females and occurs as two
population. By contrast, patients with a more limbic encephalopathy and CASPR2 broad syndromes affecting
antibodies have prominent disorientation, amnesia, seizures, usually no other the brain: (1) limbic-
coexistent antibodies, and low rates of an underlying neoplasm.8 A variety of predominant
movement disorders may be observed in patients with CASPR2 antibodies. Most encephalopathy and (2)
Morvan syndrome.
commonly these include ataxia, myoclonus, and tremor in addition to the
otherwise unusual syndromes of paroxysmal ataxia and orthostatic leg ● Patients with LGI1 and
myoclonus.40 Also, neuropathic pain is a more recently recognized common part CASPR2 antibody disease
of these syndromes, more prevalent in patients with Morvan syndrome. It can be often do not fulfill
diagnostic criteria for
very troublesome and may relate to a small fiber neuropathy, given its clinical
probable autoimmune
pattern and associated reduction in cutaneous intraepidermal nerve fibers.41 A encephalitis. Because of
similar pain syndrome can also occur in patients with LGI1 antibodies, albeit at a this, direct clinical
lower rate and with a better response to immunotherapies than in patients with recognition of these
disorders and awareness of
CASPR2 antibodies. CASE 2-3 is an illustration of a patient with CASPR2 encephalitis.
antibody titers can lead to
accurate diagnoses and
Investigations improved patient outcomes.
CSF and MRI are often normal in patients with CASPR2 antibody disease. EEG
will reflect the presence of encephalopathy in most patients. The detection of
peripheral nerve hyperexcitability by needle EMG is a specific feature and
markedly narrows the differential diagnosis. CASPR2 antibodies have been
reported as frequently positive in disease controls when commercially available
kits are used; however, higher titers and their presence in CSF help mitigate this
rate of false-positive serum results.42 A substantial proportion of these patients

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 AUTOIMMUNE ENCEPHALITIS

carry HLA-DRB1:11*01, suggesting a clear immunogenetic predisposition to this

condition.22,43

Diagnosis
As with LGI1 encephalitis, the duration of disease onset and relative paucity of
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features of inflammation on imaging and routine CSF examination mean that these
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patients often do not fulfill existing criteria for possible autoimmune encephalitis
(TABLE 2-2). Therefore, prompt consideration of these diagnoses requires an
appreciation of the differences between distinctive antibody-defined syndromes.

OTHER CELL-SURFACE ANTIBODIES

There are a variety of other antibodies that target the extracellular domain of
neuronal proteins and also show a close association with forms of autoimmune
encephalitis. In clinical experience, the remainder of the cell-surface antibodies
associated with autoimmune encephalitis are less common.

GABAB Receptor and AMPA Receptor Antibodies

GABAB receptor and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA) receptor antibodies are typically associated with classic forms of limbic
encephalitis: an acute-to-subacute onset of amnesia, seizures, and behavioral

CASE 2-3 Over 6 months, a 68-year-old man became increasingly short-tempered

and irritable, exhibiting occasional memory problems, mild imbalance,
and pain in his legs. Within the past 2 months, he reported short-lived
episodes with upper abdominal sensations that rose into his chest. These
occurred daily and left him feeling “spaced out.” On examination, he
showed a mild gait ataxia, short-term recall deficits, and disinhibition,
with some loss of pinprick sensation in his toes. There were no motor
features. His MRI and routine CSF studies were unremarkable. Contactin-
associated proteinlike 2 (CASPR2) antibodies were detected as strongly
positive in serum and CSF. After a total of 7 months from symptom onset,
he was administered high-dose corticosteroids, followed by plasma
exchange and an 18-month prednisolone taper. Many symptoms
improved over the treatment period, with pain as a residual and
disturbing symptom that was unresponsive to further
immunosuppression and neuropathic pain agents.

COMMENT This case illustrates the breadth of features observed in CASPR2 antibody
disease, traversing psychiatry, cognition, movement disorders, and
epilepsy, with a high frequency of neuropathic pain, typically in older adult
men. Despite the length of presentation, which often pushes these
patients outside of the probable autoimmune encephalitis classification,
there is usually a good response to immunotherapies. Tumors are not
common in these patients, unlike the frequent thymomas in patients with
Morvan syndrome.

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 changes, typically with mesial temporal lobe swelling and T2 hyperintensity on KEY POINTS
T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences.
● GABAB receptor and α-
Both of these antibodies commonly have paraneoplastic associations with amino-3-hydroxy-5-methyl-
underlying small cell lung cancer and thymoma (TABLE 2-1). GABAB receptor 4-isoxazole propionic acid
encephalitis can also be a cause of new-onset refractory status epilepticus, in (AMPA) receptor antibodies
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addition to a disorder consistent with a rapidly progressive dementia, without are less common and are
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typically associated with

seizures.20,44 Some patients also fulfill the criteria for probable Creutzfeldt- classic forms of limbic
Jakob disease. encephalitis. Both of these
antibodies are commonly
GABAA Receptor Antibodies associated with cancer.
GABAA receptor antibody disorders present with a more diffuse, and less limbic-
● GABAA receptor
centric, encephalitis, consistent with the characteristic multifocal cortical and antibodies result in the
subcortical lesions observed on T2-weighted MRI sequences. The MRI characteristic features of
appearance of these lesions is very suggestive of the underlying antibody, multifocal cortical and
providing a diagnostic feature with high specificity likely to be available before subcortical lesions on T2-
weighted MRI.
antibody testing results.45
● Glycine receptor
Glycine Receptor Antibodies encephalitis is typically
Patients with antibodies against the glycine receptor develop an encephalopathy associated with prominent
auditory and tactile startle
typically associated with prominent auditory and tactile startle responses, responses, spasms,
spasms, stiffness, and myoclonus in addition to brainstem ocular motor and stiffness, and myoclonus in
bulbar disturbances, pyramidal signs, and dysautonomia.46 This disorder, addition to brainstem ocular
sometimes termed progressive encephalomyelitis with rigidity and myoclonus, can motor and bulbar
disturbances, pyramidal
affect patients from a wide range of ages spanning the very young to the very old
signs, and dysautonomia.
and equally affects males and females. Only a minority of these patients have an
acute onset illness. Rather like LGI1 and CASPR2 encephalitis, most cases are ● Patients with antibodies
chronic in onset and, therefore, do not meet the criteria for possible autoimmune to DPPX often present with
encephalitis. Investigation results can be highly variable, and imaging is often striking gastrointestinal
features of diarrhea, weight
normal, but CSF may reveal inflammation. loss, and constipation.

DPPX Antibodies ● Antibodies against

Patients with antibodies to DPPX, a protein expressed in the enteric plexus in IgLON5 result in tau
deposition, and patients
addition to the brain, often present with striking gastrointestinal features of with these antibodies are
diarrhea, significant weight loss (median of 20 kg [44 lb]), and constipation.47 reported to present with
These patients develop an encephalopathy, often with prominent myoclonus, neurodegenerationlike
seizures, brainstem features, and tremor, and many show marked improvements symptoms over many
months or years.
after immunotherapies. B-cell lymphoma is a recognized, albeit relatively
uncommon, association. ● Originally recognized
in association with
IgLON5 Antibodies neuromyelitis optica, MOG
Antibodies against IgLON5 have highlighted an especially intriguing association antibodies are now also
recognized in patients with a
between neurodegeneration and neuroinflammation.48 Patients with these more cortically restricted
antibodies have prominent deposition of tau, alongside strong human leukocyte encephalitis. MOG-
antigen associations and, of course, neuronal cell surface–directed antibodies. associated syndromes are
Patients with IgLON5 antibodies typically present over many months or years likely to expand in the
future.
with sleep disturbances, bulbar dysfunction, and a pleomorphic set of movement
disorders. Cognitive impairment, ocular motor disturbances, and autonomic
dysfunction are typically more minor elements of the syndrome. The
presentation of IgLON5 antibody disease is reported to resemble that of various
neurodegenerative conditions. However, the precise nature of these features

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 AUTOIMMUNE ENCEPHALITIS

distinguishes it from most forms of neurodegeneration. For example, the

associated sleep disorder contains both rapid eye movement (REM) and non-
REM features with dream enactment and sleep apnea; the movement disorder
includes gait instability, ataxia, myoclonus, and chorea. Although this is often a
lengthy syndrome in terms of presentation, it has become increasingly clear that
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CSF pleocytosis is present in the early stages of the condition.49 Perhaps

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commensurate with this, immunotherapies in the early stages can be effective,

whereas later treatments may be associated with poor outcomes, commonly
including death.

MOG Antibodies
Antibodies against MOG were originally recognized in the setting of classic
demyelinating features of optic neuritis and myelitis within the neuromyelitis
optica spectrum, in addition to acute disseminated encephalomyelitis (ADEM).50
Since this observation, it has become recognized that MOG antibodies can also be
found in patients with a more cortically restricted encephalitis (often termed
cerebral cortical encephalitis). Although the full spectrum of MOG encephalitis is
yet to expand over the next few years, these two specific encephalitis syndromes
are worth discussing here, particularly as the frequency of MOG antibodies is
likely to be at least as high as those previously noted. ADEM is an encephalopathy
that particularly affects children, who develop confusion and seizures. It shows
white and deep gray matter imaging abnormalities and 50% of patients are now
known to be MOG antibody positive.51 By contrast, the more cortical encephalitis
associated with MOG antibodies is known as unilateral cortical FLAIR-
hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES)
and is characterized by an encephalitis in the context of unilateral or bilateral
cortical hyperintensities. In individual patients, the ADEM, cerebral cortical
encephalitis, and FLAMES presentations of encephalitis can coexist with optic
neuritis and longitudinally extensive forms of myelitis, either as a fulminant
attack or as independent relapsing events.

SYNDROMES ASSOCIATED WITH ANTIBODIES TO INTRACELLULAR

TARGETS
A variety of antibodies are also associated with autoimmune encephalitis but
target the intracellular aspects of neuroglial proteins. These include GAD65
and GFAP.

GFAP Antibodies
A commonly detected antibody in routine neurologic practice is directed against
GFAP. GFAP antibodies are found in a wide spectrum of conditions encompassing
various forms of encephalitis, meningitis, and myelitis.52 One associated radiologic
finding is the striking perivascular radial enhancement seen in around one-half of
patients. Although these antibodies are directed at intracellular epitopes and
therefore are unlikely to be directly pathogenic themselves, they appear to serve
as a useful marker of an immunotherapy-responsive illness.

GAD65 Antibodies
Antibodies against GAD65, which are likely nonpathogenic, are another
commonly detected antibody. GAD antibodies can help the diagnosis of a variety

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 of neurologic syndromes; for more information, refer to the article “Stiff Person KEY POINTS
Syndrome and GAD Antibody–Spectrum Disorders” by Marinos C. Dalakas,
● Acute disseminated
MD, FAAN,53 in this issue of Continuum. Similarly, antibodies against so-called encephalomyelitis (ADEM), a
“paraneoplastic antigens,” particularly ANNA-1 (anti-Hu), antineuronal nuclear probable MOG-antibody
antibody type 2 (ANNA-2; also known as anti-Ri), CRMP-5 (also known as encephalopathy with 50% of
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anti-CV2), and Kelch-like protein 11 (KLHL11) can be associated with a variety patients who are antibody
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positive, occurs primarily in

of encephalitis syndromes. For more information, refer to the article children and results in white
“Paraneoplastic Neurologic Disorders” by Anastasia Zekeridou, MD, PhD,7 in and deep gray matter
this issue of Continuum. imaging abnormalities.

● Glial fibrillary acidic

DIFFERENTIAL DIAGNOSES
protein (GFAP) antibodies
As these disorders are associated with deficits in cognition and behavior, are found in a wide
movement disorders, seizures, peripheral nerve involvement, and other spectrum of conditions
regions of the nervous system, the differential diagnosis is very broad. However, encompassing various forms
for each syndrome there is often a more focused differential diagnosis. For of encephalitis, meningitis,
and myelitis.
example, patients with LGI1 and CASPR2 antibodies may be best considered
within a broader differential of rapidly progressive dementia, including ● Because of the breadth of
Creutzfeldt-Jakob disease, infectious forms of encephalitis, and mesial symptoms from antibody-
temporal lobe tumors.21 In contrast, for patients with NMDA receptor mediated neurologic
diseases, the differential
encephalitis, more pertinent differential diagnoses include recreational drug diagnosis is very broad.
overdoses (eg, ketamine), metabolic encephalopathies, and primary However, details of specific
psychiatric conditions. clinical features can result in
a more focused differential
diagnosis.
ANTIBODY EVALUATIONS
It is valuable for clinical neurologists to appreciate key aspects of diagnostic ● Each neural antibody test
testing to be able to effectively interpret the results. Fundamentally, the can have its own nuances
previously discussed clinical descriptions are all contingent upon the specific and requires attention to
antibody detected. Each antibody test can have its own nuances and requires rapidly expanding literature
to meet optimal practice
attention to rapidly expanding literature to meet optimal practice standards; no standards; no one rule suits
one rule suits all. Hence, it is invaluable to discuss antibody test results, especially all.
if they do not fit the clinical scenario, with an autoimmune neurology expert,
especially as diagnostic laboratories themselves likely lack the clinical
background and knowledge of alternative assays to help evaluate the relevance of
the queried test. Despite peculiarities, there are a few broad principles worth
appreciating.

CSF Versus Serum Testing

For almost all cases of autoimmune encephalitis, it is wise to send both CSF and
serum to diagnostic laboratories. This may be difficult in situations in which CSF
is challenging to obtain (eg, neonates or behaviorally agitated patients).
Alternatively, CSF may be far preferable to serum testing in patients after plasma
exchange. Nevertheless, the two tests can have complementary value. In general,
CSF confers high specificity, with a consequently low rate of false-positive
results. However, false-positive results are still recognized with CSF, and CSF
testing alone can miss some specific instances, such as some patients with LGI1
antibodies. Serum often shows high sensitivity, likely because levels of antibodies
are far higher in serum than in CSF,54 but is limiting in its higher false-positive
rate, particularly for some antibodies such as those directed against MOG or
CASPR2.42,51 This rate of false positivity can create hazards for patients, as
proven by a high rate of misdiagnosis largely based on clinically irrelevant serum

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 AUTOIMMUNE ENCEPHALITIS

results.55 Yet, antibody levels in either biosample are of no proven value in the
longitudinal assessments of patient progress; for this, the patient’s clinical status
is the preferred metric to monitor disease status.

Testing Modality
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Antibody interpretation should also be dependent on the immunoassay

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method (FIGURE 2-2). For example, it is well proven that the use of
complementary assays (eg, live or fixed cell–based assays plus immunohistochemical
tissue-based assays) can reduce the rate of false positives over single assay
methods. However, tissue-based assays in particular require a visual judgment of
the binding pattern and are vulnerable to interrater variability. It is also worth
highlighting that, for the detection of cell-surface antibodies, enzyme-linked

FIGURE 2-2
Antibody detection methods including live and fixed cell-based assays for specific
autoantigens and neuron- and tissue-based assays for the detection of both known and
unknown autoantigens.
Reprinted with permission from Ramanathan et al, J Neurol.1 © 2019 The Authors.
CBA = cell-based assay; GFP = green fluorescent protein; MAP2 = microtubule-associated protein 2; NBA =
neuron-based assay; TBA = tissue-based assay.

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 immunosorbent assay (ELISA) testing in particular is unlikely to yield clinically KEY POINTS
useful results. Results should be interpreted with caution from laboratories using
● For almost all cases of
ELISAs or line blots. Finally, as highlighted with aquaporin-4 (AQP4) antibodies suspected autoimmune
as well as in autoimmune encephalitis, there is an additional value in using live encephalitis, it is wise to
rather than fixed cell–based assays for antibody testing. Because live cell–based send both CSF and serum to
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assays present the native antigen without fixation, it is intuitive that this diagnostic laboratories.
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These two samples provide

approach is likely to yield more clinically meaningful results.56,57 valuable results when tested
in tandem.
Seronegative Autoimmune Encephalitis
The importance of identifying patients with clinically defined forms of ● Antibody interpretation is
dependent on the
autoimmune encephalitis who lack known detectable antibodies is clear, given
immunoassay method.
this population is estimated to account for up to 30% of all autoimmune Knowledge of each assay’s
encephalitis and has some of the poorest clinical outcomes.58 Seronegative weakness is essential to
autoimmune encephalitis is best diagnosed clinically, but, as a helpful adjunct, avoid misdiagnoses. For the
expert research laboratories may provide additional evidence of novel antibody detection of cell-surface
antibodies, enzyme-linked
reactivities by evaluating binding against the surface of live neurons (live immunosorbent assay
neuron-based assay) and rodent brain sections (tissue-based assays). (ELISA) testing in particular
Characterizations of these unknown reactivities have led to some of the major should be interpreted with
breakthroughs in this field, with many others still likely awaited. However, caution.
seronegative autoimmune encephalitis should be diagnosed only after serious ● Live cell–based assays
attention is given to a broad differential diagnosis to determine if there is an present native antigen and
alternative explanation for the symptoms. hence avoid fixation altering
the natural conformation of
the human antigen.

IMMUNOTHERAPIES ● Although differential

There are a few key treatment principles, largely drawn from a combination of effects of first-line
clinical experience, expert consensus, and observational studies. Although therapies are observed
symptomatic therapies may be useful in a minority of patients, they fail to across subtypes of
autoimmune encephalitis,
address the root cause. Therefore, administration of immunotherapies is the the efficacy of
mainstay of care for patients with autoimmune encephalitis. Although prompt corticosteroids, plasma
immunotherapy administration, sometimes within a few days of disease onset, exchange, intravenous
is proven to improve patient outcomes in observational studies of the most immunoglobulin (IVIg), and
tumor removal have been
common forms of autoimmune encephalitis,11,30,59 this urgency must be balanced shown to improve patient
with the required time and thought to definitively clinch the diagnosis and, symptoms.
hence, the rational administration of potentially toxic immunotherapies. On the
other hand, given the increased understanding of clinical features associated with
autoimmune encephalitis, antibody test results per se should not be awaited
before immunotherapy administration. As clinical recognition usually relies on
repeated exposure to similar cases, when possible, clinicians experienced in
autoimmune encephalitis management should be involved in the early
recognition and care of these patients. All of these simple measures aim to
expedite rational immunotherapy administration. Furthermore, throughout the
therapeutic process, especially given the nuances between diseases, it is
important to always remain in close contact with an expert center to help consult
regarding the care of these very complex and challenging patients. Experience in
managing these patients allows a deeper appreciation of when and how to
escalate or wean immunotherapies and of which potential complications to be
aware. Immunotherapies are often helpfully divided into those that are first-line,
second-line, or third-line agents. This tiered immunotherapy escalation forms a
valuable approach in clinical care.

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 AUTOIMMUNE ENCEPHALITIS

First-line Immunotherapies
Most patients are initially treated with high-dose corticosteroids, either
intravenously or orally. In some forms of autoimmune encephalitis, the response
to steroids can be dramatic. For example, in patients with LGI1 antibodies,
seizure frequencies can go from hundreds per day to a few per day with just
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1 week of steroids, and, after approximately 2 months of corticosteroids, most

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patients are seizure free.12 Steroids are often combined with either plasma
exchange or intravenous immunoglobulin (IVIg); both are considered first-line
agents. The use of IVIg in patients with LGI1 antibodies is the only intervention
supported by a randomized controlled trial.60 Although the effect of IVIg was
superior to that of placebo, both in terms of seizure cessation and improvement
in cognition, the magnitude of the effect was relatively disappointing, suggesting
that corticosteroids are still the preferred treatment. This concept is supported by
observational comparative data.61 Plasma exchange is a proven intervention in
diseases of the peripheral nervous system, but its value in central nervous system
antibody-mediated diseases is perhaps less intuitive. Nevertheless, based on
expert opinion, it appears to be an effective intervention in many patients with
autoimmune encephalitis.62 In patients with NMDA receptor encephalitis, these
first-line interventions return approximately 50% of patients to a good functional
outcome (modified Rankin Scale [mRS] score of <3), especially if administered
within 30 days of symptom onset.30,59 Furthermore, patients with LGI1
encephalitis can be spared cognitive impairment by early administration of first-
line immunotherapies. Overall, these first-line interventions, either administered
sequentially or simultaneously, appear to be effective but with differential effects
observed across antibody-defined subtypes of autoimmune encephalitis.
Another effective intervention, sometimes considered a form of
immunotherapy, is tumor removal in patients with paraneoplastic presentations.
Although only an option in a small proportion of patients with autoimmune
encephalitis, effective tumor removal can help remove a key generator of
autoantigen-reactive lymphocytes, hence terminating a potential driver of
the condition.63,64

Second- and Third-line Immunotherapies

The key second-line immunotherapies are rituximab and cyclophosphamide.
These are rarely needed for patients with LGI1 antibodies and may be ineffective
in the setting of LGI1 encephalitis.65 By contrast, in patients with NMDA receptor
antibodies, these immunotherapies appear to rescue a number of patients who
are relatively refractory to first-line therapies. Overall, the combination of first-
and second-line immunotherapies in patients with NMDA receptor encephalitis
appears to reduce mortality as well as morbidity.30,59,65 This is also likely to be
true in patients with IgLON5 encephalitis, in whom early administration may
have even greater value, likely by avoiding the irreversible deposition of tau.49
Third-line immunotherapies, including tocilizumab and bortezomib, have also
been discussed in the literature, particularly in patients with NMDA receptor and
seronegative forms of autoimmune encephalitis.58,66,67 In this clinical context,
patients who are refractory to first- and second-line therapies may be
administered another set of agents. Of course, this theoretically puts patients at
high risk of infection and combinatorial immunotherapy complications.
However, it may be necessary in some of the patients with more refractory
autoimmune encephalitis.

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 Relapses KEY POINTS
Relapses are a common problem in many patients with autoimmune encephalitis
● B cell-depleting drugs,
and are reported at rates of between 15% and 40% in patients with LGI1, NMDA like rituximab and
receptor, CASPR2, and GABAB receptor encephalitis.8,11,12,16,25,26,30,39,43,44 It is cyclophosphamide, used as
common practice to reactively escalate immunotherapies upon relapses. a second-line
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However, it would be optimal if future research highlighted methods to identify immunotherapy, are
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effective in certain cases of

patients prone to relapses and offer them preemptive therapies. autoimmune encephalitis.

CLINICAL OUTCOMES ● Patients with autoimmune

Despite immunotherapies, patients with autoimmune encephalitis have a number encephalitis who are
refractory to first- and
of residual deficits and disabilities. Patients with LGI1 antbody encephalitis
second-line therapies may
may show limited deficits on formal cognitive testing and mRS scores, but be administered a third-line
administration of more detailed questionnaires frequently reveals deficits immunotherapy. This could
throughout mood, fatigue, and functional domains that are likely to impact quality put them at increased risk of
of life.68 Most pediatric patients with NMDA receptor encephalitis experience infection and complications
but may be necessary.
fatigue and problems with sustained attention that correlate with quality of life,
despite having satisfactory mRS scores.69 This may reflect a need for outcomes ● The relapse rate of
that significantly improve mRS scores but, additionally, identifies unmet medical patients with autoimmune
needs in these patients. Hence, advances in monitoring options are required. encephalitis is high,
between 15% and 40%.

FUTURE APPROACHES TO CLINICAL AND TRANSLATIONAL RESEARCH ● Despite receiving

Clinical trials in autoimmune encephalitis are currently underway and aim to immunotherapies that
explore various novel strategies for immunotherapies in patients with this alleviate autoimmune
encephalitis symptoms,
condition.
patients note a number of
Although only one randomized trial has been completed in autoimmune residual deficits and
encephalitis to date,60 many are now underway. These include the use of disabilities. Addressing
satralizumab, which has a similar mode of action to tocilizumab, in both LGI1 these unmet medical needs
and NMDA receptor encephalitis70; pan B-cell-surface antigen CD19 depletion requires advancements in
monitoring and treatment
with inebilizumab in NMDA receptor encephalitis71; persistent IgG reductions options.
with an FcRn inhibitor, rozanolixizumab, in patients with LGI1 encephalitis72;
and bortezomib in patients with severe autoimmune encephalitis.73 Although ● Although randomized
randomized controlled trials are considered the optimal experimental design controlled trials are the
optimal experimental design
in therapeutics for medicine, they come with many intrinsic limitations.74 for many therapeutics, there
Further, in rare and severe conditions such as autoimmune encephalitis, the are inherent limitations for
challenging feasibility of clinical trials may limit the number of patients who can rare and severe conditions
be recruited. like autoimmune
encephalitis. To overcome
Hence, in this field, there is a clear and pressing need to better understand the
this challenge, translational
therapeutically tractable immunobiology and neurobiology that underlie studies may be the best
autoimmune encephalitis (FIGURE 2-3). In the absence of sequential and thorough opportunity to decipher the
clinical trials, this may be the best opportunity to decipher the clinically relevant clinically relevant
pathogenesis to direct
pathogenesis toward therapeutic interventions. Indeed, there have been several
therapeutic interventions.
advances in this field, summarized in dedicated reviews.54,75 These include an
understanding of where immune tolerance may be lost in patients, the relative
roles of CSF and the periphery in the development of pathogenic antibodies, the
presence of predisposing potentially modifiable environmental and genetic
factors in patients, and the mechanisms by which the antibodies alter neuronal
and synaptic function. The study of these aspects aims to direct the development
of therapeutics that can better address the disease-specific biologies in patients
with autoimmune encephalitis. For example, it is now known that an NMDA
receptor agonist may both prevent and counter the behavioral deficits induced

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 AUTOIMMUNE ENCEPHALITIS
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FIGURE 2-3
Proposed dynamics of CSF, blood, and lymphatic compartments in autoimmune encephalitis.
Reprinted with permission from Sun B, et al, Nat Rev Neurol.54 © 2020 Springer Nature Limited.
ASCs = antibody-secreting cells; BBB = blood-brain barrier; CNS = central nervous system; CXCL13 = motif
chemokine ligand 13; GC = germinal center.

by passive transfer of NMDA receptor antibodies in mice, a potentially direct

translation to the clinic.76 Similarly, the role of cervical lymph nodes in the
pathogenesis of these conditions provides a rational opportunity to target the
meningeal lymphatic system as a mechanism to prevent disease propagation.63,77

CONCLUSION
An appreciation of the often characteristic clinical features associated with
autoimmune encephalitis ensures early consideration and recognition of these
diagnoses. Available criteria can assist this process but should not be considered
replacements for clinical judgment, especially given the annually expanding list
of autoimmune encephalitis conditions within increasingly diverse phenotypes.
This field is further complicated by the necessity for contemporary knowledge
and the availability of few experts in central nervous system autoimmune
neurology. Hence, in consultations with autoimmune encephalitis experts,
clinical recognition of core features, alongside MRI, CSF, and EEG studies,
should guide the accurate early use of immunotherapies to improve patient
outcomes. These clinical tests should be accompanied by antibody testing to
confirm and direct the regimes thereafter. Future trial and translational studies
will guide optimal immunotherapy regimes to further optimize patient care
and outcomes.

1016 A U G U S T 2 0 24

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 ACKNOWLEDGEMENT
The writing of this article was funded in whole or in part by a senior clinical
fellowship from the Medical Research Council (MR/V007173/1) and a Wellcome
Trust Fellowship (104079/Z/14/Z).
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