283

Autoimmune Encephalitides and Rapidly

Progressive Dementias
Sarah F. Wesley, MD, MPH1 Damien Ferguson, BM, MRCPI2

1 Department of Neurology, Yale School of Medicine, New Haven, Address for correspondence Sarah F. Wesley, MD, MPH, Department
Connecticut of Neurology, Yale School of Medicine, New Haven, CT 06510
2 Academic Unit of Neurology, University of Dublin, Trinity College, (e-mail: Sarah.Wesley@yale.edu).
Dublin 2, Ireland

Semin Neurol 2019;39:283–292.

Abstract Rapidly progressive dementia (RPD) or cognitive decline is a common presenting complaint
in neurology. While primary dementia is often a concern, other forms of reversible
dementia must be thoroughly considered. This article focuses on the growing field of
autoimmune encephalitis (AE) as it pertains to the differential diagnostic considerations in a
Keywords work-up for RPD. Understanding clues in the history and examination is the first step in

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► autoimmune identifying patients with a potential autoimmune cause for RPD. While testing for infectious
encephalitis and toxic-metabolic etiologies is commonly preformed, it is necessary to consider early
► rapidly progressive ancillary testing for AE in appropriate cases of RPD. Autoantibody testing in the spinal fluid
dementia and serum, brain imaging, and electroencephalography all form the first line of investiga-
► autoimmune tions for AE. Treatment options and strategies depend on the AE subtype and a number of
dementia individual patient considerations.

A neurologist will commonly be asked to assess a patient with
rapid onset of dementia, cognitive decline, and/or behavioral
disturbance. In this article we will review the differential
diagnosis for rapidly progressive dementia (RPD) with a focus
on autoimmune and immune-mediated etiologies.
Despite the popular-culture attention given to autoim-
mune encephalitides such as N-methyl-D-aspartate receptor
(NMDAR) encephalitis, the concept of immune-mediated
causes of cognitive dysfunction is not new to the field of
medicine. Autoimmune encephalitis (AE) as a form of non-
infectious neuroinflammation has been described in differ-
ent forms throughout the 20th century. What we now refer
to as Sydenham’s chorea was identified as a phenomenon as
far back as the Middle Ages, but the relationship to infection
was not observed until the late 19th/early 20th century.1 The
1916 to 1923 outbreak of encephalitis lethargica, also known
as von Economo’s disease or sleeping sickness, raised ques-
tions about the relationship of infections to encephalitis. This
outbreak overlapped with the 1918 influenza pandemic and
left patients with postencephalitic parkinsonism.2,3
Early descriptions of immune-mediated encephalitis
without clear relationship to infection arose in the 1960s
with what was likely the first case report of what is now
known as Hashimoto’s encephalopathy.4 The concept of
“limbic encephalitis” associated with cancers was also first
described in a paper in Brain in 1968.5
Nonetheless, it is true that AE has become an increasingly
recognized cause of acute/subacute progressive mental status
change and cognitive decline. Such recognition has been
largely driven by the discovery of multiple autoantibodies to
a variety of cell surface and intracellular targets6 with a variety
of clinical phenotypes. Despite a panoply of presenting fea-
tures, cognitive change of some sort is common to most of the
encephalitides described to date. Therefore, it is critical that
immune-mediated conditions are considered in the differen-
tial diagnosis of an evaluation for cognitive decline and RPD.
Clues to a Diagnosis of Immune-Mediated
Rapidly Progressive Dementia
In this section we will consider the various clues to an
immune-mediated cause for RPD. It is critical that clinicians
are aware of these red flags for the purposes of (1) identifying
which patients to screen for autoimmune dementia and (2)

Issue Theme Dementia; Guest Editor, Copyright © 2019 by Thieme Medical DOI https://doi.org/
Arash Salardini, MD Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1678583.
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284 Autoimmune Encephalitides Wesley, Ferguson
being confident in diagnosing AE even if the antibody status
returns negative. It is important to consider that the anti-
bodies for AE are quite often negative, and the sensitivity and
specificity of antibody tests are variable. Hence, we must look
for patterns and clues in the history, exam, imaging, and
cerebrospinal fluid (CSF).
For both seronegative and seropositive AE, a focused and
nuanced history is crucial, given that the currently available
tests are neither 100% sensitive nor specific. The first element
of the history is to discuss the timing of onset of the cognitive
decline. Immune-mediated processes tend to be subacute to
acute. For example, a patient with 5 years of slow memory loss
would be atypical, but a patient who was previously normal
but has had 2 months of forgetfulness and personality changes
would be concerning. It is important to clarify explicitly with
the collateral history when the patient was last “completely
normal and independent, as when they were 10 to 20 years
ago.” Other clues can be found in the patient’s work history:
was their retirement voluntary or forced; if they are still
working, have they been in trouble of any kind at work?
One must also establish the patient’s risk or predisposition
for autoimmunity, including a detailed personal and family
history of autoimmunity. A patient might not be aware that a
personal or family condition is autoimmune in nature. If the
patient is not volunteering any conditions, it is useful to ask
about perceived “minor” autoimmune conditions, e.g., psor-
iasis. It is often useful to list off common conditions to jog the
patient’s or relative’s memory. To screen out other primary
autoimmune causes of cognitive change, e.g., lupus cerebritis
or primary angiitis of the central nervous system (CNS), it is
necessary to review whether the patient has new rashes or
skin changes, joint pain or swelling, weight gain or loss, vision
impairment, or stroke-like episodes.
Alongside autoimmunity, it is important to consider a
patient’s risk for opportunistic or exotic infections that have
been associated with postinfectious encephalitis. Travel his-
tory, immunosuppression history, and sexually transmitted
infections should be screened. We recommend documenting
the most recent dates and nature of any systemic immu-
notherapy, as it could influence the results of antibody
testing. A full infection evaluation and history is detailed
later in the article.
For the question of paraneoplastic encephalitis, the his-
tory should include screening questions for occult malig-
nancy, such as weight loss, unexplained fractures, rectal
bleeding, as well as defining a patient’s individual risk factors
for cancer, such as smoking history or history of specific
cancers personally or in the family.
Comorbid symptomatology consistent with AE might
exist alongside cognitive decline, and patients and families
should be asked about other concerns such as seizure-like
activity, psychiatric changes, new movement disorders, and
changes in gait or balance.
Directed questioning focusing on changes in personality,
new onset anxiety, or paranoia, and establishing a change
from psychiatric baseline will be informative in differentiat-
ing primary lifelong mood disorders from a truly new
psychiatric change. Prominent psychotic features are seen
Seminars in Neurology Vol. 39 No. 2/2019
in several of the described AEs, in particular gamma-ami-
nobutyric acid-B (GABA-B) receptor encephalitis,7 NMDAR
encephalitis,8 antithyroid peroxidase-related disease,4 and
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor (AMPA-R) encephalitis.9,10 In some cases, the psy-
chiatric changes might be the only symptoms.
The patient must also be screened for potential seizure-
like activity. With major generalized seizures, this part of the
history might be volunteered, but it is important to ask about
more subtle symptoms/signs of seizures, such as momentary
inattentiveness or injuries and periods of time that are
unaccounted for. With early leucine-rich, glioma inactivated
1 (LGI-1) encephalitis, for example, a patient might only
experience faciobrachial dystonic seizures (FBDS) that last
no more than 1 to 2 seconds and could easily be missed.11
Finally, there are several antibody-associated encephali-
tides that have particular presenting syndromes. For example,
Purkinje cell antibodies cause cerebellitis and cerebellar
degeneration,12,13 in which case asking about balance changes
and examining for subtle cerebellar signs are paramount.
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Alternatively, patients with anti-NMDAR and anti-DR2 might
exhibit dystonic or choreiform movements (►Table 1).
Differential Diagnosis for Nonimmune
Rapidly Progressive Dementia
The differential of RPD is broad and has been the subject of
several review articles.14–18 One of the first tasks for the
treating clinician is to consider the diagnosis of delirium in
all patients presenting with acute changes in mental status,
impaired attention, disorganized thinking, and an altered level
of consciousness.16 The archetypal and reportedly most com-
mon RPD is prion disease; a fatal, untreatable condition. Prion
disease and other nontreatable causes of RPD such as primary
neurodegenerative disorders will not be discussed further in
this section. Besides the autoimmune encephalitides discussed
previously, there are many other important causes of (second-
ary) RPD that are treatable and potentially reversible if diag-
nosed in a timely manner by an astute neurologist. The useful
mnemonic VITAMINS was supported by Geschwind et al14 and
includes Vascular, Infectious, Toxic-metabolic, Autoimmune,
Metastatic/neoplastic, Iatrogenic, Neurodegenerative, and Sys-
temic etiologies. The forthcoming section will focus on infec-
tious and toxic-metabolic causes of secondary RPD.
Infectious Etiologies
The differential diagnosis of RPD includes infections of the CNS.
The neurological presentation of CNS infections is broad but
can include an RPD syndrome in isolation or in conjunction
with other neurological symptoms and signs. Case series and
case reports of RPD include bacterial, viral, fungal, and parasitic
infections (►Table 2).19–29 Many of these infectious organisms
cause an RPD that is reversible if treated early enough, but left
untreated can also be fatal.19,24,26 Some infectious organisms
such as herpes simplex virus and Tropheryma whipplei cause
neurological syndromes (limbic encephalitis and oculomasti-
catory myorhythmia, respectively) that are well characterized;
however, classical presentations are not always the rule.14,26
 Autoimmune Encephalitides Wesley, Ferguson 285

Table 1 History of presenting illness—clues to immune-mediated etiology for rapidly progressive dementia

Topics Questions to ask

Timing of onset • Last time “completely normal,” as in their youth or compared with 10 years in the past
(acute–subacute, <3 mo) • Employment status
• Driving status
• Reason for leaving work or retiring
• Current trouble at work (e.g., probation)
Malignancy clues • Weight loss
• Chronic cough
• Unexplained fractures
• Rectal bleeding
• Risk factor assessment: smoking history
• Personal history of malignancy
• Family history of malignancy
Predisposition • Personal and first–second degree family members with autoimmune conditions
to autoimmunity • Examples: multiple sclerosis, rheumatoid arthritis, systemic erythematous lupus,
Sjogren’s syndrome, celiac disease, inflammatory bowel disease, dermatomyositis,
vitiligo, alopecia, psoriasis, eczema, type 1 diabetes mellitus
Systemic autoimmunity • New rashes or skin changes, joint pain or swelling, hair loss, bowel trouble,
clues weight gain or loss, vision impairment, or stroke-like episodes.

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Infection risk • Exposure risk: travel, animal contact
• History of immunosuppression
• Sexual history
Seizures • Momentary inattentiveness
• Facial twitch, limb twitch
• Unexplained injuries
• Time unaccounted
Personality changes • Confirm baseline psychiatric status and history
• New onset anxiety or depression
• New onset paranoia, psychosis, delusions
Gait and limb symptoms • Involuntary movements, e.g., dystonic movements, chorea
• Balance changes, falls, new use of walking aid

Viral infections normally associated with an acute encephalitis
may also present in a more insidious manner as an RPD in
immunocompromised or immunocompetent hosts.15,20 A
thorough history and physical assessment of the RPD patient
can reveal systemic symptoms as well as noncognitive neuro-
logical signs. Combining this with initial serum, CSF and
neuroimaging investigations may provide clues that prompt
the suspicious neurologist to search for infectious etiologies
and treat accordingly.
Depending on geographical region and the level of sub-
specialization within neurology clinics, infections may
account for 2 to 21% of cases of RPD.22,23,25,28 In the Uni-
versity of California San Francisco Memory and Aging Center,
a major referral center for suspected prion disease, only 4
cases out of 187 (2%) were diagnosed with an infectious
cause (viral meningoencephalitis) of RPD over a 6-year
period. Two of these cases were pathologically proved, and
the two remaining had no causative organism identified with
good recoveries.15 A retrospective study of RPD cases from
Athens, Greece, over a 3-year period identified infections as
the cause for RPD in 5.8% of cases. Among these were
Treponema pallidum, Coxiella burnetii, and human immuno-
deficiency virus (HIV).22 On the other hand, a retrospective
study over an 8-year period in Chandigarh, India, found that
21% of RPD cases were caused by infectious organisms.
Within this cohort, subacute sclerosing panencephalitis
(SSPE) was the most common cause (Measles morbillivirus;
44%) followed by neurosyphilis (Treponema pallidum; 18%)
and progressive multifocal leukoencephalopathy in HIV-
infected individuals (JC virus, 15%). The authors reported
that only 31% of those with SSPE had received measles
immunization.28 Other diagnoses in their study included
neurocysticercosis (Taenia solium), HIV encephalopathy,
tubercular meningitis, cryptococcal meningitis, and herpes
encephalitis. In a 10-year postmortem study of RPD cases in
Barcelona, Spain, 16% of RPD cases were deemed nonprion
and nonneurodegenerative (i.e., secondary dementias). Of
these, infections accounted for 16% (2.5% of the overall
autopsied RPD cohort). Pathological diagnoses in this study
included tuberculous meningoencephalitis, bacterial menin-
goencephalitis, and Whipple’s disease.24
Clues to infectious etiologies often arise from the history,
physical examination, CSF analysis, and neuroimaging. Anuja
et al28 reported a younger mean age of disease onset with
infectious and inflammatory etiologies in comparison with
prion disease and other neurodegenerative disorders, but
this may be specific to their population. Other studies pooled
infectious etiologies together with other secondary demen-
tias (neoplastic, toxic-metabolic, vascular, etc.), and it is not
possible to draw conclusions about specific features that

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286 Autoimmune Encephalitides Wesley, Ferguson

Table 2 Possible infectious etiologies of RPD
Bacterial • Mycobacterium sp.
• Treponema pallidum
• Borrelia burgdorferi
• Bartonella henselae
• Mycoplasma pneumoniae
• Rickettsia rickettsii
• Coxiella burnetii
• Tropheryma whipplei
Viral • HIV (seroconversion or IRIS)
• Polyomavirus species
– BK virus
– JC virus
• Herpesvirus species
– Varicella Zoster
– Herpes simplex virus 1 þ 2
– Epstein–Barr virus
– Cytomegalovirus
– Human Herpes Virus 6 þ 7
• Enterovirus species
• Measles/SSPE
• West Nile virus
ciencies (B1, B3, B12, and folate), and genetic causes such as
Wilson’s disease, and porphyria. Drug and alcohol toxicity and
heavy-metal poisoning (arsenic, lead, lithium, manganese, and
mercury) are included among toxic causes. One should also
always consider iatrogenic causes such as medication toxicity
and withdrawal (e.g., anticholinergics, anticonvulsants, ben-
zodiazepines, and lithium) in the differential for reversible
causes of RPD.14–17 Very rare causes include methylmalonic
acidemia (a single case of this childhood metabolic disease has
been reported as presenting in an adult as an RPD), bismuth
salt intoxication, and methotrexate neurotoxicity.15,30
Diagnostic Criteria for Autoimmune
Encephalitis
In their 2016 Lancet article, Graus et al31 proposed diagnostic
guidelines for AE, taking into account issues surrounding
access to, as well as sensitivity and specificity of, antibody
testing. Unlike prior criteria that relied heavily on antibody
status, their group focused on other clinical, radiographic,

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Fungal • Aspergillus
• Coccidioides
• Cryptococcus
• Histoplasma
• Blastomyces
Parasitic • Toxoplasmosis
• Cysticercosis
• Trypanosomiasis
• Malaria
• Granulomatous amoebic encephalitis
Abbreviation: HIV, human immunodeficiency virus; IRIS, immune
reconstitution inflammatory syndrome; RPD, rapidly progressive
dementia; SSPE, subacute sclerosing panencephalitis.
Source: Adapted from Tang-Wai 201368 and Geschwind et al 2007.14
would point to infectious causes.22,24 One of these clinico-
pathological studies found that the presence of gait disorders
and focal neurological symptoms at disease onset was more
indicative of prion disease or secondary dementias (includ-
ing infections) but not neurodegenerative RPDs. On the other
hand, seizures and CSF pleocytosis are more indicative
of secondary dementias and not prion disease or neurode-
generative RPDs.24
Toxic and Metabolic Etiologies
Many of the disorders included in this section overlap with
conditions considered by neurologists in the assessment of
acute altered mental status/delirium patients and are often
referred to as toxic-metabolic encephalopathies. In reality, a
continuum exists and many acute encephalopathies where the
cause is not identified will progress to look like RPD if
untreated. In a review of the five largest studies looking at
the causes of RPD, it was reported that 2% of all RPDs (15%
of secondary/reversible RPDs) were toxic-metabolic, and these
were not cases fitting the diagnostic criteria for delirium.16
Toxic-metabolic etiologies for RPD include organ failure (liver,
renal, and cardiopulmonary), electrolyte disturbances, endo-
crine abnormalities (thyroid and parathyroid), vitamin defi-
and laboratory findings suggestive of AE. Based on expert
consensus, they proposed that all four of the following
criteria must be met to make a diagnosis of probable AE:
• Rapid progression of working memory deficits (short-
term memory loss), altered mental status, or psychiatric
symptoms.
• Exclusion of well-defined syndromes of AE (e.g., typical
limbic encephalitis, Bickerstaff’s brainstem encephalitis,
and acute disseminated encephalomyelitis).
• Absence of well-characterized autoantibodies in serum
and CSF, and at least two of the following criteria: mag-
netic resonance imaging (MRI) abnormalities suggestive
of AE; CSF pleocytosis, CSF-specific oligoclonal bands or
elevated CSF immunoglobulin G (IgG) index, or both;
brain biopsy showing inflammatory infiltrates and
excluding other disorders (e.g., tumors).
• Reasonable exclusion of alternative causes.
To meet the proposed criteria for possible AE, the same
timeline of onset must be met along with at least one of the
following: “new focal CNS findings, seizures not explained by
a previously known seizure disorder, CSF pleocytosis (white
blood cell count of more than five cells per mm3), and MRI
features suggestive of encephalitis.”31
Antibody Positive Encephalitides
Of the dozens of known autoantibodies, we will describe the
most common antibody-mediated syndromes, focusing on
ones with predilection for causing RPD or cognitive changes.
In AE, the known associated antibodies tend to be either
directed against cell surface or synaptic proteins or directed
against intracellular antigens, either cytosolic or nuclear. The
sensitivity and specificity of testing in the CSF is higher for
most cell surface or synaptic receptor antibodies, but we still
recommend testing CSF alongside serum.10,32 In general, the
syndromes associated with intracellular targets tend to be
less immunotherapy-responsive and are more often

Seminars in Neurology Vol. 39 No. 2/2019


associated with malignancy; however, it is important to note
that many cell surface antibody-mediated syndromes can
also be associated with cancer.33
There are specialty laboratories that provide commercial
and, on a request basis, research antibody testing. The Mayo
Clinic Laboratories in the United States offers panel testing of
antibodies associated with RPD and/or abrupt behavioral
changes. The panels are called the “Dementia, Autoimmune
Evaluation/DMC1” in the CSF and “Dementia Autoimmune
Evaluation Algorithm/DMS1” in the serum. The main differ-
ence between them is that the serum includes a few auto-
antibodies that are serologically based but could be associated
with paraneoplastic AE, such as acetylcholine receptor (AChR)
muscle binding antibody, AChR ganglionic antibody, and P/Q-
type voltage-gated calcium channel antibody.34,35
As we review specific clinical subtypes of AE, it is necessary
to understand that the type of laboratory testing will influence
the sensitivity and specificity of any given antibody. Despite
the downside of being less available and also requiring a
trained reviewer, cell-based assays (CBAs) tend to have greater
specificity than other techniques. CBA is used for detecting
antibodies to cell surface or synaptic proteins.36 Western blot
is useful for nuclear antigens, ion channel antibodies, and
cytosolic antigens. Enzyme-linked immunosorbent assay
(ELISA) alone has a high rate of false positives.37,38
Antibodies to Intracellular Targets
Type 1 antineuronal nuclear antibody encephalitis, other-
wise known as anti-Hu or ANNA-1, is the most commonly
identified autoantibody of the ANNA-related syndromes. It is
associated with peripheral sensory neuropathy in over 50%
of cases, but has been known to cause limbic encephalitis as
well, and over 80% of cases are associated with small-cell lung
cancer (SCLC).39 ANNA-2 is also known as anti-Ri and is most
associated with breast and lung cancers. Clinically, opsoclo-
nus, myoclonus, and encephalopathy amongst other presen-
tations have all been described.40,41 ANNA-3 is less common
but is also strongly associated with malignancy, with a
variety of clinical presentations, including cerebellar ataxia
and encephalopathy.42
IgG for 62 kDa collapsin response-mediator protein-5
(CRMP-5) has been associated with paraneoplastic optic
neuropathies,43 and neuropathies along with subacute cog-
nitive decline were noted in 25% of patients in a 121-person
cohort published in 2001 by Yu et al.44
Anti-Ma1 and Ma2 antibodies are associated with ence-
phalitis and are recognized often in the setting of malig-
nancy. In a study of 38 people (age range up to 70 years), 34
had identified cancers, the most common of which was
testicular, followed by lung. Over 60% of patients developed
symptoms prior to detection of the malignancy. The clinical
syndromes were variable but over 90% involved either brain-
stem, limbic, or diencephalic structures. Twenty-seven of the
38 patients had short-term memory deficits.45
The anti-Purkinje cell cytoplasmic antibodies, PCA1 (anti-
Yo), PCA2, and Tr (now anti-delta/notch-like epidermal
growth factor-related receptor/anti-DNER) are recognized
paraneoplastic causes of encephalitis. PCA1 is classically
Autoimmune Encephalitides Wesley, Ferguson 287
associated with paraneoplastic cerebellar degeneration,
manifesting with pan-cerebellar dysfunction and associated
with breast or gynecological cancers, amongst others.12
PCA2 is particularly associated with SCLC.13 Lastly, anti-
Purkinje cell antibody anti-DNER (formerly anti-Tr) has
been closely associated with Hodgkin’s lymphoma, and it
most typically manifests with cerebellar dysfunction.46,47
Antibodies to Synaptic Proteins and Cell-Surface
Antigens
Glutamic acid decarboxylase (GAD65) antibody is directed at
synaptic proteins and has been associated with neurological
and nonneurological diseases, such as type-1 diabetes mel-
litus (DMT1). Neurological manifestations are classically
refractory epilepsy, limbic encephalitis symptoms (cognitive
decline and personality change), and stiff person syndrome.
While it has been associated with malignancy such as
thymoma and SCLC, it is not as common.48 A patient with
GAD65 encephalitis will commonly be observed to have
comorbid autoimmunity, such as thyroiditis, pernicious
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anemia, or DMT1. The titers for GAD65 are significant, as a
very low positive titer in the right clinical setting might
merely be associated with DMT1 as opposed to encephalitis.
It has also been reported positive alongside other autoanti-
bodies, such as GABA-A receptor antibodies in cases of
refractory seizures.49
NMDAR encephalitis is classically characterized by psy-
chiatric changes with memory impairment. Dystonic and
choreiform movements have been reported, and dysautono-
mia is common. The most commonly associated neoplasm is
ovarian teratoma, but it also occurs commonly as a primary
AE without tumor being found.50 While the disease is
classically associated with young women, it has been
reported in patients as old as 84. Moreover, after the age
of 45, NMDAR encephalitis tends to be more common in
men.51 It is particularly important to send CSF for NMDAR
antibody, as there is a possibility of false negative with serum
studies alone.32
GABA-B receptor encephalitis often presents with refrac-
tory seizures and limbic encephalitis. It has been associated
with SCLC, amongst other malignancies.7,52
AMPA-R antibody has been associated with subacute
memory loss, personality changes, and agitation that could
mimic a primary dementia with the exception of the rapid
timeline. In the initial case series of AMPA-R encephalitis, the
average age was 60 years old, and well over half were
associated with neoplasm.9 Similar demographics and malig-
nancy association were seen in a more recent cohort, with
62% having confirmed underlying cancers, including lung,
thymoma, and breast.53
The concept of encephalitis from voltage-gated potassium
channel (VGKC) complex antibodies has recently changed
after it was discovered that the target of the antibodies was
not the VGKC complex itself but instead associated proteins,
in particular LGI-154 and contactin-associated protein-like-2
(CASPR2)-IgG.55
LGI-1 encephalitis often begins with a distinctive seizure
semiology, referred to as FBDS. Patients will report brief
Seminars in Neurology Vol. 39 No. 2/2019
288 Autoimmune Encephalitides Wesley, Ferguson
stereotyped involuntary movements of one side of the face
and ipsilateral arm. Typically, there will be unilateral facial
contortion and flexion movement of the entire arm with the
exception of the proximal and distal interphalangeal joints
which may be seen to extend. It is recommended that
neurologists acquaint themselves with the semiology of
these events. There is a high-quality video of a FBDS available
for free through the Lancet Web site.56 It is important to note
that patients tend to be immunotherapy responsive in the
beginning of their illness, but can progress to generalized
seizures and cognitive decline if treatment is delayed. A clue
that may point you toward LGI-1 encephalitis is an associated
hyponatremia. Importantly, tumors have been reported in
association with LGI-1.55
CASPR2-IgG is associated with encephalitis but also per-
ipheral nerve disease. This spectrum includes acquired neu-
romyotonia with Morvan’s syndrome (encephalopathy,
autonomic dysfunction, insomnia, and neuromyotonia). If a
tumor is found, it is most commonly a thymoma.57
Other autoantibodies associated with encephalopathy
and potentially presenting as RPD include anti-mGluR5
(metabotropic glutamate receptor 5) as well as anti-DPPX
(dipeptidyl-peptidase-like protein-6), which causes amne-
sia, confusion, exaggerated startle, and rigidity.58
One might experience the clinical dilemma of having an
antibody return positive but with a low titer or an antibody
return positive that does not fit with what is known of the
prototypical clinical presentation. For concerns of low titers,
it is advisable to contact the testing laboratory directly
regarding the sensitivity and specificity of the involved
antibody. For anti-GAD65, titers are important, as lower
serum titers might be representative of nonencephalitic
autoimmune entities, such as DMT1, but typically serum
titers are quite high in true encephalitic GAD65.59 For anti-
bodies that return positive but do not fit a “classic” clinical
presentation, one possibility to keep in mind is that your
patient is presenting with a novel clinical manifestation.
Another way to view such results would be to look at them
more as an epiphenomenon in a patient who is experiencing
an immune-mediated event. These situations can raise clin-
ical and treatment dilemmas, and therefore, must be ana-
lyzed on an individual patient basis.
Evaluation of Rapidly Progressive Dementia
Autoimmune and Paraneoplastic Evaluation
Once an autoimmune or paraneoplastic encephalitis is clinically
suspected to be the cause of RPD, there are several investiga-
tions that should be done to help confirm or support the
diagnosis. Blood testing for immune-based etiologies should
include an AE antibody panel, antithyroid antibodies, and
rheumatological screen. It is advisable to consider primary
or secondary vasculitis as well and to test erythrocyte sedi-
mentation rate (ESR), c-reactive protein (CRP), antineutrophil
cytoplasmic antibody (ANCA), and antiphospholipid antibodies.
Lumbar puncture (LP) for CSF analysis should be an early
part of the work-up. It may be wise to take and store extra CSF
fluid on the first LP to prevent repeated procedures and to
Seminars in Neurology Vol. 39 No. 2/2019
avoid later confounded samples, for example after immu-
notherapy has been initiated. It is critical that autoimmune
antibody testing is sent in both the serum and CSF given
increased sensitivity of certain antibodies in the CSF, e.g.,
NMDAR antibody.32 Of note, only 50% of AE patients will
have positive autoantibody in the CSF and/or serum. Oligo-
clonal banding (OCB) should also be sent if AE is suspected.
One study found that intrathecal OCBs were found in 41% (9-
fold increase) of antibody-associated limbic encephalitis and
NMDAR encephalitis compared with controls, with a sensi-
tivity of 36% and specificity of 96%. In particular, NMDAR had
OCBs present 75% of the time. This study also revealed that
CSF cell counts were elevated in nearly half of cases, whereas
CSF protein was elevated only 32% of the time.60 It is also
reasonable to send cytology, flow cytometry, and an infec-
tious screen as described in the next section.
All patients should have brain imaging, ideally MRI of the
brain with and without contrast, including precontrast T1,
T2, and fluid attenuated inversion recovery (FLAIR)/T2
images, postcontrast T1, susceptibility-weighted images,
Downloaded by: Kent State University. Copyrighted material.
and three-dimensional views. Patterns of increased T2 and
T2/FLAIR signals are variable, with classic limbic encephalitis
affecting the medial temporal lobes/hippocampi while other
syndromes might involve basal ganglia, cortex, brainstem, or
diencephalic structures. Acute disseminate encephalomye-
litis based on diagnostic criteria tends to have diffuse, large
predominantly white matter lesions that are poorly demar-
cated and can involve deep gray matter.31 NMDAR encepha-
litis has been associated with any number of radiological
presentations, but MRI brain is normal in over 50% of cases.
For NMDAR encephalitis, the most common abnormalities
seen are in the hippocampus, but signal abnormalities are
also seen in the frontal lobes, cerebellum, basal ganglia, and
brainstem.61 Cerebellar degeneration is seen in anti-PCA
syndromes. Diffuse cerebritis could be seen in neurolupus.
Tumefactive lesions have been reported in several of the
encephalitides, including antivoltage gated calcium channel
related encephalitis and Hashimoto’s encephalopathy.62
Most patients will require an electroencephalogram
(EEG) either to monitor clinical seizure activity or to rule
out subclinical seizures. Status epilepticus is a concern for
patients with GABA-B and GABA-A encephalitis in particu-
lar.10 Specific seizure types can also be identified, such as
FBDS in LGI-1 encephalitis and “extreme delta brush” pattern
in NMDAR encephalitis.63
Malignancy screening is a critical part of investigating and
managing a patient with AE. The search for occult malig-
nancy typically begins with computed tomography (CT) of
the chest, abdomen, and pelvis. For conditions with a high
rate of a known single malignancy, special additional screens
are appropriate. For example, MRI of the pelvis or a transva-
ginal ultrasound is a reasonable next step in NMDAR ence-
phalitis, if the CT is negative. If the concern for malignancy
remains high, either due to the nature of the involved
autoantibody, individual patient risk factors, or incomplete
response to treatment, it is important to proceed with 18F-
fluoro-deoxyglucose positron emission tomography with
low-dose CT for attenuation correction (FDG-PET/CT). One

study found that FDG-PET/CT had a sensitivity and specificity
of 100 and 97.3%, respectively, for finding occult malignancy
in paraneoplastic neurological disease. These findings are in
stark comparison to CT which had a sensitivity of only 50%
and a specificity of 100%.64
Brain biopsy is often a measure of last resort, and while it
can help to rule out infectious etiology, there is a concern for
nonspecific findings in AE. One study of brain biopsies done
for encephalitis not otherwise specified found a definitive
diagnosis in only 45% of cases, despite re-review and addi-
tional testing.65 However, it remains an important option for
patients with declining clinical status in whom no cause has
been found and/or treatment has been ineffective.
Nonimmune Rapidly Progressive Dementia Evaluation
When considering infectious and toxic causes, it is imperative
to enquire about prior exposures the patient may have had to
infectious or toxic agents. Enquiries should be made into
hobbies, dietary history, travel history, animal exposure, sex-
ual history, occupational history, social history, and drug and
alcohol history. A detailed medical and surgical history and a
medication history, including over-the-counter medications,
are also necessary as it may help identify potential underlying
organ failure, malnutrition, toxic drug exposure, or secondary
immunosuppression. Systemic symptoms such as marked
weight loss, abdominal pain, diarrhea, night-sweats, fevers,
and rashes may point toward various underlying conditions
such as malignancy, porphyria, Whipple’s disease, infections,
and connective tissue diseases. Fluctuations in cognitive abil-
ity may point toward metabolic encephalopathies. Also, with
metabolic disorders it is helpful to know about their medical
and surgical history as well as family history, e.g., cirrhosis
from chronic liver disease, gastrectomy leading to vitamin
deficiency, Wilson’s disease, etc. Neurological symptoms and
signs outside of the cognitive realm such as parkinsonism,
seizures, focal deficits, neuropathy, and cerebellar disorder
may also point toward an infectious or metabolic disorder.
Following the initial assessment of the patient, several
have suggested first-line batteries of investigations to con-
sider in all cases of RPD.14,16–18 Essential tests include
serological tests, CSF analysis, EEG, and neuroimaging at a
minimum. These initial tests are supplemented in the first
instance with other pertinent tests based on clues in the
history or physical assessment that point to a particular
infectious or toxic-metabolic etiology. A list of suggested
tests for investigating infectious and toxic-metabolic causes
of RPD is included in ►Table 3. If these first rounds of tests are
inconclusive, then further expanded testing may be war-
ranted. Given the fact that these patients have by definition
presented rapidly and may continue to decline rapidly, these
tests should be performed in tandem with tests looking for
autoimmune etiologies discussed above and other etiologies
not covered by this article (vascular, neoplastic, neurode-
generative, psychiatric, and normal pressure hydrocephalus)
as diagnostic delay can lead to increased morbidity and
mortality. An algorithm, including a diagnostic decision
tree to facilitate the diagnosis of RPDs, has been suggested
by a panel of dementia experts in the United States.66
Autoimmune Encephalitides Wesley, Ferguson 289
Treatment and Management of Immune-
Mediated Dementia
Once AE is suspected based on the proposed diagnostic
criteria, and critical infectious, metabolic, and toxic causes
have been ruled out, it is important to initiate a trial of
immunotherapy. While there have not been large rando-
mized control trials evaluating treatments for AE, it would be
considered standard of care to treat empirically first-line
with intravenous (IV) steroids, IV immunoglobulin, and/or
plasma exchange.
A recent study looked at the clinical practice of neurolo-
gists from around the world encountering the dilemma of
seronegative AE or pending antibody results with a deterior-
ating clinical situation. It also interviewed three experts in
AE from three different continents. The consensus was
resoundingly in favor of a trial of immunotherapy for ser-
onegative AE that meets the proposed diagnostic criteria for
possible or probably AE. Common practice is to start with IV
methylprednisolone 1 g daily  5 days, IV immunoglobulin
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(1–2 g/kg), and/or plasma exchange.37
Another management dilemma with acute encephalitis is
when to proceed with immunotherapy if more esoteric infec-
tious etiologies have not been ruled out. IV immunoglobulin
and plasma exchange have the benefit of typically not worsen-
ing an underlying infection. However, prior to IV immunoglo-
bulin, it is advised that all antibody-based testing is sent, given
that false positives from passive exposure to pooled antibodies
could develop and confound further investigations.
In terms of second-line options and long-term mainte-
nance options, variation exists, and this is often related to
pharmaceutical access issues in each country. Need
for second-line immunotherapy is common, with the most
frequently used agents being rituximab and cyclophospha-
mide. In patients who relapse on second-line therapies, one
option is to treat with another round of first-line agents, such
as IV steroids, IV immunoglobulin, or plasma exchange.
Third-line options include mycophenolate mofetil, metho-
trexate, and azathioprine.33
In patients who are refractory to multiple lines of immu-
notherapies, the question of occult malignancy must be revis-
ited. If a body FDG-PET/CT has not been done, it is advised to
proceed with this screening. In some cases of refractory
NMDAR encephalitis, rare exploratory laparoscopy has been
done despite negative imaging, with positive teratoma pathol-
ogy and clinical improvement.67 In cases where a malignancy
is identified, removal of the tumor can be curative, for example
in NDMAR encephalitis. However, it has also been observed
that intracellular antibodies, which are more commonly asso-
ciated with paraneoplastic encephalitis, tend to have a less
robust response to immunotherapy.
Discussion and Conclusions
The differential of RPD is broad. Neurologists are generally
quick to consider prion disease and neurodegenerative dis-
orders as causative etiologies for RPD, but this article should
help to highlight the importance of considering autoimmune
Seminars in Neurology Vol. 39 No. 2/2019
290 Autoimmune Encephalitides Wesley, Ferguson

Table 3 Useful diagnostic tests in suspected infectious or metabolic RPD

Extended infection testing Core serum/urine testing Extended metabolic testing

• Hepatitis screen • CBC • Copper and caeruloplasmin
• Lyme screen • ESR • Urinary copper
• Malaria screen • CRP • Drug toxicology (urine or serum)
• Toxoplasma IgG/M • Renal profile • Heavy metal screen (urine or serum)
• Galactomannan • Liver profile including ammonia • Urinary organic acids
• β-D glucan • Coagulation profile • Methylmalonic acid
• Electrolytes (Ca2þ, Mg2þ, PO43-) • Homocysteine
• Vitamin B12 • Thyroid antibodies
• Thyroid function tests • Parathyroid hormone
• Syphilis screen • Vitamins D and E
• HIV screen • Vitamin B1 and B3
• Urinalysis  culture • Urinary porphobilinogen
• Blood culture
Extended CSF infection tests Core CSF tests Extended CSF metabolic tests
• HIV PCR • Cell count • CSF pyruvate and lactate
• Lyme antibody • Protein
• Whipple’s PCR • Glucose
• Measles antibody • Gram stain
• Specific bacterial • Acid-fast bacilli stain

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antibody/PCR testing • Bacterial culture including Mycobacterium
• Fungal stain
• Fungal culture
• Cryptococcal antigen
• Viral encephalitis PCR
• Oligoclonal bands
Core neurophysiology Extended neurophysiology for
• EEG toxic-metabolic disorders
• NCS (if neuropathy present)
Core neuroimaging
• MRI brain including T1 pre- and
postcontrast, FLAIR, DWI, ADC
and GE/SWI sequences
Other tests
• Duodenal biopsy for Whipple’s
• Brain biopsy

Abbreviations: ADC, apparent diffusion coefficient; CBC, complete blood count; CRP, C-reactive protein; CSF, cerebrospinal fluid; DWI, diffusion-
weighted imaging; EEG, electroencephalogram; ESR, erythrocyte sedimentation rate; FLAIR, fluid attenuated inversion recovery; HIV, human
immunodeficiency virus; IgG, immunoglobulin G; NCS, nerve conduction velocity; PCR, polymerase chain reaction; RPD, rapidly progressive
dementia; SWI, susceptibility-weighted imaging.
Note: This table does not include autoimmune, vascular, or neoplastic investigations that would also be included in the differential of RPD.

encephalopathies and other reversible causes such as infec- Damien Ferguson has received travel grants from Biogen
tions and toxic-metabolic encephalopathies among the dif- Idec for attendance at international conferences. He is
ferentials. Cases of RPD require a multifaceted approach to currently enrolled in a PhD program funded by the Health
achieve hasty investigation and management. There are Research Board of Ireland.
several immune-mediated causes that were not known
even 10 years ago but are now treatable. As the testing for Conflict of Interest
antibodies becomes more sophisticated and we anticipate None.
the discovery of hopefully dozens more antibodies, the need
for guideline-based approaches to diagnosis and treatment
will become all the more paramount.
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Sarah F. Wesley is a former editorial staff member for
Neurology Resident and Fellow Section. She is currently a
guest reviewer for Neurology without compensation. She
also serves as a guest reviewer for Clinical Therapeutics
and has received compensation.
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