Paraneoplastic and autoimmune encephalitis

Authors: Josep Dalmau, MD, PhD, Myrna R Rosenfeld, MD, PhD

Section Editor: Patrick Y Wen, MD
Deputy Editor: April F Eichler, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Mar 2019. | This topic last updated: Mar 25, 2019.

What's New

Autoimmune encephalitis after herpes simplex virus encephalitis

(October 2018)

Individual cases of anti-N-methyl-D-aspartate (NMDA) receptor encephal…

Read more

INTRODUCTION

Encephalitis is an inflammatory condition of the brain with many etiologies.

There are several types of encephalitis that are immune mediated, including the
classic paraneoplastic encephalitis syndromes, often associated with
antibodies against intracellular neuronal proteins (onconeuronal proteins), and
the encephalitis syndromes associated with antibodies against neuronal cell
surface/synaptic proteins. The latter are often referred to as "autoimmune
encephalitis."

While the paraneoplastic encephalitis syndromes are invariably cancer related,

the autoimmune encephalitis syndromes may occur in the presence or absence
of cancer. Thus, nomenclature can be confusing, as the paraneoplastic
encephalitis syndromes are autoimmune, and autoimmune encephalitis may be
paraneoplastic. In this topic, the term "autoimmune encephalitis" refers
specifically to those syndromes that are associated with antibodies to neuronal
cell surface/synaptic proteins.

An overview of paraneoplastic syndromes and other paraneoplastic disorders

are discussed separately. (See "Overview of paraneoplastic syndromes of the
nervous system" and "Paraneoplastic syndromes affecting peripheral nerve and
muscle" and "Paraneoplastic syndromes affecting the spinal cord and dorsal
root ganglia" and "Paraneoplastic cerebellar degeneration" and "Opsoclonus-
myoclonus syndrome".)

PARANEOPLASTIC ENCEPHALITIS

Clinical features — Paraneoplastic encephalitis may manifest as limbic or

brainstem encephalitis or be part of widespread involvement of the neuraxis, as
in paraneoplastic encephalomyelitis. In the majority of cases, symptoms have
an acute to subacute onset, and evaluation of the cerebrospinal fluid (CSF)
often shows abnormalities such as pleocytosis, increased protein
concentration, oligoclonal bands, and elevated immunoglobulin G (IgG) index,
suggesting an inflammatory process. In more than half of patients, the
neurologic syndrome develops before the cancer diagnosis is known.

Limbic encephalitis — Limbic encephalitis refers to an inflammatory process

localized to structures of the limbic system (eg, hippocampus, amygdala,
hypothalamus, cingulate gyrus, limbic cortex), although the pathologic, clinical,
and radiologic findings are often not confined to these areas. Limbic
encephalitis is considered a classical paraneoplastic syndrome, defined as a
disorder that is commonly due to a paraneoplastic process. However, as noted
below, limbic encephalitis is the main manifestation of several of the
autoimmune encephalitis syndromes that may occur without a cancer
association. (See 'Autoimmune encephalitis' below.)

Limbic encephalitis is characterized by acute or subacute mood and behavioral

changes, short-term memory problems, focal seizures with impaired awareness
(complex partial seizures), and cognitive dysfunction [1,2]. Hypothalamic
dysfunction may also occur with manifestations such as hyperthermia,
somnolence, and endocrine abnormalities. Symptoms typically evolve over days
to weeks, but more indolent presentations over months have been described [1].

Electroencephalographic (EEG) findings include focal or generalized slowing

and/or epileptiform activity, which is maximal in the temporal regions [2].
Magnetic resonance imaging (MRI) may show areas of T2/fluid-attenuated
inversion recovery (FLAIR) hyperintensity in the medial temporal lobes (image
1); contrast enhancement in these regions is very infrequent. Positron emission
tomography (PET) may demonstrate hypermetabolism in the medial temporal
lobes; later in the course of disease, hypometabolism may be present [3].

MRI findings in the medial temporal lobes are reasonably sensitive but not
specific for limbic encephalitis. Approximately 80 percent of patients with
symptoms of limbic encephalitis, in whom the diagnosis is eventually confirmed
during the course of disease, will have uni- or bilateral increased FLAIR signal in
the medial temporal lobes on MRI. The other patients may show late changes or
no changes on MRI.

The most frequent neoplasms associated with paraneoplastic limbic

encephalitis are cancer of the lung (usually small cell lung cancer [SCLC]),
seminoma and other testicular tumors, thymoma, breast cancer, and Hodgkin
lymphoma. Neurologic symptoms typically precede discovery of the tumor by
weeks or months.

The type of associated autoantibody varies with tumor type (table 1). With
SCLC, most patients have anti-Hu (also known as antineuronal nuclear antibody
type 1 [ANNA-1]) or CV2/collapsin-responsive mediator protein-5 (CRMP5)
antibodies in their serum and CSF, and they are more likely to develop other
manifestations of paraneoplastic encephalomyelitis [2,4]. Responses to
treatment (in particular after successful treatment of the tumor) have been
reported but are rare.
Limbic encephalitis and, less commonly, other syndromes have been reported in
some patients with cancer who have been treated with immune checkpoint
inhibitors. Some of these patients had anti-Hu or other autoantibodies [5-7].
(See "Patient selection criteria and toxicities associated with checkpoint
inhibitor immunotherapy", section on 'Neurologic'.)

Brainstem encephalitis — Paraneoplastic brainstem dysfunction often

occurs during the course of other paraneoplastic syndromes, such as limbic
encephalitis, cerebellar degeneration, or encephalomyelitis [8]. In some patients,
however, the neurologic symptoms and pathologic findings (such as
perivascular and interstitial inflammatory infiltrates, gliosis, and loss of
neurons) appear restricted to the brainstem (picture 1) [9]. The term
"rhombencephalitis" is sometimes used to denote inflammatory conditions
affecting the lower brainstem [10].

A wide spectrum of symptoms localized to the pons and/or medulla can

develop in these patients, including supranuclear, internuclear, and nuclear
extraocular movement deficits; opsoclonus; nystagmus; dysphagia; dysarthria;
sensorineural deafness; trigeminal sensory loss; central hypoventilation; and
vertigo [8,11,12].

Any of the antibodies seen in paraneoplastic encephalomyelitis can be

associated with predominant brainstem dysfunction (table 1). Anti-Hu
antibodies are more often associated with lower brainstem involvement, while
anti-Ma2 antibodies commonly associate with upper brainstem findings.

Many different underlying tumors have been identified. Patients with SCLC
typically have anti-Hu antibodies [8,12], while most patients with testicular
cancer have anti-Ma2 antibodies [13]. Anti-Hu brainstem encephalitis has also
been described in association with breast cancer, renal cell carcinoma, prostate
adenocarcinoma, and, rarely, in patients who appear cancer free [12].

Encephalomyelitis — Paraneoplastic encephalomyelitis is characterized by

involvement of several areas of the nervous system, including the temporal-
limbic regions, brainstem, cerebellum, spinal cord, dorsal root ganglia, and
autonomic nervous system [8,9]. The distribution of disease and symptoms
varies.

Pathologic examination usually reveals perivascular and interstitial

inflammatory infiltrates of T lymphocytes, gliosis, neuronophagic nodules, and
loss of neurons. In addition to T cell infiltrates, B cells preferentially cluster
around vessels and may be associated with plasma cell infiltrates [14,15]. The
findings are typically more extensive than symptoms would suggest and may
involve any area of the central nervous system (CNS), dorsal root ganglia, or
autonomic neurons.

Most patients with paraneoplastic encephalomyelitis have anti-Hu antibodies

(table 1) [8,16,17]. These antibodies are directed against neuron-specific RNA-
binding nuclear proteins (picture 2) and are associated with paraneoplastic
sensory neuronopathy as well as encephalomyelitis [8,16,18]. The expression of
the target antigens is highly restricted to the nervous system and the tumor [9].
(See "Paraneoplastic syndromes affecting peripheral nerve and muscle", section
on 'Peripheral nerve syndromes'.)

Virtually all cancer types have been associated with paraneoplastic

encephalomyelitis or its variants (limbic encephalitis, brainstem encephalitis,
myelitis) [8,9]. However, the underlying tumor is SCLC in approximately 75
percent of patients. This has been confirmed in four large series comprising
over 500 patients [8,16,17,19]. The tumor is frequently undiagnosed at the time
that the neurologic syndrome develops and may be difficult to demonstrate
because of its small size. This stands in direct contrast to the fact that most
SCLCs (over 60 percent) are widely metastatic at diagnosis. (See "Pathobiology
and staging of small cell carcinoma of the lung".)

Myelitis — Paraneoplastic myelitis occurs as part of encephalomyelitis,

usually in association with SCLC. Patients often develop sensory neuronopathy
(eg, involvement of the dorsal root ganglia) as well and have anti-Hu antibodies
in their serum and CSF [8,9]. Motor neuron syndromes are also described.
Sensory neuronopathy differs from the usual peripheral neuropathy in that the
sensory loss is not distal and symmetrical and may involve proximal areas such
as the face and trunk. Limb ataxia is often prominent due to early loss of
vibratory and position sensation. (See "Paraneoplastic syndromes affecting the
spinal cord and dorsal root ganglia".)

Specific antibody-associated syndromes

Anti-Hu encephalomyelitis — Anti-Hu paraneoplastic syndromes are often

multifocal, affecting temporal lobes, brainstem, cerebellum, dorsal roots, and/or
autonomic nervous system [1,8,16,19]. In many patients, symptoms begin with,
and may remain restricted to, the dorsal root ganglia, causing a subacute
sensory neuronopathy [8,16]. (See "Paraneoplastic syndromes affecting the
spinal cord and dorsal root ganglia", section on 'Subacute sensory
neuronopathy'.)

Other patients with anti-Hu antibodies present with a more restricted brainstem
or limbic encephalitis [8,12]. A presentation with nonconvulsive seizures has
been described in several case reports [20-23]. (See 'Limbic encephalitis' above
and 'Brainstem encephalitis' above.)

SCLC is found in most patients with anti-Hu encephalitis [1,16,19]. Some

patients have other cancer types; no cancer is found in approximately 15
percent of patients [16,19]. Some children with anti-Hu antibodies have
opsoclonus-myoclonus and neuroblastoma, but more commonly, the
encephalitis is not paraneoplastic. In one referral-based cohort, six of eight
children with anti-Hu encephalitis were cancer free compared with none of 243
adults [24].

Early recognition of anti-Hu encephalomyelitis and prompt antitumor treatment

are important in stabilizing or sometimes improving the neurologic symptoms.
In one series of 200 patients with paraneoplastic encephalomyelitis and anti-Hu
antibodies, antitumor treatment was associated with a significantly greater
likelihood of neurologic improvement or stabilization (odds ratio [OR] 4.6) and a
lower mortality rate (relative risk of death with no antitumor treatment 2.6) [16].

Immunotherapy (eg, corticosteroids, immune globulin, plasma exchange, etc),

either given with antitumor treatment or alone, has also been associated with
stabilization in a smaller proportion of patients [19,25]. One report describes
improvement with rituximab in two patients with paraneoplastic
encephalomyelitis associated with the anti-Hu antibody [26]. In children, the
syndrome appears to be more treatment resistant and associated with long-
term sequelae of intractable epilepsy and cognitive impairment [24].

Neurologic dysfunction is a frequent cause of death, particularly when there is

brainstem and autonomic dysfunction [8]. However, prolonged survival can
occur in association with regression of the tumor [16,27]. Neurologic function
rarely improves spontaneously [28].

Ma2-associated encephalitis — Testicular cancer is associated with anti-

Ma2 (also called anti-Ta) antibodies [13]. The Ma2 antigen is selectively
expressed in neurons and the testicular tumor (picture 2). Ma2 shares
homology with Ma1, a protein that is associated with other paraneoplastic
neurologic syndromes, particularly brainstem and cerebellar dysfunction (table
1) [15,29].

The clinical presentation of anti-Ma2-associated encephalitis differs from

classic paraneoplastic limbic encephalitis. In a series of 38 patients with anti-
Ma2 encephalitis, 34 (89 percent) developed isolated or combined limbic (n =
27), diencephalic (n = 13), or brainstem encephalopathy (n = 25) [15]. MRI
abnormalities were frequent in these brain regions, and inflammatory changes
were typically present in the CSF. Four patients developed other syndromes,
including two with a predominant cerebellar ataxia that remained stable for
several years, and two with myelopathy.

Other prominent neurologic features included excessive daytime sleepiness and

eye movement abnormalities, particularly a vertical gaze paresis that
sometimes evolved to total external ophthalmoplegia. Three patients developed
atypical parkinsonism, and two developed a severe hypokinetic syndrome. An
additional case report describes an individual whose syndrome included
amyotrophy of the upper extremities with an associated cervical cord lesion
[30].

Testicular germ cell tumors are the most common associated neoplasms,
identified in 18 of 34 patients found to have cancer in the above described
series [15]. Orchiectomy may be required to reveal microscopic testicular germ
cell neoplasia, as occurred in six men (age 26 to 40 years) with Ma2-associated
encephalitis and no evidence of other cancer by rigorous testing [31]. All six
men were identified to be at risk for testicular cancer because of new testicular
enlargement, testicular microcalcifications, and/or cryptorchidism.
Extragonadal germ cell tumors have also been described in association with
this syndrome [32,33]. The diagnosis of testicular germ cell tumors is discussed
separately. (See "Clinical manifestations, diagnosis, and staging of testicular
germ cell tumors".)

Coexisting antibodies to Ma1 were seen in 15 of 34 patients with anti-Ma2

encephalitis and were significantly more common in patients with tumors other
than testicular cancer (usually lung cancer) [15]. Compared with patients with
antibodies only to Ma2, these patients are also more likely to develop ataxia and
to have a worse prognosis.

Anti-Ma2-associated encephalitis is more responsive to oncologic and

immunologic treatment than other types of paraneoplastic encephalomyelitis
[32]. In the series cited above, neurologic improvement or stabilization occurred
in 18 of 33 patients with outcome information [15]. Features significantly
associated with improvement or stabilization included male sex, age 45 years or
less, testicular tumor with complete response to treatment, absence of anti-
Ma1 antibodies, and limited CNS involvement. However, a positive treatment
response can occur in other patients as well [34].
 Anti-CRMP5 encephalomyelitis — Antibodies to CRMP5 have been
associated with paraneoplastic encephalitis. Cortical symptoms are often not
confined to the limbic system; distinctive symptoms including cerebellar ataxia,
chorea, cranial neuropathies, loss of olfaction and taste, and/or optic
neuropathy have been described [35-39]. Other paraneoplastic syndromes
associated with these antibodies include axonal sensorimotor neuropathy,
uveitis, and optic neuritis.

The most common associated cancers are SCLC and thymoma. Improvement
with anticancer therapy and corticosteroids has been described.

Others — Stiff-person syndrome may occur in isolation or as part of

encephalomyelitis. Paraneoplastic stiff-person syndrome is associated with
antiamphiphysin antibodies and rarely with antibodies to glutamic acid
decarboxylase (GAD) or the glycine receptors that are more commonly
associated with the nonparaneoplastic syndrome [40-42]. (See "Paraneoplastic
syndromes affecting the spinal cord and dorsal root ganglia", section on 'Stiff-
person syndrome'.)

Although GAD antibodies are usually nonparaneoplastic, one study showed that
patients with these antibodies should be screened for an underlying cancer if
they have clinical presentations different from those typically associated with
GAD antibodies (ie, stiff-person syndrome, cerebellar ataxia), or develop
classical paraneoplastic syndromes (eg, limbic encephalitis, encephalomyelitis,
opsoclonus-myoclonus) [43]. The risk for cancer increased with age, male sex,
and the presence of coexisting neuronal cell-surface antibodies.

Antibodies to adenylate kinase 5 (AK5) were initially described in two patients

with the subacute onset of a severe limbic encephalitis refractory to therapy
[44], and additional patients have been encountered in clinical practice. None of
the patients had cancer.

Antibodies to Ri are found in patients with paraneoplastic opsoclonus-

myoclonus and ataxia. These antibodies have also been described in some
patients with paraneoplastic brainstem encephalitis with eye movement
disorders, dysphagia, ptosis, laryngospasm, and/or jaw dystonia [45]. While
most patients do not respond to therapy, as with other paraneoplastic
neurologic disorders, there are reports of responses to early initiation of
immunotherapy and tumor-directed treatment. (See "Opsoclonus-myoclonus
syndrome", section on 'Pathogenesis'.)

AUTOIMMUNE ENCEPHALITIS

Clinical spectrum — The autoimmune encephalitis syndromes have a wide

clinical spectrum that ranges from typical limbic encephalitis to syndromes with
complex neuropsychiatric symptoms such as deficits of memory, cognition,
psychosis, seizures, abnormal movements, or coma (table 2). For some
autoimmune encephalitides, children and women are more often affected.

This group of disorders is associated with antibodies to neuronal cell

surface/synaptic proteins [46]. The target antigens usually play critical roles in
synaptic transmission and plasticity. These syndromes are variably associated
with cancer, as noted below.

While patients are often severely affected, these disorders are highly responsive
to immunomodulatory therapies. At this time, the treatment approach to these
patients is largely based on the experience with patients with anti-N-methyl-D-
aspartate (NMDA) receptor encephalitis, which is the largest group studied to
date. As early initiation of treatment (immunotherapy and tumor-directed
therapy, if present) has been shown to improve outcomes, speed recovery, and
reduce the risk of relapses, it is important that these syndromes are promptly
recognized.

Specific autoimmune encephalitis syndromes

Anti-NMDA receptor encephalitis — Anti-NMDA receptor encephalitis is the

best characterized of the autoimmune encephalitis syndromes and is
associated with a predictable set of symptoms that combine to make up a
characteristic syndrome [47-51].

Clinical features — Many patients present with prodromal headache, fever,

or a viral-like process, followed in a few days by a multistage progression of
symptoms that include:

● Prominent psychiatric manifestations (anxiety, agitation, bizarre behavior,

hallucinations, delusions, disorganized thinking); isolated psychiatric
episodes may rarely occur at initial onset or at relapse [52]

● Insomnia

● Memory deficits

● Seizures

● Decreased level of consciousness, stupor with catatonic features

● Frequent dyskinesias: orofacial, choreoathetoid movements, dystonia,

rigidity, opisthotonic postures

● Autonomic instability: hyperthermia, fluctuations of blood pressure,

tachycardia, bradycardia, cardiac pauses, and sometimes hypoventilation
requiring mechanical ventilation

● Language dysfunction: diminished language output, mutism, echolalia

Accompanying opsoclonus-myoclonus has been described in at least two

patients [53,54]. Of note, a brainstem-cerebellar syndrome associated with
opsoclonus-myoclonus has been described in young women with ovarian
teratoma, but these patients do not have NMDA receptor antibodies [55-57].

Children as young as eight months have been reported with this syndrome
[49,58-61]; in the authors' experience, children as young as two months may be
affected. In children, the symptoms are similar to those of the adults, with
prominent early psychiatric symptoms in most patients; dysautonomia and
hypoventilation are less frequent and severe. Presenting symptoms usually
include acute behavioral change, seizures, language dysfunction, and prominent
dyskinesias, including dystonia and chorea [62,63]. Although rare, approximately
5 percent of patients are >45 years of age [64]. In this group, the disease is less
severe but outcomes tend to be worse, possibly due to delay in diagnosis and
treatment.

Diagnosis and differential diagnosis — The disorder should be suspected

in adults or children that develop the above clinical symptoms, usually
accompanied by:

● Cerebrospinal fluid (CSF) lymphocytic pleocytosis or oligoclonal bands

(although basic CSF parameters can be normal initially).

● Electroencephalography (EEG) with infrequent epileptic activity, but

frequent slow, disorganized activity that does not correlate with most
abnormal movements. In one study, 7 of 23 adults had a unique
electrographic pattern called extreme delta brush, a finding associated with
a more prolonged illness [65].

● Brain magnetic resonance imaging (MRI) that is often normal or shows

transient fluid-attenuated inversion recovery (FLAIR) or contrast-enhancing
abnormalities in cortical (brain, cerebellum) or subcortical (hippocampus,
basal ganglia, white matter) regions [48,66]. While not routinely performed,
positron emission tomography (PET) reportedly shows a characteristic
increase in the frontal-occipital gradient of cerebral glucose metabolism,
which correlates with disease severity [67].

The diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection

of immunoglobulin G (IgG) antibodies to the GluN1 (also known as NR1) subunit
of the NMDA receptor in serum or CSF (table 3) [68]. CSF IgG antibody testing is
highly sensitive and specific for anti-NMDA receptor encephalitis; false-positive
and -negative results may occur when testing only serum [69]. IgM and IgA
antibodies against the NMDA receptor, which have been described in some
patients with chronic schizophrenia or other chronic neurologic disorders, are
nonspecific, do not alter NMDA receptors in vivo, and have no additional value in
the diagnosis of NMDA receptor encephalitis [70,71].

CSF antibodies are always present at the time of presentation; most patients
have intrathecal synthesis of antibodies [72]. After treatment or in advanced
stages of the disease, the CSF antibodies usually remain elevated if there is no
clinical improvement, while serum antibodies may be substantially decreased
by treatments [66,73,74]. The titer of CSF antibodies appears to correlate more
closely with the clinical outcome than serum titers [48,66,69,73].

The differential diagnosis of this clinical presentation includes primary

psychiatric disorders (acute psychosis or schizophrenia), malignant catatonia,
neuroleptic malignant syndrome [75], viral encephalitis [76], and encephalitis
lethargica [77], among others [78]. A study examining the serum or CSF of 20
patients (mostly children) that had been considered to have "idiopathic
encephalitis with dyskinesias" showed that 10 (50 percent) had anti-NMDA
receptor encephalitis. A similar study examining patients with dyskinetic
"encephalitis lethargica," a descriptive term that likely includes several forms of
idiopathic encephalitis, showed that 10 of 20 patients had anti-NMDA receptor
encephalitis [77].

Association with ovarian teratoma and other tumors — The detection of

an ovarian teratoma is age dependent; approximately 50 percent of female
patients older than 18 years have uni- or bilateral ovarian teratomas, while less
than 9 percent of girls younger than 14 years have a teratoma [51]. A review of
400 cases showed that African-American patients have a mild predominance to
have ovarian teratomas compared with patients from other ethnic groups [50].
Ovarian teratomas are often revealed by MRI and computed tomography (CT) of
the abdomen and pelvis, along with abdominal or transvaginal ultrasound [66].
(See "Ovarian germ cell tumors: Pathology, clinical manifestations, and
diagnosis", section on 'Teratomas'.)
In male patients, the detection of a tumor is rare. Cases with associated tumors
other than ovarian teratoma include testicular germ cell tumor [79], teratoma of
the mediastinum, small cell lung cancer (SCLC) [48], Hodgkin lymphoma [80],
ovarian cystadenofibroma [81], and neuroblastoma [82]. The frequency of
underlying tumors in older patients (>45 years) is low, and when present, tumors
are more often carcinomas instead of teratomas [64]. Cases have been
described in patients with metastatic cancer being treated with checkpoint
inhibitor immunotherapy [83]. (See "Patient selection criteria and toxicities
associated with checkpoint inhibitor immunotherapy".)

Association with HSVE — Although preceding infections have been

suspected to play a role in triggering autoimmune encephalitis, to date this has
only been demonstrated for herpes simplex viral encephalitis (HSVE). Studies
have shown that approximately 20 to 30 percent of patients who are NMDA
receptor antibody-negative in serum and CSF at the time of HSVE infection
seroconvert to positive NMDA receptor antibodies (or less commonly other
antineuronal antibodies) in the setting of relapsing symptoms not attributable to
HSVE relapse [84-87]. A smaller proportion develop NMDA receptor or other
antibodies in the absence of clinical symptoms [87].

Symptoms of anti-NMDA receptor encephalitis in these cases begin at a median

of four to six weeks after initial viral infection and may occur in contiguity with
or after recovery from the HSVE [85,87-91]. In a series of 58 patients with
antibody-confirmed autoimmune encephalitis after HSVE (74 percent with
NMDA antibodies), the most common symptoms were change of behavior (93
percent), decreased level of consciousness (57 percent), choreoathetosis (47
percent, all in children four years of age or younger), seizures (38 percent), and
dysautonomia (27 percent) [87]. In most pediatric cases, symptoms have
included choreoathetosis and/or orofacial dyskinesias [85]; teenagers and
young adults are more likely to develop behavioral and psychiatric symptoms
[86]. Prompt diagnosis and treatment with immunotherapy improve symptoms
and outcome despite persistence of deficits from the HSVE, especially in older
children and adults [85,87].
In addition to NMDA receptor antibodies, antibodies to gamma-aminobutyric
acid A (GABA-A), dopamine 2 receptor, and unknown neuronal cell-surface
antigens have been reported in patients with autoimmune encephalitis after
HSVE [86,87].

Treatment and prognosis — Treatment options include

immunosuppression and tumor resection when indicated [51,66,73,92].
Progressive neurologic deterioration and death can occur without treatment.
However, spontaneous recovery has also been described in a few patients after
several months of severe symptoms [93].

In the absence of prospective and randomized data, treatment decisions should

be individualized and take into consideration patient age, the presence or
absence of a tumor, and symptom severity. Based on observational studies
reviewed below and clinical experience, we suggest initial treatment with
intravenous methylprednisolone (eg, 1 gram daily for five days in an adult) and
either intravenous immunoglobulin G (IVIG; eg, 400 mg/kg per day for five days)
or plasma exchange in most patients, in addition to tumor removal when
appropriate. It is unknown whether IVIG and plasma exchange have similar
efficacy; some clinicians may find IVIG easier to administer in patients with anti-
NMDA receptor encephalitis, who may be very young and have severe
dyskinesias, agitation, and autonomic instability.

If there is no evidence of clinical improvement with initial therapies, we proceed

with second-line therapies including rituximab (either 375 mg/m2 weekly for
four weeks, or 1 g twice two weeks apart), cyclophosphamide (750 mg/m2
monthly for four to six months depending on results), or both. A similar
escalation approach is being used in children by many experts; however, in
children the dose of medications is less clear and often has been adapted from
the use of the same medications in other autoimmune conditions (eg,
cyclophosphamide in pediatric systemic lupus erythematosus). (See "Systemic
lupus erythematosus (SLE) in children: Treatment, complications, and
prognosis", section on 'Severe SLE'.)
An alternative approach to stepwise escalation of immunotherapy is to use
rituximab in combination with steroids and IVIG or plasma exchange as initial
therapy. We increasingly favor this approach in severely affected patients, based
on personal experience and accumulating data supporting the effectiveness of
rituximab in reducing relapses when used in the second-line setting.

The largest published experience on treatment and outcomes in anti-NMDA

receptor encephalitis is a retrospective study of 577 patients that included 501
patients for whom treatment effects and outcome were assessable [51]. Nearly
all patients (94 percent) were treated with tumor removal and first-line
immunotherapy, including steroids, IVIG, and/or plasma exchange.

● Half of patients improved within the first four weeks of first-line therapy. Of
these, 97 percent had a good outcome at 24-month follow-up.

● Of the 221 patients who did not improve within the first four weeks of first-
line therapy, 125 (57 percent) received rituximab, cyclophosphamide, or
both. Patients who received second-line therapy had a higher likelihood of a
good outcome (modified Rankin Scale [mRS] 0 to 2) than those who did not
(odds ratio [OR] 2.7, 95% CI 1.2-5.8). Response rates were similar in adults
and children.

● By 24 months, approximately 80 percent of patients achieved a good

outcome (mRS 0 to 2) and 30 patients had died. Outcomes continued to
improve for up to 18 months after symptom onset.

● Twelve percent of patients relapsed within the first two years of the initial
episode. Patients without a tumor and those who did not receive second-
line immunotherapy were at increased risk for relapse.

The utility and safety of rituximab was examined in another retrospective study
of 144 children with inflammatory or autoimmune encephalitis, including 39
with anti-NMDA receptor encephalitis [94]. All children in the series received
rituximab at a median of six months from diagnosis. Early use of rituximab was
associated with greater likelihood of good outcome. Infectious adverse events
occurred in 8 percent of patients, including serious or fatal infection in four
patients.

These and other smaller series support a treatment approach based on

escalation of immunotherapy that results in substantial improvement in 75 to
80 percent of patients by 24 months [51,94-96]. Most studies show that
predictors of good outcome are early treatment and low severity of disease (eg,
no need for admission to an intensive care unit) [51,96].

Patients may require intensive care support for several weeks or months, and
afterwards a multidisciplinary team including physical rehabilitation and
psychiatric management of protracted behavioral symptoms [48,93]. Symptoms
of frontal lobe dysfunction (poor attention and planning, impulsivity, behavioral
disinhibition, memory deficits) typically improve gradually over months but can
persist long term in some patients [97]. Substantive persistent cognitive
impairments are more common and more severe when there is a delay to
diagnosis and treatment [98]. The strongest risk factors for poor one-year
functional outcomes are lack of clinical improvement within the first four weeks
of treatment and requirement for intensive care unit admission [99].

As noted above, patients with anti-NMDA receptor encephalitis are at risk for
relapse. Relapse occurs in 15 to 24 percent of patients, sometimes after several
years [48,66,100]. Relapse may occur in the absence of a tumor or in
association with an occult or recurrent teratoma. In several series, relapses
were more common among those who did not receive immunotherapy with the
initial presentation [51,100]. Relapses are typically treated similarly to the
approach in newly diagnosed patients, with a lower threshold to initiate second-
line therapies early in the course of the relapse.

Pregnancy and fetal effects — Transplacental transfer of IgG anti-NMDA

receptor antibodies has been documented in serum of babies born to mothers
with anti-NMDA receptor encephalitis. The effect of these autoantibodies on the
fetus is not well described and may be variable.
Case reports have described short-term fetal outcomes ranging from normal to
early neonatal death [101-106]. In the most severe case reported, the mother
had recovered from anti-NMDA receptor encephalitis 18 months before delivery
and presented to medical attention with eclampsia at 37 weeks gestation
without prior knowledge of the pregnancy or prenatal care, making it difficult to
determine whether measured fetal and maternal autoantibodies or other factors
were responsible for fetal demise [101]. Nonetheless, this report and others
suggest that close prenatal monitoring and measurement of antibody titers is
warranted in women with a history of anti-NMDA receptor encephalitis, even if
remote, who are pregnant or considering pregnancy.

Anti-LGI1 encephalitis — Patients anti-leucine-rich glioma inactivated 1

(LGI1) encephalitis develop memory disturbances, confusion, and seizures [107-
110]. Memory and cognitive deficits may be preceded by short faciobrachial
dystonic seizures that can be mistaken for myoclonus or dystonia and are often
poorly responsive to antiseizure drug therapy. Patients may develop
hyponatremia and rapid eye movement (REM) sleep behavior disorder.

MRI usually shows findings typical of limbic encephalitis (eg, medial temporal
lobe hyperintensity) [111], while CSF is often normal or only shows oligoclonal
bands [112]. Only 5 to 10 percent of cases are associated with cancer; the most
common associated tumor is thymoma. The association with other tumors may
be coincidental [113].

The associated antibodies target the LGI1 protein, a secreted neuronal protein
that functions as a ligand for two epilepsy-related proteins, ADAM22 and
ADAM23 [114]. The binding of the antibodies to LGI1 disrupts pre- and
postsynaptic LGI1 signaling, resulting in neuronal hyperexcitability [115].

Treatment with glucocorticoids, IVIG, mycophenolate mofetil, and/or plasma

exchange results in significant improvement in 70 to 80 percent of patients
[107,116-118]. Early initiation of immunotherapy in patients with faciobrachial
dystonic seizures may prevent the development of cognitive impairment and
improve long-term outcomes [109]. Experience with rituximab as an add-on
therapy is limited [119]. In our experience, complicating severe hyponatremia
and nonconvulsive status epilepticus can be life threatening and should be
aggressively treated. (See "Nonconvulsive status epilepticus".)

Relapses occur in up to one-third of patients, often but not exclusively during

the first six months of the disease, and are associated with worse outcome. In
one study, the median time to relapse after initial presentation was 35 months
[120]. Despite substantial recovery, cognitive deficits and disability persist in
many patients, along with evidence of hippocampal atrophy on MRI [113,121].

Anti-Caspr2 associated encephalitis — Anti-contactin-associated protein-like

2 (Caspr2)-associated encephalitis can manifest as limbic encephalitis, as
Morvan syndrome (neuromyotonia, memory loss and confusion, sleep
disturbances, autonomic instability), and in a small number of patients with
isolated neuromyotonia [112,122-124]. The target antigen is Caspr2, which
plays a role in maintaining the normal function of voltage-gated potassium
channels (VGKC) [122]. Caspr2 autoantibodies inhibit cell adhesion interactions
between Caspr2 and contactin-2 [125].

This disorder predominantly affects older men with a median age of 65 years,
although rare pediatric cases have been described [110,124,126]. The
presentation and disease course are slower than those of other autoimmune
encephalitis syndromes. In one study, the median time to disease nadir was
four months, but in 30 percent of cases it was >12 months.

Although the clinical syndrome is varied, almost 80 percent of patients develop

three or more of the following core symptoms: cognitive changes, cerebellar
symptoms, peripheral nerve hyperexcitability, autonomic dysfunction, insomnia,
neuropathic pain, and weight loss [126]. The disorder is usually not associated
with cancer. Patients with a tumor (usually thymoma) are more likely to develop
Morvan syndrome than isolated central or peripheral symptoms. Most patients
have responses to immunotherapy and approximately 25 percent will have
relapses.
 Anti-AMPA receptor encephalitis — Encephalitis associated with antibodies
against the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptor affects predominantly females, with a median age of onset of 50 to 60
years [127-131]. In a case series of 22 patients with anti-AMPA receptor
antibodies, limbic encephalitis with or without seizures was the most common
clinical presentation (55 percent); other presentations included limbic
dysfunction along with multifocal or diffuse encephalopathy (36 percent), motor
deficits followed by limbic encephalitis (one patient), and psychosis with bipolar
features (one patient) [130].

An underlying neoplasm is identified in approximately two-thirds of the patients,

most commonly lung, thymus, or breast [127,130]. A lymphocytic pleocytosis in
the CSF has been reported in 50 to 90 percent of patients (range 5 to 164 cells)
[127,130]. MRI is usually abnormal, with FLAIR signal abnormality in the medial
temporal lobes.

In one series, 9 of 10 patients responded to treatment of the underlying

neoplasm and/or immunotherapy, but subsequent relapses occurred in five (in
the absence of tumor recurrence) and were associated with an incomplete
treatment response and death from status epilepticus in one patient [127]. In
another series, 15 of 21 patients had a full or partial response to treatment of
the underlying neoplasm and/or immunotherapy [130].

Anti-GABA-A receptor encephalitis — Patients with encephalitis due to

antibodies against the GABA-A receptor develop a rapidly progressive
encephalitis with refractory seizures, status epilepticus, and/or epilepsia
partialis continua [132]. Nearly half of reported cases are in children [133]. In
these patients, the development of dyskinesias can suggest the diagnosis of
anti-NMDA receptor encephalitis.

The CSF often shows lymphocytic pleocytosis with increased protein

concentration. Unlike other causes of autoimmune encephalitis, in which the
MRI is normal or shows abnormalities limited to the limbic system, the MRI in
anti-GABA-A receptor encephalitis often shows multifocal cortical/subcortical
and widespread FLAIR and T2 signal abnormalities [133]. Tumors (mostly
thymoma) occur in 40 percent of patients, almost all adults; isolated cases with
other tumors have been reported [132,133]. In children, anti-GABA-A receptor
encephalitis may develop as a postviral encephalitis and coexist with NMDA
receptor antibodies. (See 'Association with HSVE' above.)

Patients respond to immunotherapy but often require pharmacologic-induced

coma for prolonged seizures.

Anti-GABA-B receptor encephalitis — Encephalitis due to antibodies against

the B1 subunit of the gamma-aminobutyric acid B (GABA-B) receptor has been
described primarily in adults presenting with limbic encephalitis, although
presentations may vary and include limbic encephalitis with seizures, status
epilepticus, ataxia, or opsoclonus-myoclonus [134]. In one report, anti-GABA-B
antibodies were the most common antibodies found in limbic encephalitis
syndromes associated with SCLC that were previously considered seronegative
[135]. One pediatric case was characterized by encephalopathy, refractory
seizures, and a mixed movement disorder (opsoclonus, ataxia, and chorea)
[136].

Approximately 50 percent of cases are paraneoplastic and almost always

associated with SCLC [134,137]. MRI shows FLAIR and T2 signal abnormalities
consistent with limbic encephalitis in approximately one-half of patients and
over one-half of patients have CSF pleocytosis and/or elevated protein levels
[134].

Most patients have substantial improvement with treatment (ie, immunotherapy

and tumor treatment when indicated).

Anti-IgLON5 encephalopathy — Patients with antibodies against IgLON

family member 5 (IgLON5), a neuronal cell adhesion protein, develop REM and
non-REM sleep parasomnias with abnormal sleep movements and obstructive
sleep apnea [138-141].
The most common presenting symptoms include sleep problems, gait
abnormalities, dysautonomia, and bulbar dysfunction. Based on a review of 22
cases, four clinical syndromes have been described at diagnosis: a sleep
disorder with parasomnias and sleep-disordered breathing; a bulbar syndrome
including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency; a
syndrome resembling progressive supranuclear palsy (PSP), with vertical and
horizontal supranuclear gaze palsies; and cognitive decline with or without
chorea [141]. All patients eventually develop parasomnias, sleep apnea,
insomnia, or excessive daytime sleepiness.

Video-polysomnography is essential to define the complex sleep disorder and

identify characteristic features of the disorder (see "Polysomnography in the
evaluation of parasomnias and epilepsy"). CSF and imaging studies tend to be
normal aside from the presence of IgLON5 antibodies in CSF and serum. There
appears to be a strong association with the human leucocyte antigen (HLA)
DRB1*10:01 allele [141]. Prognosis is poor, with few patients responding to
immunotherapy and a high mortality rate.

Neuropathologic evaluation of two patients at autopsy revealed neuronal loss

and extensive deposits of hyperphosphorylated tau, mainly involving the
brainstem tegmentum and hypothalamus. Neuropathologic criteria of anti-
IgLON5-related tauopathy have been proposed [142].

Anti-DPPX encephalitis — Patients with antibodies against dipeptidyl-

peptidase-like protein-6 (DPPX) develop severe prodromal symptoms of loss of
weight, diarrhea, or other gastrointestinal symptoms followed within a few
months (average four months) by the development of encephalitis with central
hyperexcitability such as hyperekplexia, agitation, myoclonus, tremor, and
seizures [143,144]. Some patients have symptoms suggestive of progressive
encephalomyelitis with rigidity and myoclonus (PERM) [144,145]. Most patients
have a protracted course, although subacute presentations have been reported
[143,146]. Tumors are rare, and when they do occur, most are B cell neoplasms
[146].
Other common features included CSF lymphocytic pleocytosis, but studies may
be normal; the MRI is usually not specific. Patients usually have an initial benefit
from immunotherapy, but often relapse when immunotherapy is tapered.

Anti-GlyR encephalopathy — Antibodies to the α-1 subunit of the glycine

receptor (GlyR) have been associated with a syndrome of PERM, acquired
hyperekplexia, and stiff-person syndrome in some patients without glutamic
acid decarboxylase (GAD) antibodies [147-150]. A few patients have been
reported with limbic or other encephalopathy without brainstem or spinal cord
features. In a series of 45 patients, 5 had a past history and successful
treatment of a tumor, and in 4 patients, the tumor diagnosis was concurrent
with the neurologic disease [151]. Most patients have responses to
immunotherapy. Antibodies to α-1 GlyR have also been reported in serum (and
at low titers) of some patients with isolated optic neuritis, multiple sclerosis, or
cerebellar ataxia without stiff-person syndrome or PERM [42,152].

Anti-mGluR5 encephalitis — Antibodies against the metabotropic glutamate

receptor 5 (mGluR5) have been associated with a limbic encephalitis, often
including movement disorders, sleep dysfunction, and seizures [153-156]. The
clinical spectrum includes prominent neuropsychiatric features (eg, progressive
mood and personality changes, anterograde amnesia, disorientation),
prosopagnosia, headaches, involuntary movements, and seizures. The CSF
often shows pleocytosis, and in approximately half of the cases, the MRI shows
FLAIR abnormalities in limbic or extralimbic regions [156].

The disorder is highly responsive to immunotherapy and treatment of the tumor,

but relapses can occur. The syndrome is most commonly associated with
Hodgkin lymphoma (Ophelia syndrome) or SCLC but can also occur in the
absence of a tumor.

Anti-mGluR1 encephalitis — Patients with antibodies against the

metabotropic glutamate receptor 1 (mGluR1) develop cerebellar ataxia rarely
accompanied by cognitive changes, seizures, or psychiatric symptoms
[157,158]. The disorder appears to affect women and men in equal proportions,
with a median age in one series of 58 years [158]. The disorder is usually not
cancer associated, although a few patients have had a history of a hematologic
malignancy and one patient had a concurrent cutaneous T cell lymphoma. The
disorder can improve with early immunotherapy.

Anti-neurexin-3 alpha encephalitis — Antibodies to neurexin-3 alpha have

been described in a series of five patients who developed a severe encephalitis
with rapid decline in consciousness, orofacial dyskinesias, and central
hypoventilation that in some patients resembled anti-NMDA receptor
encephalitis [159]; however, NMDA receptor antibodies were absent in all cases.
Patients were relatively young (median age 44 years) and all had prodromal
symptoms before the rapid decline. The CSF was abnormal in all (four with
pleocytosis and one with elevated IgG index); brain MRI was normal in four and
showed FLAIR abnormalities in the temporal lobes in one. All five patients
received immunotherapy and three had partial recovery. One patient died from
the disease and the other from sepsis. Four of the patients had evidence of
systemic autoimmunity but none had a cancer history. A more complete clinical
spectrum of this syndrome remains to be described.

Encephalopathy with antibodies against GFAP — Antibodies against glial

fibrillary acidic protein (GFAP) have been described as a marker for a relapsing
autoimmune meningoencephalitis or encephalitis, with or without myelitis
[160,161]. Although these antibodies do not target a neuronal protein, they are
included in this section because many of the reported patients had other
relevant autoimmune responses (eg, anti-NMDA receptor antibodies, anti-GAD
antibodies, and aquaporin-4 [AQP4] antibodies, among others) that may have
driven the clinical syndrome. The patients had a range of clinical symptoms
including headache, optic disc edema and optic papillitis, progressive
encephalopathy, autonomic instability, myelopathy, tremor, and psychiatric
disturbances [160,161]. Approximately one-third of the patients had a past or
current systemic tumor. The CSF often showed a leukocytic pleocytosis, and a
variety of MRI features were described including diffuse T2 abnormalities in
periventricular white matter, leptomeningeal or perivascular enhancement
(sometimes in a radial distribution), and longitudinally extensive T2
hypointensity in the spine. Most of the patients responded to glucocorticoids.

DIAGNOSTIC APPROACH

In the appropriate clinical context, detection of specific autoantibodies

establishes a definitive diagnosis of autoimmune or paraneoplastic
encephalitis. However, not all patients with paraneoplastic or autoimmune
encephalitis have antibodies, and the absence of antibodies does not rule out
an autoimmune mechanism.

For patients without antibodies, the suspicion for a paraneoplastic or

autoimmune etiology is based on the presence of a subacute, progressive
neurologic syndrome conforming to the clinical features reviewed above,
clinical history including cancer risk factors, and supportive laboratory and
radiologic findings.

In all patients, consideration of alternative etiologies for the encephalitis

syndrome is critical (table 4), as treatment decisions should be made before
confirmatory antibody test results are available, and infectious etiologies in
particular should be excluded before embarking on immunosuppressive
therapies.

Differential diagnosis — The differential diagnosis of autoimmune or

paraneoplastic encephalitis includes a variety of alternative causes of
encephalitis and encephalopathy. Broad categories include infection, toxic and
metabolic disturbances, vascular disorders, neoplastic disorders, demyelinating
and inflammatory disorders, psychiatric disease, neurodegenerative dementias,
and rare heritable or metabolic disorders (table 4).

Some clinical syndromes, such as limbic encephalitis, may initially have a wide
differential diagnosis. For example, metastatic disease affecting the brain or
leptomeninges, viral encephalitis, Creutzfeldt-Jakob disease, ischemic and
hemorrhagic cerebrovascular disease, Whipple disease, psychiatric disease,
toxic-metabolic encephalopathy, Wernicke encephalopathy, and primary
degenerative dementia have all been reported to cause a clinical syndrome for
which the diagnosis of paraneoplastic or autoimmune limbic encephalitis was
considered [1,68,78,162-164].

The differential diagnosis in patients with predominant brainstem encephalitis

includes multiple sclerosis, Behçet syndrome, Listeria infection, enterovirus, and
tuberculosis infection [10].

Some of the autoimmune encephalitides have early and prominent psychiatric

manifestations, leading many of these patients to be admitted to psychiatry
units, thought to be malingering, or to have a substance use disorder. Careful
examination may reveal subtle neurologic deficits at this stage, findings that
should lead to the consideration of autoimmune encephalitis. Most patients
develop additional features of the syndrome within days or a few weeks
[51,165].

Clinical evaluation and imaging — Patients with suspected paraneoplastic or

autoimmune encephalitis (table 5) should have neuroimaging,
electroencephalography (EEG), lumbar puncture, and serologic testing for
appropriate biomarkers to confirm the diagnosis and exclude alternative
etiologies.

A brain magnetic resonance image (MRI) is helpful in this clinical setting to

exclude a cerebrovascular event or metastatic disease, among others.
Characteristic MRI findings in patients with paraneoplastic or autoimmune
encephalitis include signal hyperintensities on fluid-attenuated inversion
recovery (FLAIR) or T2-weighted images in affected brain regions (eg, medial
temporal lobes and/or brainstem); subcortical regions and the cerebellum are
sometimes affected as well. Contrast enhancement is variable. Although MRI
findings are neither sensitive nor specific for these disorders, in the appropriate
clinical setting they can be highly suggestive of specific syndromes (eg,
multifocal FLAIR and T2 signal abnormalities in gamma-aminobutyric acid A
[GABA-A] receptor encephalitis) [132]. (See 'Anti-GABA-A receptor encephalitis'
above.)

An EEG should be performed in most cases to exclude nonconvulsive seizures.

In patients with paraneoplastic and autoimmune encephalitis, nonspecific EEG
abnormalities are common and include focal or generalized slowing,
epileptiform activity, and periodic lateralized epileptiform discharges (PLEDs)
[2]. Approximately one-third of patients with N-methyl-D-aspartate (NMDA)
receptor encephalitis have an EEG pattern called extreme delta brush that is
considered characteristic for the disorder [65].

Cerebrospinal fluid (CSF) examination should be performed and should include

cell count, protein, and glucose; viral cultures and other studies to exclude viral
infection and other pathogens should also be performed (see "Viral encephalitis
in adults", section on 'Diagnosis'). Cytology should also be performed on the
CSF to exclude leptomeningeal metastasis. (See "Clinical features and
diagnosis of leptomeningeal metastases from solid tumors", section on
'Diagnostic evaluation'.)

Patients with paraneoplastic and autoimmune encephalitis may have normal or

abnormal CSF findings. Abnormalities include modest elevation of protein (<100
mg/dL), mild to moderate lymphocytic pleocytosis, elevated immunoglobulin G
(IgG) index, and/or the presence of oligoclonal bands [2,166]. However, these
findings are variable, and some syndromes, such as anti-leucine rich glioma
inactivated 1 (LGI1) encephalitis, often have only mildly abnormal or normal CSF
studies [167]. A lack of inflammatory findings on CSF and MRI may be
particularly common in older adults [168].

Metabolic and toxic encephalopathies should also be considered and excluded.

(See "Acute toxic-metabolic encephalopathy in adults", section on 'Diagnosis'.)

If the patient does not have a known cancer diagnosis, evaluation for occult
malignancy should also ensue, with the syndrome often providing a clue as to
the tumor location (table 1 and table 2). For example, as small cell lung cancer
(SCLC) comprises the majority of underlying neoplasms in older patients with
limbic encephalitis, chest imaging should have a high priority in patients with
this syndrome, whereas young women with anti-NMDA receptor encephalitis
should be thoroughly investigated for an ovarian teratoma. (See "Overview of
paraneoplastic syndromes of the nervous system", section on 'Occult
malignancy'.)

Antibody testing — Paraneoplastic and autoimmune antibody testing should be

performed on both serum and CSF (table 1 and table 2) [68]. Not all biomarkers
have commercially available testing, and some antigens remain to be
characterized. Thus, negative results do not exclude a paraneoplastic or
autoimmune disorder [166]. A sample of patient's CSF and serum can be sent to
a research laboratory for examination in these cases. Other caveats regarding
antibody testing are discussed separately. (See "Overview of paraneoplastic
syndromes of the nervous system", section on 'Antibody screening'.)

General principles to follow when assessing and interpreting antibody testing in

a patient with symptoms suggesting autoimmune encephalitis include the
following:

● Test for antibodies in serum and CSF. The approach of first testing serum
and then, if negative, testing CSF is not recommended, as it delays
diagnosis and may lead to false-positive results.

● If serum antibody testing is positive but the CSF is negative, consider that
the serum result is a false-positive diagnosis. Contact the laboratory and
request retesting of the samples.

● If the clinical picture does not fit with the antibody identified, the antibody
may be a false-positive result [169], particularly if only serum has been
examined, or it the antibodies were only identified in serum. In this case,
contact the clinical laboratory for retesting or a research laboratory for
guidance.
 ● Clinical decisions should be based on clinical assessment rather than on
antibody titers. Although the antibody titers may correlate with the clinical
course, this correlation is imperfect, and antibody titers often remain
detectable even after recovery.

Diagnostic criteria — Criteria for diagnosing paraneoplastic disorders and a

clinical approach to the diagnosis of the autoimmune encephalitis have been
developed by expert panels [170,171]. Because autoantibody test results and
response to antitumor and immunosuppressive therapy are not available at
disease onset, these criteria rely on neurologic assessment and conventional
neuroimaging and CSF testing reviewed above [171].

As an example, diagnostic criteria for definite autoimmune limbic encephalitis

require all four of the following criteria (table 6):

● Subacute onset (rapid progression of <3 months) of working memory

deficits (short-term memory loss), seizures, or psychiatric symptoms
suggesting involvement of the limbic system

● Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to

the medial temporal lobes

● At least one of the following:

• CSF pleocytosis (>5 white blood cells per mm3)

• EEG with epileptic or slow-wave activity involving the temporal lobes

● Reasonable exclusion of alternative causes.

In the presence of antibodies against neuronal cell-surface/synaptic antigens or

onconeural proteins, a definite diagnosis of autoimmune limbic encephalitis can
be made when at least two of the first three criteria are met and alternative
causes have been excluded [171]. In addition to limbic encephalitis, specific
criteria for probable and definite anti-NMDA receptor encephalitis are also
available (table 3). (See 'Anti-NMDA receptor encephalitis' above.)
Diagnostic criteria for paraneoplastic syndromes are reviewed separately [170].
(See "Overview of paraneoplastic syndromes of the nervous system", section on
'Diagnostic criteria'.)

TREATMENT APPROACH

The use of immunosuppressive therapy should not await the cancer diagnosis
or antibody characterization in patients with a classical paraneoplastic
syndrome or a highly characteristic autoimmune encephalitis syndrome (eg,
anti-N-methyl-D-aspartate [NMDA] receptor encephalitis), provided an underlying
infectious etiology has been ruled out [172] and there are no other
contraindications. The results of antibody testing can then be used to refine or
alter the treatment strategy [171].

There are no controlled studies of any form of immunotherapy in patients with

paraneoplastic or autoimmune encephalitis. For the classical paraneoplastic
encephalitis syndromes, the neuronal damage is T cell mediated, occurs rapidly,
and is largely irreversible. Thus, these patients often have limited to no
neurologic recovery even with maximal treatment. The best chance for
symptom stabilization or improvement appears to be early identification and
treatment of the tumor [173-175] and the use of immunotherapy
(glucocorticoids, intravenous immune globulin [IVIG], plasma exchange,
cyclophosphamide, or rituximab) in various combinations [173]. Exceptions
include Ma2 encephalitis, in which approximately one-third of patients will
improve with immunotherapy and tumor treatment, and some cases of
paraneoplastic limbic encephalitis.

In contrast with paraneoplastic encephalitis, the autoimmune encephalitis

syndromes are often treatment responsive, as the associated antibodies are
pathogenic and reversibly affect the target antigens. Thus, treatments are
aimed at antibody depletion and immunosuppression (see 'Anti-NMDA receptor
encephalitis' above). Recovery can be slow (eg, up to two years in anti-NMDA
receptor encephalitis). Patient response to treatment should be based on
clinical evaluation, as antibody titers often do not correlate with disease activity
[69].

Seizures should be treated aggressively with antiseizure drugs during the acute
illness (see "Initial treatment of epilepsy in adults"). Most patients will not
require long-term antiseizure drug therapy [50].

The overall prognosis in patients with autoimmune encephalitis is highly

variable, depending on the underlying tumor and its stage as well as the severity
of the neurologic syndrome. Some patients make a complete recovery, while
others die or have permanent neurologic sequelae of varying severity. Delay to
diagnosis and treatment has been associated with a worse prognosis and
increased relapse [51].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries

and regions around the world are provided separately. (See "Society guideline
links: Paraneoplastic neurologic disorders".)

SUMMARY AND RECOMMENDATIONS

● Immune-mediated encephalitis includes the classic paraneoplastic
encephalitis syndromes and the encephalitis syndromes associated with
antibodies against neuronal cell surface/synaptic proteins, often referred to
as "autoimmune encephalitis."

● Paraneoplastic encephalitis can involve the limbic system (limbic

encephalitis), brainstem (brainstem encephalitis), spinal cord (myelitis), or
the entire neuraxis (encephalomyelitis). In most cases, symptoms have an
acute to subacute onset and are accompanied by evidence of inflammation
in the cerebrospinal fluid (CSF). (See 'Paraneoplastic encephalitis' above.)
● Examples of classic antibody-mediated paraneoplastic encephalitis
syndromes include anti-Hu encephalomyelitis, often associated with small
cell lung cancer (SCLC), Ma2-associated encephalitis related to testicular
cancer, and anti-collapsin-responsive mediator protein-5 (CRMP5)
encephalomyelitis related to SCLC or thymoma (table 1). (See 'Specific
antibody-associated syndromes' above.)

● The autoimmune encephalitis syndromes have a wide clinical spectrum

that ranges from typical limbic encephalitis to syndromes with complex
neuropsychiatric symptoms such as deficits of memory, cognition,
psychosis, seizures, abnormal movements, or coma (table 2). These
disorders are associated with antibodies to neuronal cell surface/synaptic
proteins and may occur in the presence or absence of cancer. (See
'Autoimmune encephalitis' above.)

● Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a well-

characterized autoimmune encephalitis with prominent psychiatric
manifestations and cognitive dysfunction, speech dysfunction, seizures,
dyskinesias and other movement abnormalities, decreased level of
consciousness, and autonomic instability (table 3). The disorder affects
primarily children and adults up to age 45 years; females may have an
associated ovarian teratoma. (See 'Anti-NMDA receptor encephalitis'
above.)

● Patients with suspected paraneoplastic or autoimmune encephalitis (table

5) should have neuroimaging, electroencephalogram (EEG), lumbar
puncture, and antibody testing on serum and CSF. Although antibody
studies can confirm the diagnosis, initiation of treatment should not be
delayed while waiting for antibody results. A provisional diagnosis should
be based on the medical history and clinical features, laboratory and
radiologic evidence of central nervous system (CNS) inflammation, and
exclusion of infection and other alternative etiologies. (See 'Diagnostic
approach' above.)
 ● The differential diagnosis of autoimmune or paraneoplastic encephalitis
includes a variety of alternative causes of encephalitis and encephalopathy.
Broad categories include infection, toxic and metabolic disturbances,
vascular disorders, neoplastic disorders, demyelinating and inflammatory
disorders, psychiatric disease, neurodegenerative dementias, and rare
heritable or metabolic disorders (table 4). (See 'Differential diagnosis'
above.)

● For paraneoplastic neurologic disorders in general, there is evidence that

prompt identification and treatment of the tumor and early initiation of
immunotherapy while the neurologic syndrome is still progressing offers
the best opportunity to stabilize or slow the progression of the neurologic
symptoms. For the autoimmune encephalitis syndromes, early treatment
(including that of the tumor, if present) is recommended, as this has been
shown in some syndromes to improve outcome, speed recovery, and
reduce the risk of relapses. (See 'Treatment approach' above.)

REFERENCES

1. Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic

encephalitis: neurological symptoms, immunological findings and tumour
association in 50 patients. Brain 2000; 123 ( Pt 7):1481.

2. Lawn ND, Westmoreland BF, Kiely MJ, et al. Clinical, magnetic resonance
imaging, and electroencephalographic findings in paraneoplastic limbic
encephalitis. Mayo Clin Proc 2003; 78:1363.

3. Basu S, Alavi A. Role of FDG-PET in the clinical management of

paraneoplastic neurological syndrome: detection of the underlying
malignancy and the brain PET-MRI correlates. Mol Imaging Biol 2008;
10:131.

4. Alamowitch S, Graus F, Uchuya M, et al. Limbic encephalitis and small cell

lung cancer. Clinical and immunological features. Brain 1997; 120 ( Pt
 6):923.

5. Papadopoulos KP, Romero RS, Gonzalez G, et al. Anti-Hu-Associated

Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-
Responsive Myxoid Chondrosarcoma. Oncologist 2018; 23:118.

6. Matsuoka H, Kimura H, Koba H, et al. Nivolumab-induced Limbic

Encephalitis with Anti-Hu Antibody in a Patient With Advanced Pleomorphic
Carcinoma of the Lung. Clin Lung Cancer 2018; 19:e597.

7. Graus F, Dalmau J. Paraneoplastic neurological syndromes in the era of

immune-checkpoint inhibitors. Nat Rev Clin Oncol 2019.

8. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu--associated

paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study
of 71 patients. Medicine (Baltimore) 1992; 71:59.

9. Henson RA, Hoffman HL, Urich H. Encephalomyelitis with carcinoma. Brain

1965; 88:449.

10. Moragas M, Martínez-Yélamos S, Majós C, et al. Rhombencephalitis: a

series of 97 patients. Medicine (Baltimore) 2011; 90:256.

11. Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and
"optic neuritis": paraneoplastic effects of bronchial carcinoma. Neurology
1984; 34:788.

12. Saiz A, Bruna J, Stourac P, et al. Anti-Hu-associated brainstem encephalitis.

J Neurol Neurosurg Psychiatry 2009; 80:404.

13. Voltz R, Gultekin SH, Rosenfeld MR, et al. A serologic marker of

paraneoplastic limbic and brain-stem encephalitis in patients with
testicular cancer. N Engl J Med 1999; 340:1788.

14. Jean WC, Dalmau J, Ho A, Posner JB. Analysis of the IgG subclass
distribution and inflammatory infiltrates in patients with anti-Hu-associated
paraneoplastic encephalomyelitis. Neurology 1994; 44:140.
15. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated
encephalitis. Brain 2004; 127:1831.

16. Graus F, Keime-Guibert F, Reñe R, et al. Anti-Hu-associated paraneoplastic

encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138.

17. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic
profiles of patients seropositive for type 1 antineuronal nuclear
autoantibodies. Neurology 1998; 50:652.

18. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the
Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in
human normal and tumor tissues. Am J Pathol 1992; 141:881.

19. Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73

anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory
neuronopathy. J Neurol 2002; 249:745.

20. Mut M, Schiff D, Dalmau J. Paraneoplastic recurrent multifocal encephalitis

presenting with epilepsia partialis continua. J Neurooncol 2005; 72:63.

21. Shavit YB, Graus F, Probst A, et al. Epilepsia partialis continua: a new
manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann
Neurol 1999; 45:255.

22. Kinirons P, O'Dwyer JP, Connolly S, Hutchinson M. Paraneoplastic limbic

encephalitis presenting as lingual epilepsia partialis continua. J Neurol
2006; 253:256.

23. Jacobs DA, Fung KM, Cook NM, et al. Complex partial status epilepticus
associated with anti-Hu paraneoplastic syndrome. J Neurol Sci 2003;
213:77.

24. Honnorat J, Didelot A, Karantoni E, et al. Autoimmune limbic

encephalopathy and anti-Hu antibodies in children without cancer.
Neurology 2013; 80:2226.
25. van Broekhoven F, de Graaf MT, Bromberg JE, et al. Human chorionic
gonadotropin treatment of anti-Hu-associated paraneoplastic neurological
syndromes. J Neurol Neurosurg Psychiatry 2010; 81:1341.

26. Shams'ili S, de Beukelaar J, Gratama JW, et al. An uncontrolled trial of

rituximab for antibody associated paraneoplastic neurological syndromes.
J Neurol 2006; 253:16.

27. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in

patients with paraneoplastic neuronal antibodies. Lancet 1993; 341:21.

28. Byrne T, Mason WP, Posner JB, Dalmau J. Spontaneous neurological

improvement in anti-Hu associated encephalomyelitis. J Neurol Neurosurg
Psychiatry 1997; 62:276.

29. Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-
specific protein, is recognized by the serum of patients with paraneoplastic
neurological disorders. Brain 1999; 122 ( Pt 1):27.

30. Waragai M, Chiba A, Uchibori A, et al. Anti-Ma2 associated paraneoplastic

neurological syndrome presenting as encephalitis and progressive
muscular atrophy. J Neurol Neurosurg Psychiatry 2006; 77:111.

31. Mathew RM, Vandenberghe R, Garcia-Merino A, et al. Orchiectomy for

suspected microscopic tumor in patients with anti-Ma2-associated
encephalitis. Neurology 2007; 68:900.

32. Hoffmann LA, Jarius S, Pellkofer HL, et al. Anti-Ma and anti-Ta associated
paraneoplastic neurological syndromes: 22 newly diagnosed patients and
review of previous cases. J Neurol Neurosurg Psychiatry 2008; 79:767.

33. Al-Thubaiti I, Al-Hayek K, Binfalah M. Anti-Ma-associated encephalitis due

to dysgerminoma in a woman with Swyer syndrome. Neurology 2013;
80:1439.

34. Blumenthal DT, Salzman KL, Digre KB, et al. Early pathologic findings and
long-term improvement in anti-Ma2-associated encephalitis. Neurology
 2006; 67:146.

35. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody:

marker of lung cancer and thymoma-related autoimmunity. Ann Neurol
2001; 49:146.

36. Vernino S, Tuite P, Adler CH, et al. Paraneoplastic chorea associated with
CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002; 51:625.

37. Muehlschlegel S, Okun MS, Foote KD, et al. Paraneoplastic chorea with
leukoencephalopathy presenting with obsessive-compulsive and behavioral
disorder. Mov Disord 2005; 20:1523.

38. Werry C, Götz F, Wurster U, et al. Paraneoplastic autoimmune encephalitis

associated with CV2/CRMP-5 IgG antineuronal antibodies in a patient with
thymoma. J Neurol 2009; 256:129.

39. Rickman OB, Parisi JE, Yu Z, et al. Fulminant autoimmune cortical

encephalitis associated with thymoma treated with plasma exchange.
Mayo Clin Proc 2000; 75:1321.

40. De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated

protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with
breast cancer. J Exp Med 1993; 178:2219.

41. Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin

antibodies: distinctive features of a rare disease. Neurology 2008; 71:1955.

42. Martinez-Hernandez E, Ariño H, McKeon A, et al. Clinical and Immunologic

Investigations in Patients With Stiff-Person Spectrum Disorder. JAMA
Neurol 2016; 73:714.

43. Ariño H, Höftberger R, Gresa-Arribas N, et al. Paraneoplastic Neurological

Syndromes and Glutamic Acid Decarboxylase Antibodies. JAMA Neurol
2015; 72:874.
44. Tüzün E, Rossi JE, Karner SF, et al. Adenylate kinase 5 autoimmunity in
treatment refractory limbic encephalitis. J Neuroimmunol 2007; 186:177.

45. Sutton IJ, Barnett MH, Watson JD, et al. Paraneoplastic brainstem
encephalitis and anti-Ri antibodies. J Neurol 2002; 249:1597.

46. Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med 2018;

378:840.

47. Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate

receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;
61:25.

48. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor

encephalitis: case series and analysis of the effects of antibodies. Lancet
Neurol 2008; 7:1091.

49. Florance-Ryan N, Dalmau J. Update on anti-N-methyl-D-aspartate receptor

encephalitis in children and adolescents. Curr Opin Pediatr 2010; 22:739.

50. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and

laboratory investigations in patients with anti-NMDAR encephalitis. Lancet
Neurol 2011; 10:63.

51. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic

factors for long-term outcome in patients with anti-NMDA receptor
encephalitis: an observational cohort study. Lancet Neurol 2013; 12:157.

52. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and

characteristics of isolated psychiatric episodes in anti–N-methyl-d-
aspartate receptor encephalitis. JAMA Neurol 2013; 70:1133.

53. Smith JH, Dhamija R, Moseley BD, et al. N-methyl-D-aspartate receptor

autoimmune encephalitis presenting with opsoclonus-myoclonus:
treatment response to plasmapheresis. Arch Neurol 2011; 68:1069.
54. Kurian M, Lalive PH, Dalmau JO, Horvath J. Opsoclonus-myoclonus
syndrome in anti-N-methyl-D-aspartate receptor encephalitis. Arch Neurol
2010; 67:118.

55. Fitzpatrick AS, Gray OM, McConville J, McDonnell GV. Opsoclonus-

myoclonus syndrome associated with benign ovarian teratoma. Neurology
2008; 70:1292.

56. Kawachi I, Saji E, Toyoshima Y, et al. Treatment responsive opsoclonus-

ataxia associated with ovarian teratoma. J Neurol Neurosurg Psychiatry
2010; 81:581.

57. Armangue T, Titulaer MJ, Sabater L, et al. A novel treatment-responsive

encephalitis with frequent opsoclonus and teratoma. Ann Neurol 2014;
75:435.

58. Luca N, Daengsuwan T, Dalmau J, et al. Anti-N-methyl-D-aspartate receptor

encephalitis: a newly recognized inflammatory brain disease in children.
Arthritis Rheum 2011; 63:2516.

59. Baizabal-Carvallo JF, Stocco A, Muscal E, Jankovic J. The spectrum of

movement disorders in children with anti-NMDA receptor encephalitis. Mov
Disord 2013; 28:543.

60. Armangue T, Titulaer MJ, Málaga I, et al. Pediatric anti-N-methyl-D-

aspartate receptor encephalitis-clinical analysis and novel findings in a
series of 20 patients. J Pediatr 2013; 162:850.

61. Gable M, Glaser C. Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Appearing as a New-Onset Psychosis: Disease Course in Children and
Adolescents Within the California Encephalitis Project. Pediatr Neurol 2017;
72:25.

62. Wright S, Hacohen Y, Jacobson L, et al. N-methyl-D-aspartate receptor

antibody-mediated neurological disease: results of a UK-based surveillance
study in children. Arch Dis Child 2015; 100:521.
63. Gorman MP, Gombolay GY, Mehan WA Jr, Thibert RL. Case 27-2018: A 3-
Year-Old Boy with Seizures. N Engl J Med 2018; 379:870.

64. Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor

encephalitis. Neurology 2013; 81:1058.

65. Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique
EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology
2012; 79:1094.

66. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor

(NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66:11.

67. Leypoldt F, Buchert R, Kleiter I, et al. Fluorodeoxyglucose positron emission

tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct
pattern of disease. J Neurol Neurosurg Psychiatry 2012; 83:681.

68. Prüss H, Dalmau J, Harms L, et al. Retrospective analysis of NMDA

receptor antibodies in encephalitis of unknown origin. Neurology 2010;
75:1735.

69. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis

and during follow-up of anti-NMDA receptor encephalitis: a retrospective
study. Lancet Neurol 2014; 13:167.

70. Dahm L, Ott C, Steiner J, et al. Seroprevalence of autoantibodies against

brain antigens in health and disease. Ann Neurol 2014; 76:82.

71. Hara M, Martinez-Hernandez E, Ariño H, et al. Clinical and pathogenic

significance of IgG, IgA, and IgM antibodies against the NMDA receptor.
Neurology 2018; 90:e1386.

72. Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y, et al. Analysis of

complement and plasma cells in the brain of patients with anti-NMDAR
encephalitis. Neurology 2011; 77:589.
73. Seki M, Suzuki S, Iizuka T, et al. Neurological response to early removal of
ovarian teratoma in anti-NMDAR encephalitis. J Neurol Neurosurg
Psychiatry 2008; 79:324.

74. Okamoto S, Hirano T, Takahashi Y, et al. Paraneoplastic limbic encephalitis

caused by ovarian teratoma with autoantibodies to glutamate receptor.
Intern Med 2007; 46:1019.

75. Sansing LH, Tüzün E, Ko MW, et al. A patient with encephalitis associated
with NMDA receptor antibodies. Nat Clin Pract Neurol 2007; 3:291.

76. Gable MS, Gavali S, Radner A, et al. Anti-NMDA receptor encephalitis: report
of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol
Infect Dis 2009; 28:1421.

77. Dale RC, Irani SR, Brilot F, et al. N-methyl-D-aspartate receptor antibodies in
pediatric dyskinetic encephalitis lethargica. Ann Neurol 2009; 66:704.

78. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with
diseases of the CNS: new developments and future challenges. Lancet
Neurol 2011; 10:759.

79. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies

to synaptic and neuronal cell surface proteins. Neurology 2011; 77:179.

80. Zandi MS, Irani SR, Follows G, et al. Limbic encephalitis associated with
antibodies to the NMDA receptor in Hodgkin lymphoma. Neurology 2009;
73:2039.

81. Sanmaneechai O, Song JL, Nevadunsky N, et al. Anti-N-methyl-d-aspartate

encephalitis with ovarian cystadenofibroma. Pediatr Neurol 2013; 48:232.

82. Lebas A, Husson B, Didelot A, et al. Expanding spectrum of encephalitis

with NMDA receptor antibodies in young children. J Child Neurol 2010;
25:742.
83. Williams TJ, Benavides DR, Patrice KA, et al. Association of Autoimmune
Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for
Metastatic Cancer. JAMA Neurol 2016; 73:928.

84. Leypoldt F, Titulaer MJ, Aguilar E, et al. Herpes simplex virus-1 encephalitis
can trigger anti-NMDA receptor encephalitis: case report. Neurology 2013;
81:1637.

85. Armangue T, Moris G, Cantarín-Extremera V, et al. Autoimmune post-herpes

simplex encephalitis of adults and teenagers. Neurology 2015; 85:1736.

86. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is

a trigger of brain autoimmunity. Ann Neurol 2014; 75:317.

87. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors,

and outcomes of autoimmune encephalitis after herpes simplex
encephalitis: a prospective observational study and retrospective analysis.
Lancet Neurol 2018; 17:760.

88. Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies

in herpes simplex encephalitis. Ann Neurol 2012; 72:902.

89. Hacohen Y, Deiva K, Pettingill P, et al. N-methyl-D-aspartate receptor

antibodies in post-herpes simplex virus encephalitis neurological relapse.
Mov Disord 2014; 29:90.

90. Sutcu M, Akturk H, Somer A, et al. Role of Autoantibodies to N-Methyl-d-

Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A
Retrospective, One-Center Experience. J Child Neurol 2016; 31:345.

91. Titulaer MJ, Leypoldt F, Dalmau J. Antibodies to N-methyl-D-aspartate and

other synaptic receptors in choreoathetosis and relapsing symptoms post-
herpes virus encephalitis. Mov Disord 2014; 29:3.

92. Suppiej A, Nosadini M, Zuliani L, et al. Plasma exchange in pediatric anti-

NMDAR encephalitis: A systematic review. Brain Dev 2016; 38:613.
 93. Iizuka T, Sakai F, Ide T, et al. Anti-NMDA receptor encephalitis in Japan:
long-term outcome without tumor removal. Neurology 2008; 70:504.

94. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric
autoimmune and inflammatory CNS disease. Neurology 2014; 83:142.

95. Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of adult male

patients with NMDA receptor antibodies encephalitis. Neurology 2014;
82:556.

96. Nosadini M, Mohammad SS, Ramanathan S, et al. Immune therapy in

autoimmune encephalitis: a systematic review. Expert Rev Neurother 2015;
15:1391.

97. de Bruijn MAAM, Aarsen FK, van Oosterhout MP, et al. Long-term
neuropsychological outcome following pediatric anti-NMDAR encephalitis.
Neurology 2018; 90:e1997.

98. Finke C, Kopp UA, Prüss H, et al. Cognitive deficits following anti-NMDA
receptor encephalitis. J Neurol Neurosurg Psychiatry 2012; 83:195.

99. Balu R, McCracken L, Lancaster E, et al. A score that predicts 1-year

functional status in patients with anti-NMDA receptor encephalitis.
Neurology 2019; 92:e244.

100. Gabilondo I, Saiz A, Galán L, et al. Analysis of relapses in anti-NMDAR

encephalitis. Neurology 2011; 77:996.

101. Chourasia N, Watkins MW, Lankford JE, et al. An Infant Born to a Mother
With Anti-N-Methyl-d-Aspartate Receptor Encephalitis. Pediatr Neurol 2018;
79:65.

102. Jagota P, Vincent A, Bhidayasiri R. Transplacental transfer of NMDA

receptor antibodies in an infant with cortical dysplasia. Neurology 2014;
82:1662.
103. Hilderink M, Titulaer MJ, Schreurs MW, et al. Transient anti-NMDAR
encephalitis in a newborn infant due to transplacental transmission. Neurol
Neuroimmunol Neuroinflamm 2015; 2:e126.

104. Magley J, Towner D, Taché V, Apperson ML. Pregnancy outcome in anti-N-

methyl-D-aspartate receptor encephalitis. Obstet Gynecol 2012; 120:480.

105. Kumar MA, Jain A, Dechant VE, et al. Anti-N-methyl-D-aspartate receptor

encephalitis during pregnancy. Arch Neurol 2010; 67:884.

106. Lamale-Smith LM, Moore GS, Guntupalli SR, Scott JB. Maternal-fetal
transfer of anti-N-methyl-D-aspartate receptor antibodies. Obstet Gynecol
2015; 125:1056.

107. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede
Lgi1 antibody limbic encephalitis. Ann Neurol 2011; 69:892.

108. Sen A, Wang J, Laue-Gizzi H, et al. Pathognomonic seizures in limbic

encephalitis associated with anti-LGI1 antibodies. Lancet 2014; 383:2018.

109. Thompson J, Bi M, Murchison AG, et al. The importance of early

immunotherapy in patients with faciobrachial dystonic seizures. Brain
2018; 141:348.

110. López-Chiriboga AS, Klein C, Zekeridou A, et al. LGI1 and CASPR2

neurological autoimmunity in children. Ann Neurol 2018; 84:473.

111. Navarro V, Kas A, Apartis E, et al. Motor cortex and hippocampus are the
two main cortical targets in LGI1-antibody encephalitis. Brain 2016;
139:1079.

112. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-
complex proteins leucine-rich, glioma inactivated 1 protein and contactin-
associated protein-2 in limbic encephalitis, Morvan's syndrome and
acquired neuromyotonia. Brain 2010; 133:2734.
113. Ariño H, Armangué T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive
impairment: Presentation and long-term outcome. Neurology 2016; 87:759.

114. Fukata Y, Lovero KL, Iwanaga T, et al. Disruption of LGI1-linked synaptic

complex causes abnormal synaptic transmission and epilepsy. Proc Natl
Acad Sci U S A 2010; 107:3799.

115. Petit-Pedrol M, Sell J, Planagumà J, et al. LGI1 antibodies alter Kv1.1 and
AMPA receptors changing synaptic excitability, plasticity and memory.
Brain 2018; 141:3144.

116. Jacob S, Irani SR, Rajabally YA, et al. Hypothermia in VGKC antibody-
associated limbic encephalitis. J Neurol Neurosurg Psychiatry 2008;
79:202.

117. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-

associated encephalopathy: a potentially immunotherapy-responsive form
of limbic encephalitis. Brain 2004; 127:701.

118. Wong SH, Saunders MD, Larner AJ, et al. An effective immunotherapy
regimen for VGKC antibody-positive limbic encephalitis. J Neurol
Neurosurg Psychiatry 2010; 81:1167.

119. Irani SR, Gelfand JM, Bettcher BM, et al. Effect of rituximab in patients with
leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy.
JAMA Neurol 2014; 71:896.

120. van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis:
Clinical syndrome and long-term follow-up. Neurology 2016; 87:1449.

121. Finke C, Prüss H, Heine J, et al. Evaluation of Cognitive Deficits and

Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-
Inactivated 1 Antibodies. JAMA Neurol 2017; 74:50.

122. Lancaster E, Huijbers MG, Bar V, et al. Investigations of caspr2, an

autoantigen of encephalitis and neuromyotonia. Ann Neurol 2011; 69:303.
123. Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and
serological observations in 29 cases. Ann Neurol 2012; 72:241.

124. Joubert B, Saint-Martin M, Noraz N, et al. Characterization of a Subtype of

Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2
Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and
Seizures. JAMA Neurol 2016; 73:1115.

125. Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in

autoimmune encephalitis and neuromyotonia. Ann Neurol 2018; 83:40.

126. van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of

Caspr2 antibody-associated disease. Neurology 2016; 87:521.

127. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic
encephalitis alter synaptic receptor location. Ann Neurol 2009; 65:424.

128. Bataller L, Galiano R, García-Escrig M, et al. Reversible paraneoplastic

limbic encephalitis associated with antibodies to the AMPA receptor.
Neurology 2010; 74:265.

129. Graus F, Boronat A, Xifró X, et al. The expanding clinical profile of anti-
AMPA receptor encephalitis. Neurology 2010; 74:857.

130. Höftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and AMPA

receptor antibodies: Novel findings in a case series of 22 patients.
Neurology 2015; 84:2403.

131. Joubert B, Kerschen P, Zekeridou A, et al. Clinical Spectrum of Encephalitis

Associated With Antibodies Against the α-Amino-3-Hydroxy-5-Methyl-4-
Isoxazolepropionic Acid Receptor: Case Series and Review of the
Literature. JAMA Neurol 2015; 72:1163.

132. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory

seizures, status epilepticus, and antibodies to the GABAA receptor: a case
series, characterisation of the antigen, and analysis of the effects of
antibodies. Lancet Neurol 2014; 13:276.
133. Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABAA
receptor antibody-associated encephalitis. Neurology 2017; 88:1012.

134. Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor
antibodies: novel findings in a new case series of 20 patients. Neurology
2013; 81:1500.

135. Boronat A, Sabater L, Saiz A, et al. GABA(B) receptor antibodies in limbic

encephalitis and anti-GAD-associated neurologic disorders. Neurology
2011; 76:795.

136. Kruer MC, Hoeftberger R, Lim KY, et al. Aggressive course in encephalitis
with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of γ-
aminobutyric acid type B receptor autoimmunity. JAMA Neurol 2014;
71:620.

137. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in

limbic encephalitis with seizures: case series and characterisation of the
antigen. Lancet Neurol 2010; 9:67.

138. Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-
eye-movement parasomnia with sleep breathing disorder associated with
antibodies to IgLON5: a case series, characterisation of the antigen, and
post-mortem study. Lancet Neurol 2014; 13:575.

139. Högl B, Heidbreder A, Santamaria J, et al. IgLON5 autoimmunity and

abnormal behaviours during sleep. Lancet 2015; 385:1590.

140. Simabukuro MM, Sabater L, Adoni T, et al. Sleep disorder, chorea, and
dementia associated with IgLON5 antibodies. Neurol Neuroimmunol
Neuroinflamm 2015; 2:e136.

141. Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5

disease. Neurology 2017; 88:1736.
142. Gelpi E, Höftberger R, Graus F, et al. Neuropathological criteria of anti-
IgLON5-related tauopathy. Acta Neuropathol 2016; 132:531.

143. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies

to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium
channels. Ann Neurol 2013; 73:120.

144. Hara M, Ariño H, Petit-Pedrol M, et al. DPPX antibody-associated

encephalitis: Main syndrome and antibody effects. Neurology 2017;
88:1340.

145. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity

and myoclonus: a new variant with DPPX antibodies. Neurology 2014;
82:1521.

146. Tobin WO, Lennon VA, Komorowski L, et al. DPPX potassium channel
antibody: frequency, clinical accompaniments, and outcomes in 20
patients. Neurology 2014; 83:1797.

147. Mas N, Saiz A, Leite MI, et al. Antiglycine-receptor encephalomyelitis with

rigidity. J Neurol Neurosurg Psychiatry 2011; 82:1399.

148. Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis,

rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008;
71:1291.

149. Clerinx K, Breban T, Schrooten M, et al. Progressive encephalomyelitis with

rigidity and myoclonus: resolution after thymectomy. Neurology 2011;
76:303.

150. Turner MR, Irani SR, Leite MI, et al. Progressive encephalomyelitis with
rigidity and myoclonus: glycine and NMDA receptor antibodies. Neurology
2011; 77:439.

151. Carvajal-González A, Leite MI, Waters P, et al. Glycine receptor antibodies in

PERM and related syndromes: characteristics, clinical features and
outcomes. Brain 2014; 137:2178.
152. Martinez-Hernandez E, Sepulveda M, Rostásy K, et al. Antibodies to
aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor
α1 subunit in patients with isolated optic neuritis. JAMA Neurol 2015;
72:187.

153. Prüss H, Rothkirch M, Kopp U, et al. Limbic encephalitis with mGluR5

antibodies and immunotherapy-responsive prosopagnosia. Neurology
2014; 83:1384.

154. Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies to

metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology
2011; 77:1698.

155. Mat A, Adler H, Merwick A, et al. Ophelia syndrome with metabotropic

glutamate receptor 5 antibodies in CSF. Neurology 2013; 80:1349.

156. Spatola M, Sabater L, Planagumà J, et al. Encephalitis with mGluR5

antibodies: Symptoms and antibody effects. Neurology 2018; 90:e1964.

157. Sillevis Smitt P, Kinoshita A, De Leeuw B, et al. Paraneoplastic cerebellar

ataxia due to autoantibodies against a glutamate receptor. N Engl J Med
2000; 342:21.

158. Lopez-Chiriboga AS, Komorowski L, Kümpfel T, et al. Metabotropic

glutamate receptor type 1 autoimmunity: Clinical features and treatment
outcomes. Neurology 2016; 86:1009.

159. Gresa-Arribas N, Planagumà J, Petit-Pedrol M, et al. Human neurexin-3α

antibodies associate with encephalitis and alter synapse development.
Neurology 2016; 86:2235.

160. Fang B, McKeon A, Hinson SR, et al. Autoimmune Glial Fibrillary Acidic
Protein Astrocytopathy: A Novel Meningoencephalomyelitis. JAMA Neurol
2016; 73:1297.
161. Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic protein
immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis
of 102 patients. Ann Neurol 2017; 81:298.

162. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet

Neurol 2008; 7:327.

163. Blanc F, Ben Abdelghani K, Schramm F, et al. Whipple limbic encephalitis.

Arch Neurol 2011; 68:1471.

164. Blondin NA, Vortmeyer AO, Harel NY. Paraneoplastic syndrome of

inappropriate antidiuretic hormone mimicking limbic encephalitis. Arch
Neurol 2011; 68:1591.

165. Lejuste F, Thomas L, Picard G, et al. Neuroleptic intolerance in patients with

anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;
3:e280.

166. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune

encephalopathies: clinical features, laboratory investigations and outcomes
in patients with or without antibodies to known central nervous system
autoantigens. J Neurol Neurosurg Psychiatry 2013; 84:748.

167. Jarius S, Hoffmann L, Clover L, et al. CSF findings in patients with voltage
gated potassium channel antibody associated limbic encephalitis. J Neurol
Sci 2008; 268:74.

168. Escudero D, Guasp M, Ariño H, et al. Antibody-associated CNS syndromes

without signs of inflammation in the elderly. Neurology 2017; 89:1471.

169. Ebright MJ, Li SH, Reynolds E, et al. Unintended consequences of Mayo

paraneoplastic evaluations. Neurology 2018; 91:e2057.

170. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for
paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry
2004; 75:1135.
171. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of
autoimmune encephalitis. Lancet Neurol 2016; 15:391.

172. Darnell RB, Posner JB. A new cause of limbic encephalopathy. Brain 2005;
128:1745.

173. Vedeler CA, Antoine JC, Giometto B, et al. Management of paraneoplastic

neurological syndromes: report of an EFNS Task Force. Eur J Neurol 2006;
13:682.

174. Vernino S, O'Neill BP, Marks RS, et al. Immunomodulatory treatment trial for
paraneoplastic neurological disorders. Neuro Oncol 2004; 6:55.

175. Keime-Guibert F, Graus F, Broët P, et al. Clinical outcome of patients with

anti-Hu-associated encephalomyelitis after treatment of the tumor.
Neurology 1999; 53:1719.

Topic 15759 Version 49.0

© 2019 UpToDate, Inc. All rights reserved.