Autoimmune-Associated Seizures

Autoimmune-Associated REVIEW ARTICLE

Seizures CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Lisa Gillinder, MBBS, FRACP; Jeffrey Britton, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article focuses on the seizure manifestations and
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presentations of autoimmune-associated epilepsy and acute symptomatic

seizures in autoimmune encephalitis. It discusses the specificity of the various
central nervous system autoantibodies and clarifies when their presence
can be considered indicative of an immune etiology. Finally, current
recommendations regarding patient selection for autoimmune antibody
evaluation are reviewed, and an approach to immunotherapy is provided.
RECENT FINDINGS: Although autoimmune seizures are caused by a

heterogeneous group of autoantibodies, key features reported in the
literature should alert clinicians to the possible diagnosis. In particular,
seizure characteristics including frequency, timing, duration, and CITE AS:
symptomatology can provide vital clues to help differentiate autoimmune- CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):363–398.
associated seizures from other causes of epilepsy. Diagnostic certainty also
requires an understanding and integration of the spectrum of clinical and
Address correspondence to
paraclinical presentations, and several scoring systems have been developed Dr Lisa Gillinder, Mater Advanced
that may be useful to aid the identification of autoimmune seizures. Epilepsy Unit, Level 8 Salmon
Building, Raymond Terr, South
Brisbane, QLD 4101, Australia,
SUMMARY: Seizures due to autoimmune etiology are increasingly lisa.gillinder@mater.org.au.
encountered in clinical practice. It is critical that clinicians recognize
RELATIONSHIP DISCLOSURE :
immune seizure etiologies early in their course given they are often Dr Gillinder reports no
responsive to immunotherapy but are usually resistant to antiseizure disclosure. Dr Britton has
medications. Currently, however, it is unfortunately not uncommon for received personal
compensation in the range of
autoimmune-associated seizure disorders to remain undiagnosed, $0 to $499 for serving as an
resulting in missed opportunities to administer effective therapies. Efforts online course instructor for the
American Clinical
to better understand autoimmune seizure manifestations and treatment Neurophysiology Society.
strategies are ongoing.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE :
Drs Gillinder and Britton
INTRODUCTION discuss the unlabeled/
S
eizures due to autoimmune etiology are increasingly encountered in investigational use of
azathioprine,
clinical practice. This was formally acknowledged by the International
cyclophosphamide, IVIg,
League Against Epilepsy (ILAE) in 2017, with the addition of “immune” methylprednisolone,
as an etiology in the ILAE’s Classification of the Epilepsies.1 Although mycophenolate mofetil,
prednisone, and rituximab for
seizures due to immune causes represent less than 20% of patients the treatment of autoimmune
encountered in an epilepsy clinic, it is critical that immune seizure etiologies be encephalitis.
identified early in their course given they are responsive to immunotherapy and are
usually resistant to antiseizure medications. This is especially true since improved © 2022 American Academy
outcomes are associated with earlier use of immunotherapy. of Neurology.
CONTINUUMJOURNAL.COM 363
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

AUTOIMMUNE-ASSOCIATED SEIZURES
In current practice, it is unfortunately not uncommon for autoimmune-

associated seizure disorders to remain undiagnosed for weeks to months.
Such delays may result in missing a window of opportunity to effectively treat
the underlying etiology in these cases. This article focuses on the seizure
manifestations and presentations of autoimmune-associated epilepsy and
acute symptomatic seizures in autoimmune encephalitis. It discusses the
specificity of the various central nervous system (CNS) autoantibodies and
clarifies when their presence can be considered indicative of an immune etiology.
Finally, current recommendations regarding patient selection for autoimmune
antibody evaluation are reviewed, and an approach to immunotherapy
is provided.
DEFINITIONS
Seizures and epilepsy may both result from autoimmune disorders affecting the
CNS, but these terms should not be considered interchangeable. The term
autoimmune epilepsy has been used in recent years in reference to any seizures
occurring in the context of autoimmune disorders. However, when reflecting on
the concepts and meanings of seizure and epilepsy as laid out by the ILAE, the
term autoimmune epilepsy has not held up as the most appropriate one for use in
these conditions. One reason for this is that seizures are a common clinical
feature in autoimmune encephalitis but are typically not the only clinical feature.
Also, after resolution of the active phase of encephalitis, seizures may resolve,
thus not meeting the definition of epilepsy, which implies an ongoing
predisposition to seizures. Therefore, the term recommended for use in reference
to seizures occurring in the setting of active autoimmune encephalitis is acute
symptomatic seizures secondary to autoimmune encephalitis.2
However, some patients with autoimmune encephalitis continue to have
seizures after resolution of acute encephalitis. In addition, some patients with
chronic epilepsy may be discovered to have findings suggesting an immune
etiology despite a long history of seizures and the absence of a clear prior episode
of acute encephalitis. Finally, ongoing drug-resistant seizures are a hallmark of
Rasmussen encephalitis, an immune-mediated disorder stemming from chronic
encephalitis and its structural cerebral aftermath, leading to an enduring
predisposition to unprovoked seizures. In these cases, the concept of “epilepsy” is
appropriate, given the presence of an ongoing potential for seizures. Hence,
autoimmune-associated epilepsy has been proposed as the most appropriate term
for those situations.2
PATHOPHYSIOLOGY AND DIAGNOSIS

Autoimmune seizure disorders may result from antibody-, cytokine-, and T-cell–
mediated immune mechanisms. Certain autoantibodies targeting particular
neural cell surface antigens have been demonstrated to be directly pathogenic,
leading to seizures, as well as affecting other behavioral functions.3 Several
antibodies targeting intracellular neural antigens have also been identified in
patients with acute symptomatic seizures and chronic epilepsy. In these cases,
the direct pathogenicity of these antibodies has been called into question, and
their significance has been interpreted to be that of a nonspecific marker of past
or present immune cell-mediated processes. Finally, it is increasingly realized
that humoral mediators of inflammation, such as cytokines, interleukins, and
interferons, may play a role in the pathogenesis of seizures and epilepsy and that
364 APRIL 2022

a clearer understanding of these may allow discovery of innovative and unique KEY POINTS
antiseizure and antiepileptic treatment options in the future.4-6
● Immune seizure etiologies
A disruption in the normal homeostatic balance of neuronal excitation and are often responsive to
inhibition caused by immune pathophysiologic processes is hypothesized to immunotherapy but are
underly the occurrence of seizure generation in patients with autoimmune- usually resistant to
associated seizures.7 Indeed, the demonstration of direct effects of antibodies antiseizure medications.
targeting specific cell surface antigens in experimental models (eg, leucine-rich
● The term autoimmune-
glioma inactivated protein 1 [LGI1],8,9 N-methyl-D-aspartate [NMDA] associated epilepsy is now
receptor3,10) supports a pathogenic role for these CNS autoantibodies. Currently, proposed to describe a
autoantibodies targeting neuronal structures are the most commonly used clinical presentation with an
biomarker for diagnosing acute symptomatic seizures secondary to autoimmune enduring predisposition to
unprovoked seizures with
encephalitis and autoimmune-associated epilepsy. Neuronal cell surface evidence of an immune
antibodies that have been clearly linked to limbic encephalitis, in particular, are etiology, whereas acute
considered specific for the presence of an underlying autoimmune etiology, symptomatic seizures
provided the clinical picture is consistent.11-13 secondary to autoimmune
encephalitis is
However, the significance of other neuronal antibodies is less clear.7 For recommended for seizures
example, recent studies have called into question the pathogenic significance of that occur as a symptom of
antibodies such as low-titer (less than 20 nmol/L or less than 1000 U/mL) active autoimmune
glutamic acid decarboxylase 65 (GAD65) antibodies and voltage-gated potassium encephalitis.
channel antibodies that do not have LGI1 or contactin-associated proteinlike
● Not all neural antibodies
2 (CASPR2) affinity.14,15 Therefore, clinicians must have a clear understanding are considered definitively
of the pathogenic significance of each antibody type to ensure appropriate pathogenic, so clinicians
diagnosis and treatment decisions (TABLE 5-1). must have an understanding
of the pathogenic
Although antibodies serve an important role as a biomarker for autoimmune-
significance of each
mediated seizure disorders, in occasional cases, immunity is suspected based on antibody to ensure accurate
clinical, imaging, and CSF results, but antibodies are absent.16 In these cases, the diagnostic and treatment
possible presence of pathogenic autoantibodies that are not yet detectable by decisions are made.
current techniques has been suggested by reports of such patients undergoing
● Seizures in adults with
successful treatment with rituximab,17 a medication that prevents differentiation autoimmune encephalitis
of mature B cells into antibody-producing plasma cells.18 Seronegative cases such are reported to occur at a
as these provide evidence suggesting a broader role of immunity in clinical higher frequency and with
epilepsy and highlight the need to identify additional biomarkers to facilitate shorter duration than
seizures due to other
diagnosis. etiologies.
ACUTE SYMPTOMATIC SEIZURES SECONDARY TO AUTOIMMUNE

ENCEPHALITIS
Autoimmune encephalitis classically presents with a cluster of symptoms,
including cognitive and memory impairment, personality and psychiatric
changes, movement disorders, and seizures. Seizures are common and often the
presenting symptom in antibody-mediated autoimmune encephalitis. It is crucial
that neurologists recognize the types of seizures that can indicate the presence of
neuronal cell surface antibody–mediated autoimmune encephalitis. A discussion
of seizure manifestations and paraclinical findings that may be encountered in
patients with seizures due to autoimmune encephalitis follows.
Seizure and Clinical Characteristics

The most common seizure types in autoimmune encephalitis at presentation are
focal seizures. In studies evaluating the clinical features of seizures associated
with autoimmune encephalitis, they tend to occur without impaired awareness
or postictal confusion.19 In a study comparing seizures associated with

hippocampal sclerosis and seizures secondary to autoimmune encephalitis, those

associated with autoimmune encephalitis were significantly shorter in duration,
lasting seconds as opposed to 1 to 3 minutes.19 In this study, it was also noted
that bilateral tonic-clinic seizures, especially nocturnal, were more common in
acute symptomatic seizures secondary to autoimmune encephalitis than in
epilepsy caused by hippocampal sclerosis.
Seizure frequency in autoimmune encephalitis is also unusually high
compared with seizures in most patients with focal epilepsy due to other causes,
often occurring daily, and in some many times per day.19,20 In addition, a
preceding febrile illness and a history of systemic autoimmunity or malignancy
should also raise suspicion of an immune etiology.
The clinical seizure symptomatology is often the first information obtained in
seizure evaluation and can be helpful in identifying seizures of autoimmune
etiology. Autoimmune encephalitis often affects the limbic structures, especially the
mesial temporal, insula, and perisylvian networks, so it is not unexpected that this is
reflected in the seizure symptoms. Clinical features of seizures that have been
reported in cases of autoimmune encephalitis are summarized in TABLE 5-2.21-25
Anti–Leucine-Rich Glioma Inactivated Protein 1 Antibody Encephalitis

Anti-LGI1 encephalitis most commonly presents with focal seizures. Patients are
typically between the ages of 40 and 80 years (median, 65 years). It is somewhat
TABLE 5-1 Neural Autoantibodies With Definite and Uncertain Association With
Autoimmune Encephalitis
Antibodies with definite association with autoimmune encephalitis

◆ Antineuronal nuclear antibody type 1 (ANNA-1)
◆ α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
◆ Contactin-associated proteinlike 2 (CASPR2)
◆ Dipeptidyl-peptidase–like protein 6 (DPPX)
◆ High-titer glutamic acid decarboxylase 65 (GAD65)
◆ γ-Aminobutyric acid A (GABAA)
◆ γ-Aminobutyric acid B (GABAB)
◆ Leucine-rich glioma inactivated protein 1 (LGI1)
◆ Ma/Ta
◆ Metabotropic glutamate receptor 5 (mGluR5)
◆ N-methyl-D-aspartate (NMDA) receptor
Antibodies with uncertain association with autoimmune encephalitis
◆ Ganglionic nicotinic acetylcholine receptor
◆ Low-titer CASPR2
◆ Low-titer GAD65
◆ Voltage-gated calcium channel
◆ Voltage-gated potassium channel (without reactivity to LGI1 or CASPR2)
366 APRIL 2022

Seizure Clinical Features Reported in Autoimmune Encephalitis TABLE 5-2
Experiential and perceptive

◆ Déjà vu
◆ Jamais vu
◆ Autoscopy
◆ Psychic sensations (fear)
◆ Sense of levitation
◆ Dizziness (nonvertiginous)
Somatosensory
◆ Paresthesia
◆ Pain
◆ Thermal sensations (warm or cold waves)
◆ Numbness
Viscerosensitive
◆ Pharyngeal sensation and throat-clearing
◆ Taste
◆ Epigastric sensations
◆ Hiccups
Auditory
◆ Musical aura
◆ Musicogenic seizures
Language
◆ Vocalizations
◆ Dysarthria
Autonomic
◆ Tachycardia
◆ Flushing
◆ Salivation
◆ Piloerection
◆ Shuddering
Motor
◆ Posturing
◆ Dystonia
◆ Automatisms (orofacial or bimanual)
◆ Clonic
◆ Twitching
Visual
◆ Not defined

more common in men than women (66%). Hyponatremia is relatively

common.26,27 Faciobrachial dystonic seizures are the most characteristic seizure
type in this disorder, although they are absent in more than half of cases.
Faciobrachial dystonic seizures are brief, lasting seconds, occur multiple times
per day, and typically present with simultaneous contraction of the upper limb
muscles and ipsilateral facial and neck muscles. Within a single seizure, they
often remain unilateral but can quickly be followed by a similar attack affecting
the other side. In some cases, one side is affected exclusively; however, bilateral
independent attacks can also occur. Sometimes the lower extremities can be
involved, and sometimes they involve the face or upper extremity alone. These
seizures usually precede the onset of other features suggestive of encephalitis.
A wide range of other clinical features has been described in seizures
associated with anti-LGI1 encephalitis. These include autonomic symptoms such
as piloerection; sensations of alteration of temperature, referred to as thermal
seizures; somatosensory changes, especially paresthesia or pain; a sensation that
can only be characterized as a “wave”; body-shuddering; and paroxysmal
nonvertiginous dizziness.21,25 Additional manifestations that can also occur
include automatisms, vocalizations, blinking, clonus, dystonia, and posturing
(CASE 5-1).
It is important to realize that EEG may show no ictal findings even during
focal seizures in anti-LGI1 encephalitis. This is presumed to be because of either
(1) localization of seizures involving deeper structures such as the insula, and in
the case of faciobrachial dystonic seizures, potentially the basal ganglia; or (2)
perhaps the size of the seizure onset zone falling below that necessary to allow
scalp EEG detection. When EEG correlate is present, the ictal and interictal
abnormalities are most commonly localized to the temporal and frontal regions.
They can also be multifocal. Both slowing and epileptiform discharges may be
present; however, it is important to note that the EEG may be completely
normal.21 Although faciobrachial dystonic seizures are typically not associated
with EEG abnormalities during an attack, use of specialized ultralow-frequency
filtering can demonstrate a contralateral slow wave potential before clinical
seizure onset.29
MRI may be negative but may show abnormalities in the mesial temporal
structures, basal ganglia, and insula and, less commonly, in the extratemporal
regions.30-33 A unique finding in anti-LGI1 encephalitis with faciobrachial
dystonic seizures is the presence of T1, fluid-attenuated inversion recovery
(FLAIR), and T2 hyperintensities in the basal ganglia. Fludeoxyglucose positron
emission tomography (FDG-PET) may show hypometabolism or
hypermetabolism involving the basal ganglia and mesial temporal structures.20,34
CSF may show mild to moderate inflammatory changes with mild pleocytosis
(6 to 11 cells/mm3) and mild protein elevation (63 to 110 mg/dL), but in 50% of
cases CSF is normal.20,26 LGI1 antibodies are absent in spinal fluid in up to 50%
of patients even in clear cases of anti-LGI1 encephalitis, especially when using
cell-based assays, so clinicians should take care not to exclude LGI1 as a cause of
seizures or encephalitis based on a negative CSF antibody result.27,35
Anti–N-methyl-D-aspartate Receptor Encephalitis

Anti–NDMA receptor encephalitis most commonly occurs in women in the third
decade of life but can affect the very young, older adults, and males as well.
Seizures are common in anti–NMDA receptor encephalitis, occurring in 70% of
368 APRIL 2022

patients; however, they are the presenting symptom in less than 50% of adult KEY POINTS
cases.36 Seizures occur more commonly in the early phase of disease in children
● Anti-LGI1 encephalitis
and young men. Later in the course, status epilepticus may occur in most commonly presents
approximately one-quarter of cases.37 Neurobehavioral abnormalities are with focal seizures. Patients
typically the most prominent presenting feature and include psychosis, speech are typically between the
disorder, catatonia, personality changes, impaired cognition, and memory ages of 40 and 80 years. It is
somewhat more common in
disturbance.
men than women.
The seizure types present in anti–NMDA receptor encephalitis include focal Hyponatremia is relatively
aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures, common. Faciobrachial
which occur in almost 80% of cases.22 Specific clinical features of seizures in dystonic seizures are the
most characteristic seizure
anti–NMDA receptor encephalitis include autonomic symptoms such as
type in this disorder,
piloerection and palpitations or, less commonly, sensory changes.19,22,38 Motor although they are absent in
manifestations occur in 50% of patients with seizures,22 and multiple seizure more than half of cases.
types can occur in the same patient.39 Movement disorder manifestations are also
a common feature and may cause diagnostic uncertainty as some findings, such ● EEG may show no ictal
findings even during focal
as orofacial dyskinesias, can resemble seizure-related oral automatisms. seizures in anti-LGI1
The first EEG after presentation may show a normal background rhythm or encephalitis.
only mild slowing, which correlates with a better prognosis.40 However, the EEG
usually becomes abnormal, typically showing prominent slowing initially. As the ● Certain seizure
manifestations can provide
encephalopathy progresses, generalized rhythmic delta activity is commonly
clues about an autoimmune
present (FIGURE 5-3A).41 A characteristic EEG finding in anti–NMDA receptor etiology.
encephalitis is the “extreme delta brush” pattern, present in up to 30% of
cases. This consists of generalized rhythmic delta activity with superimposed ● Although seizures are
1- to 2-second bursts of high-frequency low-amplitude beta or gamma activity common in anti–N-methyl-
D-aspartate (NMDA)
(FIGURE 5-3B).42 Focal seizures are the most common seizure type seen on EEG, receptor encephalitis,
and they can be multifocal. Prolonged EEG monitoring or serial EEG recordings affecting approximately 70%
are useful in clarifying the epileptic nature of clinical symptoms, monitoring of cases, it is less common
progression of the encephalopathy, quantifying seizure frequency, and for them to be the
presenting symptom in
determining efficacy of treatment. adults. Seizures are most
Structural MRI is normal in up to 70% of anti–NMDA receptor encephalitis common in children and
cases.36 However, several findings have been reported, especially cortical young men.
hyperintensity on FLAIR or T2-weighted images. These findings most commonly
● EEG changes in anti–
involve the temporal lobe and, in particular, the hippocampus; however, other
NMDA receptor encephalitis
regions may be affected, including the frontal lobe, insula, cingulate gyrus, and typically progress in parallel
subcortical structures such as the thalamus and basal ganglia.43,44 FDG-PET may with the severity of the
show alterations in brain metabolism throughout the course of the disease. In the clinical illness, and a higher
degree of abnormality on
acute phase, cortical hypometabolism may occur, especially in the occipital
EEG can correlate with a
cortex.45 Often, mild hypermetabolism can also be seen in the frontal regions, poorer prognosis.
including the basal ganglia.46,47 Importantly, these findings have been found to
correlate with the severity of clinical symptoms and prognosis. ● A characteristic EEG
CSF is abnormal in the majority of anti–NMDA receptor encephalitis cases, finding in anti–NMDA
receptor encephalitis
showing mononuclear pleocytosis and mild to moderate protein elevation, is the “extreme delta
especially in the acute phase of the illness.36,48 CSF anti–NMDA receptor brush” pattern, present in
antibody testing is important because in some cases NMDA receptor antibodies up to 30% of cases.
are found only in CSF and not in serum.
Seizure Manifestations in Other Antibody-Mediated Encephalitides

Other encephalitides associated with neuronal cell surface antibodies that may
present with seizures include those with antibodies targeting γ-aminobutyric
acid B (GABAB) receptor, γ-aminobutyric acid A (GABAA) receptor,

CASE 5-1 A 46-year-old man was self-referred for recent onset of confusion and
seizures. Eight weeks before presentation to clinic, he began
experiencing “out of body” episodes, and 3 weeks later, he experienced
an acute confusional episode. EEG recorded a right temporal seizure.
Levetiracetam was initiated, then valproate and low-dose
oxcarbazepine, but he continued experiencing 30 focal aware seizures
daily, manifested by the sensation of “a wave.”
He presented to clinic continuing to experience the above episodes
multiple times per day. Neurologic examination was unremarkable,
including mental status testing. Head MRI showed subtle right
hippocampal enlargement (FIGURE 5-1). He was admitted to the hospital,
where EEG monitoring captured 100 “wave” seizures in the first 2 days,
most accompanied by right or left temporal seizure discharges (FIGURE 5-2)
but some without correlate. IV methylprednisolone 1 g/d was initiated on
admission. By day 3, seizures declined to four daily. Serum leucine-rich
glioma inactivated protein 1 (LGI1) antibody positivity was reported on day
3; CSF showed mildly elevated protein (65 mg/dL [normal range, 15 to
35 mg/dL]).
Oral prednisone 60 mg/d resulted in seizure freedom for 6 weeks. The
seizures recurred, and the patient was re-treated with 1000 mg/d IV
methylprednisolone for 3 days without benefit. Intravenous
immunoglobulin (IVIg) was initiated at 0.4 g/kg/d for 3 days and then
weekly for 5 weeks, leading to an initial 1 month of seizure freedom; then
seizures recurred during treatment. Mycophenolate mofetil 1000 mg
2 times a day was initiated, and oxcarbazepine was increased to 450 mg
2 times a day, resulting in
sustained seizure freedom.
Three months later,
levetiracetam was tapered.
Prednisone was discontinued
after 16 months of treatment.
Nine months after prednisone
discontinuation, he developed
a recurrence of pilomotor
seizures, which resolved
following an oxcarbazepine
dose increase to 750 mg
2 times a day. Oxcarbazepine
was tapered successfully
56 months after illness onset,
and mycophenolate mofetil
was discontinued 5 years after FIGURE 5-1
illness onset. He continued to Coronal fluid-attenuated inversion recovery (FLAIR)
MRI of the patient in CASE 5-1 who had anti–leucine-
work, but experienced rich glioma inactivated protein 1 (LGI1) encephalitis
occasional name and word- showing subtle hyperintensity and enlargement of
finding errors. the right hippocampus (arrow).
370 APRIL 2022

FIGURE 5-2
EEG in the patient in CASE 5-1 with anti–leucine-rich glioma inactivated protein 1 (LGI1)
encephalitis showing a left temporal predominant (A, arrow) and a right temporal onset
(B, arrow) seizure during initial admission, each manifested by the feeling of a “wave.”
CONTINUED ON
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CONTINUED FROM
PAGE 371
COMMENT This patient had acute symptomatic seizures secondary to anti-LGI1

antibody encephalitis presenting with frequent focal aware seizures with
autonomic and sensory symptomatology. The ultrahigh seizure frequency
provided the first clinical clue suggesting autoimmune encephalitis.20
Regarding symptomatology, it is important to note that, although
faciobrachial dystonic seizures are characteristic of LGI1 antibody
encephalitis, this seizure type is present in only one-third of patients, and
other seizure types may be present.21,25 Early immunotherapy is associated
with the greatest chance for a favorable outcome, which justifies initiation
of treatment before laboratory confirmation in select cases. Of note, MRI
was not specific in this patient for the diagnosis of limbic encephalitis,
which contributed to delay in diagnosis.20 EEG confirmed the presence of
seizures in this case, but EEG can be unremarkable in this disease, even
when focal seizures without impaired awareness occur during the
recording.21
This patient responded to immunotherapy, but a sustained response did
not occur immediately, and several adjustments were necessary, with
definitive control finally occurring after initiation of mycophenolate mofetil
and an increase in the oxcarbazepine dose. This complexity of response is
not always made clear in retrospective case series of autoimmune
encephalitis. Although the management focus in these patients
understandably pivots to immunotherapy after diagnosis, antiseizure
medication can achieve seizure control in 15% and can play a contributing
role in management.22,28
anti–α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor,

dipeptidyl-peptidase–like protein 6 (DPPX), and metabotropic glutamate
receptor 5 (mGluR5). The clinical and paraclinical features are summarized
in TABLE 5-3.
Anti-GABAB receptor encephalitis most commonly presents with seizures
and, in many cases, status epilepticus.49 The seizures can be either focal or
bilateral tonic-clonic in nature. The condition most commonly occurs in men
between the ages of 40 and 80 years. Additional neurologic symptoms at
presentation include memory deficit, confusion, delirium, hallucinations, and
behavioral changes including aggression; however, seizures are the only
symptom in some cases. Extralimbic symptoms can also occur, including
cerebellar ataxia, opsoclonus-myoclonus, and progressive encephalomyelopathy.
EEG and MRI may be normal and do not provide information specific enough to
allow clinical diagnosis. The presence of anti-GABAB receptor antibodies in
serum should be confirmed in the CSF.50 Mortality rates are higher than in
anti-LGI1 or anti–NMDA receptor encephalitis. Poor prognosis is associated with
older age at presentation, presence of malignancy (especially small cell lung
cancer), and medical complications during hospital admission.50
Anti–GABAA receptor encephalitis commonly presents with drug-resistant
seizures, may present with epilepsia partialis continua or status epilepticus in
372 APRIL 2022

KEY POINT
● Although anti–leucine-
rich glioma inactivated
protein 1 (LGI1) and anti–
NMDA receptor encephalitis
are most commonly
associated with seizures,
many other autoimmune
encephalitides can also
cause seizures.
FIGURE 5-3
EEGs in anti–N-methyl-D-aspartate (NMDA) receptor encephalitis. A, Generalized rhythmic
delta activity in a minimally responsive 27-year-old woman. Diffuse alpha is also present.
B, Extreme delta brush in a 24-year-old woman. EEG background contains generalized
rhythmic delta activity with triphasic morphology and superimposed diffuse, maximal
anterior bursts of high-frequency activity located on crests of delta waves.
addition to encephalopathy, and has no clear age or sex preference.51 Unlike anti–
GABAB receptor encephalitis, often clear MRI abnormalities are present and are
most apparent on T2-weighted sequences, affecting both gray and white matter.
These lesions are often multifocal, non–diffusion-restricting, nonenhancing, and
of a medium to large size.52 Therefore, anti–GABAA receptor encephalitis should
also be considered in the differential diagnosis of fulminant multiple sclerosis and
acute disseminated encephalomyelitis (ADEM). Similar to GABAB receptor
antibodies, the presence of GABAA receptor antibodies in serum should be
confirmed in the CSF.
Anti–AMPA receptor encephalitis typically presents as limbic encephalitis,
often with prominent psychiatric symptoms and hyponatremia. Although
seizures are associated with this condition, they are uncommonly a presenting or
prominent feature. Anti–AMPA receptor antibodies are often paraneoplastic,
seen in association with cancer of the lung and breast, thymoma, and ovarian

TABLE 5-3 Summary of Clinical and Paraclinical Features Associated With Specific
Neural Autoantibodies
Main presenting FDG-PET Cancer

Antibody targets symptom Seizure types MRI findings findings association
Antibodies targeting neuronal cell surface antigens associated with encephalitis and seizures
N-methyl-D- Psychiatric Focal aware Normal or transient Increased Ovarian teratoma,

aspartate (adults), seizures seizures, focal non–region- frontal and others (in patients
(NMDA) receptor (pediatric) impaired awareness specific T2 temporal FDG older than
seizures, hyperintensities uptake; 40 years)
generalized tonic- decreased
clonic seizures, occipital
autonomic update
symptoms
(piloerection and
palpitations),
sensory changes,
motor
manifestations
(orofacial and
manual
automatisms,
twitching)
Leucine-rich Seizures, memory Faciobrachial Hyperintense T2 Basal ganglia Rare: thymoma,

glioma impairment dystonic seizures, signal, subtle and temporal small cell lung
inactivated autonomic enlargement increased cancer,
protein 1 (LGI1) symptoms (acutely) in mesial uptake adenocarcinoma
(piloerection, temporal lobes, (breast, prostate)
sensations of insula, and basal
alteration of ganglia;
temperature hippocampal
[“thermal” atrophy (chronic)
seizures]),
somatosensory
changes
(paresthesia or pain),
a sensation of a
“wave,” body-
shuddering,
paroxysmal
nonvertiginous
dizziness,
automatisms,
vocalizations,
blinking, clonus,
dystonia, and
posturing
γ-Aminobutyric Seizures Focal or focal to Normal or Increased Small cell lung

acid B (GABAB) bilateral tonic-clonic hyperintense T2 uptake in cancer
receptor seizures, status signal in mesial temporal lobes
epilepticus temporal lobes
CONTINUED ON PAGE 375
374 APRIL 2022

CONTINUED FROM PAGE 374
Main
Main presenting
presenting FDG-PET
FDG-PET Cancer
Cancer
Antibody
Antibody targets
targets symptom
symptom Seizure types
Seizure types MRI
MRI findings
findings findings
findings association
association
γ-Aminobutyric Encephalopathy Focal seizures, Hyperintense signal May show Thymoma
acid A (GABAA) and seizures epilepsia partialis in multiple cortical increased
receptor continua, or status and subcortical uptake in the
epilepticus areas region of MRI
abnormalities
α-Amino-3- Psychiatric, Focal seizures, Bilateral mesial Increased Thymoma, small

hydroxy-5- hyponatremia symptomatology temporal T2 temporal cell lung cancer,
methylisoxazole- not clarified in the hyperintensities uptake breast
4-propionic acid literature adenocarcinoma
(AMPA) receptor
Dipeptidyl- Diarrhea, weight Focal seizures as Normal or non– No specific B-cell lymphoma,
peptidase–like loss, part of central region-specific reports in the leukemia
protein 6 (DPPX) parkinsonism nervous system changes literature
hyperexcitability
(can also result in
hyperekplexia,
tremor, or
myoclonus)
Metabotropic Psychiatric Focal, secondary Normal or Normal or Hodgkin

glutamate generalized hyperintense signal decreased lymphoma
receptor 5 seizures, status in various brain uptake in
(mGluR5) epilepticus (more regions various regions
common in children)
Antibodies targeting intracellular antigens that can be associated with encephalitis and seizures
Glutamic acid Stiff person Focal aware Normal, T2 Normal or Rare; thymoma,
decarboxylase syndrome seizures; hyperintensities increased or adenocarcinoma
65 (GAD65) musicogenic and enlargement of decreased (lung, breast,
seizures; the amygdalae and uptake mesial colon)
experiential hippocampi; late temporal
phenomena hippocampal regions
(especially déjà vu, atrophy
but also anxiety,
déjà vécu,
derealization, and
autoscopy); auditory
(especially musical),
olfactory,
somatosensory, and
visual auras;
ascending epigastric
sensations and
nausea; motor
manifestations
(manual or orofacial
automatisms,
dystonic limb
posturing)

Main presenting FDG-PET Cancer

Antibody targets symptom Seizure types MRI findings findings association
Antineuronal Seizures, memory Focal aware seizures Normal or T2 Increased Strongly
nuclear antibody disturbance, and focal impaired hyperintense non- uptake of associated with
type 1 (ANNA-1) sensory awareness seizures enhancing focal affected small cell lung
neuropathy (often described as lesions (can be in regions in cancer
temporal lobe the sensorimotor acute setting
seizures), epilepsia cortex in patients
partialis continua with epilepsia
(especially affecting partialis continua)
the face or arm),
status epilepticus
Ma/Ta Encephalitis Focal impaired Brainstem FLAIR Normal or Testicular, non–

(including awareness seizures hyperintensity or decreased small cell lung
brainstem), generalized tonic- mesial temporal uptake of cancer, breast
parkinsonism clonic seizures FLAIR various regions
hyperintensity
FDG-PET = fludeoxyglucose positron emission tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
teratoma. One-third of cases are associated with the presence of additional

neuronal cell surface antibodies, which can influence the presenting phenotype.53
MRI is often abnormal and most commonly demonstrates increased FLAIR and
T2 signal hyperintensities in both mesial temporal regions. EEG is abnormal in
almost half of patients, but the findings are often nonspecific and, most
commonly, generalized slowing is seen.54
Anti-DPPX encephalitis differs from other encephalitides in that patients
often present after a subacute or chronic course with symptoms of weight loss
and gastrointestinal symptoms, especially diarrhea, owing to the prominent
expression of DPPX in the myenteric plexus. The most common presentation
consists of a triad of (1) gastrointestinal symptoms/weight loss; (2) limbic
symptoms (cognitive or mental); and (3) CNS hyperexcitability. Seizures form
part of the expression of CNS hyperexcitability, but this can also take the form of
myoclonus, hyperekplexia, or tremor.55 EEG can either be normal or demonstrate
nonspecific findings, and it is less common to see epileptiform discharges or
seizures. Similarly, MRI may be normal or demonstrate nonspecific T2/FLAIR
hyperintensities, and CSF can be normal or reveal a mild to moderate pleocytosis.
An association with lymphoma has been reported, so clinicians should take care
to exclude this in these patients.
Anti-mGluR5 encephalitis most often presents with psychiatric symptoms,
but seizures are common. In children, generalized seizures and status epilepticus
are much more common. The median age at presentation is 29 (range, 6 to
75 years), and no clear sex preference exists. Malignancy is present in just more
than half of cases.56 MRI abnormalities are present in about half of cases and are
not restricted to the mesial temporal structures, often involving extratemporal
cortical regions, the thalamus, and even the cerebellum and pons.56 CSF
376 APRIL 2022

pleocytosis is common in reported cases, and more than half of patients will have KEY POINTS
an abnormal EEG, usually comprising focal or generalized slowing. Epileptiform
● Autoimmune encephalitis
abnormalities are uncommon. can occur in the absence of
Anti-GAD65 antibody acute limbic encephalitis is relatively uncommon. This detectable neural
antibody is more commonly associated with chronic focal epilepsy of temporal autoantibodies, and if the
lobe origin, which is discussed later in this article. Importantly, a diagnosis of pretest probability is high,
then the diagnosis of
anti-GAD65 encephalitis should not be made unless concomitant behavioral
seronegative autoimmune
change or cognitive or memory impairment is present, and these features should limbic encephalitis should
help clinicians differentiate the phenotypes of encephalitis and epilepsy. be considered.
Seronegative Autoimmune Limbic Encephalitis ● Examples of autoimmune-

associated epilepsy include
Symptoms of limbic encephalitis can also occur in the absence of CNS the persistence of seizures
autoantibodies. In such cases, provided other secondary causes of encephalitis after resolution of the active
are reasonably excluded, the diagnosis of seronegative autoimmune limbic phase of encephalitis;
encephalitis can be made.57 Seronegative autoimmune limbic encephalitis chronic unresolving
encephalitis including
(SNALE) accounts for approximately 7% of cases of limbic encephalitis, and it Rasmussen encephalitis;
typically affects older men (median age, 62 years; age range, 40 to 79 years).58 and in patients with epilepsy
Clinicians should note that this can occur as a paraneoplastic condition even in with compelling evidence of
the absence of paraneoplastic antibodies. In half of cases, patients may have a a CNS autoimmune
condition where no
prodrome of viral symptoms and memory difficulties lasting up to weeks before alternative etiology for the
the onset of encephalitis. epilepsy is identified.
The predominant presenting symptom is short-term memory difficulties, and
in one-third of cases, this may be the only symptom. In other cases, patients may
experience disorientation and confusion, whereas more florid behavioral and
neuropsychiatric symptoms are uncommon.58 Seizures are reported in only 8% of
cases; however, not all reported cases are evaluated with prolonged EEG
monitoring, so the frequency of seizures might be underreported. When seizures
do occur, they may not be the predominant presenting symptom. The EEG is
often abnormal but with nonspecific slowing, and epileptiform discharges may
be absent. MRI changes with T2/FLAIR hyperintensities in both hippocampi are
required to make the diagnosis, and involvement of the insula, orbitofrontal
cortex, or basal ganglia is also common.58 CSF pleocytosis occurs in almost 60% of
cases; however, it is often mild when present (median, 13 cells/mm3; range, 9 to
25 cells/mm3).
SEIZURE AND CLINICAL CHARACTERISTICS IN AUTOIMMUNE-

ASSOCIATED EPILEPSY
The term autoimmune-associated epilepsy denotes a condition characterized by an
enduring predisposition to unprovoked seizures in which evidence of an immune
etiology is present. This can occur in several contexts, including persistence of
seizures after resolution of the active phase of encephalitis, in the setting of
chronic unresolving encephalitis, and in patients with epilepsy with compelling
evidence of a CNS autoimmune condition and where no alternative etiology for
the epilepsy is identified.
Postencephalitic Epilepsy
Although seizures eventually resolve in the majority of patients after timely
treatment of the active phase of autoimmune encephalitis with immunotherapy,
a subset of patients will continue to experience seizures or experience a
recurrence after initial resolution of the active phase. Persistent seizures occur in

up to 37% of cases of autoimmune encephalitis, and additional immunotherapy

does not always result in seizure freedom.59 Postencephalitic epilepsy typically
emerges 3 to 6 months after initial presentation. Initially, this may be difficult to
distinguish from autoimmune encephalitis relapse, but it is characterized by a
predominant presentation with seizures in the absence of other symptoms of
encephalitis.59,60 Clinicians should be vigilant, however, to monitor for
additional features of encephalitis, which can occur in 11% of cases. At the time of
seizure recurrence, it is advisable to reassess the entire clinical picture and
consider rechecking antibody titer, neuroimaging, and CSF to determine if
additional immunotherapy is warranted.59
An important risk factor for the development of postencephalitic epilepsy is
delayed initiation of immunotherapy.60 Other risk factors include a history of
status epilepticus, interictal epileptiform discharges, and high CSF protein
level.59,60 Antibody type is also important to determine the likelihood of seizure
recurrence. For example, anti–NDMA receptor antibody–mediated disease
rarely results in postencephalitic epilepsy.44,59 However, persistent seizures may
be present after resolution of encephalitis associated with anti-LGI1 antibodies in
up to 47% of cases and GABAB antibodies in up to 64% of cases.59 Seizure
outcome is not thought to be affected by early or late withdrawal of antiseizure
medications, so antiseizure medication discontinuation can be considered after a
significant period of seizure freedom without concern that doing so will
influence the ultimate development of epilepsy.60
Anti–Glutamic Acid Decarboxylase 65 Antibody–Associated Epilepsy

Despite their discovery more than 30 years ago, the role of anti-GAD65
antibodies in CNS diseases is uncertain and controversial. Anti-GAD65
antibodies are unique among other neural antibodies discussed in the context of
autoimmune-associated seizure disorders in that they are more commonly seen
in association with chronic epilepsy than the neuronal cell surface antibodies
summarized previously. The pathogenicity of anti-GAD65 antibodies is heavily
debated on the basis that GAD65 is an intracellular antigen, and the ability of the
antibody to pass intracellularly is not fully established.15,61,62 Anti-GAD65
antibodies are also associated with other neurologic presentations, including
cerebellar ataxia and stiff person syndrome.63
Anti-GAD65 antibodies were initially described in association with chronic
temporal lobe epilepsy, and this finding has been confirmed in several
studies.64-67 They have also been described in new-onset epilepsy, epilepsy of
unknown cause, drug-resistant epilepsy, pediatric epilepsy, and in association
with systemic autoimmunity.12,68-70 Anti-GAD65 antibody–associated epilepsy is
most common in women (70% to 80%) in the third decade of life (median age,
26 years), and up to 40% will have comorbid autoimmune conditions, especially
type 1 diabetes mellitus or thyroid disease.
The seizure types in anti-GAD65 antibody–associated epilepsy vary;
however, certain characteristics can serve as clinical clues for the diagnosis.
The seizures are relatively frequent. Focal aware seizures are common; however,
focal seizures with impaired awareness and focal to bilateral tonic-clonic
seizures can also occur.24 The symptomatology is often reflective of temporal-
perisylvian seizure involvement. One unique clinical characteristic that should
raise suspicion for the diagnosis of anti-GAD65 antibody–associated epilepsy is
the presence of musical auras and musicogenic seizures.23 Other clinical features
378 APRIL 2022

that can occur are varied and include experiential phenomena (especially
déjà vu, anxiety, déjà vécu, derealization, and autoscopy); olfactory,
somatosensory, and visual auras; ascending epigastric sensations; and
nausea.24,71,72 Motor manifestations can also occur during focal seizures,
including manual or orofacial automatisms and dystonic limb posturing
(CASE 5-2).
A 35-year-old right-handed woman presented for epilepsy management CASE 5-2

recommendations. Her seizures began at the age of 4 years and were
currently manifested as focal impaired awareness seizures that were
often provoked by music. She had type 1 diabetes mellitus but no history
of head injury, perinatal difficulties, febrile convulsions, or family history
of epilepsy. Her focal seizures were reported as daily and focal to
bilateral tonic-clonic seizures once per month. She had previously tried
seven antiseizure medications, all of which failed; her current regimen
included cannabidiol, gabapentin, and levetiracetam. Brain MRI showed
left hippocampal atrophy but was otherwise unremarkable.
EEG monitoring showed four left and two right temporal-onset
seizures. Given her history of type 1 diabetes mellitus and observations
that her seizure frequency was very high, a serum neuroimmunology
panel was ordered; it showed a high anti–glutamic acid decarboxylase 65
(GAD65) antibody titer (1482 nmol/L [normal, less than 0.02 nmol/L]). CSF
showed one nucleated cell, a protein level of 17 mg/dL, five oligoclonal
bands, and elevated CSF anti-GAD65 antibody titer of 53.7 nmol/L
(normal, less than 0.02 nmol/L). Given the bilateral seizure localization
and probable autoimmune etiology, resective surgery was excluded.
Immunotherapy with IVIg was offered but declined. Neuromodulation
was considered.
This patient has epilepsy as defined as an enduring predisposition to COMMENT

seizures. The high serum anti-GAD65 antibody titer and its presence in CSF
suggest a possible autoimmune etiology. Anti-GAD65 antibodies are
suspected to be a marker of autoimmunity, but they are not considered
directly pathogenic given that GAD65 is located intracellularly. Several
studies have shown these patients generally have a poor response to
immunotherapy.73,74 Immunotherapy was presented to the patient as an
option, along with a transparent discussion about the limited reported
efficacy, and she declined.
The clinical cues that prompted anti-GAD65 antibody evaluation were
the high seizure frequency,20 presence of a musicogenic trigger,23 and type
1 diabetes mellitus. Musicogenic seizures may be a characteristic
manifestation in patients with GAD65 antibody–associated seizures.
Although anti-GAD65 antibodies are found in more than 50% of patients
with type 1 diabetes mellitus, the titers are generally much lower than that
found in this patient.75 Titers less than 20 nmol/L are generally considered
nonspecific in the evaluation of neuroimmunologic disorders.

No EEG findings are specific to anti-GAD65 antibody–associated epilepsy. The

EEG may be normal, but temporal slowing and epileptiform discharges are
common and often have a bilateral distribution.73 Rarely, status epilepticus
including epilepsia partialis continua may occur. Where intracranial EEG has
been used, an unusually high frequency of subclinical seizures has been reported,
occurring up to hundreds of times daily.76 MRI changes vary over the course of
the illness and early in the presentation may demonstrate T2 or FLAIR
hyperintensities and enlargement of the amygdalae and hippocampi.77,78 Later in
the disease, hippocampal atrophy may develop. FDG-PET may demonstrate
mesial temporal hypermetabolism.79 CSF in chronic anti-GAD65 antibody–
associated epilepsy is typically noninflammatory, although occasionally mild
pleocytosis or CSF protein elevation may be present. Oligoclonal bands may also
be present. Anti-GAD65 antibody testing in CSF is generally recommended in
suspected cases to help assess the significance of serum anti-GAD65 antibody
positivity. As outlined earlier, only high titer results should be considered
potentially etiologically relevant. Results are considered potentially significant in
quantitative tests (radioimmunoassays or enzyme-linked immunosorbent assays
[ELISAs]) when the titer is greater than 20 nmol/L or greater than 1000 U/mL
or if confirmatory testing with qualitative methods (immunohistochemistry,
cell-based assays, or line-blot assays) is positive.63
Rasmussen Encephalitis
Chronic encephalitis can also result in an enduring predisposition to seizures, of
which Rasmussen encephalitis is the classic example. Rasmussen encephalitis is a
rare neuroinflammatory disorder resulting in chronic focal seizures, emanating
from one hemisphere, progressive hemiparesis, other lateralized cortical deficits,
and cognitive impairment. Unlike the other conditions discussed earlier,
Rasmussen encephalitis is thought to be mediated predominantly by T-cell
inflammatory processes.80 Several antibodies have been described in association
with Rasmussen encephalitis, including those targeting the GluN2 subunit of the
NMDA receptor, the GluA3 (or GluR3) subunit of the AMPA receptor, and
other neuronal antigens. However, these antibodies have also been found in up to
40% to 60% of epilepsy cases without Rasmussen encephalitis, so their specific
significance referable to Rasmussen encephalitis is generally disputed at
this time.74
Rasmussen encephalitis most commonly presents in children (median age,
6 years) but can occur in young adults. Three phases of disease have been
described.81 In stage 1, the patient may present with a prodrome of mild
hemiparesis and infrequent focal seizures up to years before the acute phase.
Stage 2 is heralded by a more acute presentation with frequent unilateral motor
seizures that evolve into treatment-refractory epilepsia partialis continua in 50%
of cases.81 As the disease progresses, other seizure types can occur, including
focal nonmotor seizures with or without impaired awareness and focal to
bilateral tonic-clonic seizures, suggestive of ongoing neuroinflammatory activity
in this stage.82 Loss of cortical function typically develops, resulting in varying
degrees of unilateral hemiplegia, hemianopia, cognitive decline, and dysphasia
over time.80 Neuroimaging characteristically shows contralateral hemiatrophy,
which is progressive over time, and FDG-PET typically demonstrates
hemispheric hypometabolism.83 Stage 3 represents a relative stagnation of
progression and underlying active inflammation. This is sometimes accompanied
380 APRIL 2022

by a reduction in seizures, although focal seizures often persist to a degree for KEY POINTS
several years. Unfortunately, despite the inflammatory etiology, Rasmussen
● Rasmussen encephalitis is
encephalitis is inconsistently responsive to immunotherapy, even in the active a rare neuroinflammatory
stage. Surgery, specifically hemispheric disconnection, is often necessary to gain disorder resulting in chronic
seizure control in very young children with Rasmussen encephalitis and high focal seizures, emanating
seizure burden. This procedure, which risks cortical neurologic deficits, from one hemisphere,
progressive hemiparesis,
nonetheless can result in seizure freedom in 60% to 85% of patients.84
other lateralized cortical
deficits, and cognitive
NEURAL AUTOANTIBODY PRESENCE IN EPILEPSY AND GUIDES TO impairment.
SELECT PATIENTS FOR TESTING
Among patients with epilepsy, the relative increased prevalence of CNS ● Immunotherapy can lead
to seizure freedom when
autoantibody positivity outside of the context of encephalitis has been reported due to autoimmune
for many years. Although the clinical relevance of some autoantibodies in the etiologies; consideration of
epilepsy clinic setting continues to be debated, some cases with pathogenic these disorders should be
autoantibodies have been reported where immunotherapy resulted in improved given in the setting of drug-
resistant seizures, especially
seizure outcome and even seizure freedom. Therefore, the diagnosis of those of recent onset and
autoimmune-associated epilepsy warrants consideration in the epilepsy intractability from inception.
outpatient setting, especially when treatment with standard antiseizure
medications has been unsuccessful. The literature in this area continues to ● Diagnostic accuracy
requires an understanding
evolve, but certain features should raise suspicion for a potential diagnosis.
and integration of the
Potentially pathogenic CNS autoantibodies have been more commonly spectrum of clinical and
reported in focal epilepsy of unknown cause,12,13,85 where structural, genetic, and paraclinical presentations,
metabolic causes have been excluded. CNS autoantibodies have also been and several scoring systems
have been developed that
reported in cases of temporal lobe epilepsy with and without hippocampal
may be useful in aiding the
sclerosis,13,65-67,86 drug-resistant epilepsy,87,88 new-onset focal epilepsy,85,89 identification of
epilepsy in female patients,90 and pediatric epilepsy.68,91,92 Importantly, these autoimmune seizures.
patients do not always present with acute encephalitic features. The frequency of
autoantibodies reported in patients with epilepsy varies greatly. The highest
frequencies reported are 15% to 25% of patients69,85,86,93; however, other studies
have reported a rate of 0%.94-97 The most commonly identified antibodies in
these series are anti-GAD65 (3.94%), with high-titer anti-GAD65 comprising
2.16%. Other antibodies that have been reported include anti–glycine receptor
(2.36%), anti–NMDA receptor (2.15%), anti-CASPR2 (1.37%), and anti-LGI1
(1.37%) antibodies.
Patient Selection for Immune Etiology Evaluation

In the outpatient setting, seizure manifestations and other clinical features can be
used to help identify patients who are most appropriate for autoantibody testing.
The presence of faciobrachial dystonic seizures should clearly prompt neural
autoantibody testing, which includes anti-LGI1 antibody. Clinicians should also
consider antibody screening in new-onset focal epilepsy of unknown cause,12
especially in patients with a high daily seizure burden98 and in the presence of
perisylvian99-101 or autonomic symptomatology.102 For example, ictal
piloerection, which is a common finding in the autoimmune encephalitides, has
been found to be a predictive clinical feature for autoantibody positivity.21,103,104
The EEG is often abnormal in autoimmune-associated epilepsy; however, the
findings are rarely specific enough to trigger consideration of an autoimmune
etiology, and the EEG may be normal.
Neuroimaging is also of varying clinical utility in identification of patients
with autoimmune-associated epilepsy. Brain MRI findings may demonstrate

FLAIR or T2 signal abnormalities in the mesial temporal lobe but may be

normal.105 Therefore, MRI might be suggestive of an autoimmune etiology, but a
normal study does not exclude the diagnosis.
CSF evaluation should be performed if autoimmune-associated epilepsy is
suspected. It is important to remember that the sensitivity for certain CNS
autoantibodies, particularly anti–NMDA receptor antibody, may be higher in
CSF than serum.42,106 CSF testing should also include nucleated cell count,
protein level, IgG index, and evaluation for the presence of oligoclonal bands.
However, the absence of inflammatory CSF findings in the setting of possible
autoimmune-associated epilepsy does not completely exclude the diagnosis.
Diagnostic Criteria and Scoring Systems

Diagnostic criteria have been developed to assist in the identification of
patients with autoimmune encephalitis. The criteria developed by Graus and
colleagues57 for possible and definite autoimmune encephalitis are shown in
TABLE 5-4. These criteria are highly specific for patients with clear limbic
encephalitis; however, they may not identify those with more subtle
encephalitis presentations and are often not confirmatory in patients with
autoimmune-associated epilepsy.
TABLE 5-4 Diagnostic Criteria for Possible and Definite Autoimmune Encephalitisa
Diagnosis of possible autoimmune encephalitis can be made when all three of the following
criteria have been met:
1 Subacute onset (rapid progression of less than 3 months) of working memory deficits
(short-term memory loss), altered mental status, and/or psychiatric symptoms
2 At least one of the following:
◇ New focal central nervous system findings
◇ Seizures not explained by a previously known seizure disorder
◇ CSF pleocytosis (white blood cell count of more than 5 cells/mm3)
◇ MRI features suggestive of encephalitis
3 Reasonable exclusion of alternative causes
Diagnosis of definite autoimmune encephalitis can be made when all four of the following
criteria have been met:
1 Subacute onset (rapid progression of less than 3 months) of working memory deficits,
seizures, and/or psychiatric symptoms suggesting involvement of the limbic system
2 Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the mesial
temporal lobes
3 At least one of the following:
◇ CSF pleocytosis (white blood cell count of more than 5 cells/mm3)
◇ EEG with epileptic or slow-wave activity involving the temporal lobes
4 Reasonable exclusion of alternative causes
CSF = cerebrospinal fluid; EEG = electroencephalogram; FLAIR = fluid-attenuated inversion recovery;

MRI = magnetic resonance imaging.
a
Modified with permission from Graus F, et al, Lancet Neurol.57 © 2016 Elsevier Ltd.
382 APRIL 2022

Scoring systems have also been developed to aid in the identification of an
autoimmune etiology in patients presenting with seizures. These scales typically
include elements that are weighted toward the identification of acute or subacute
encephalitis phenotypes. Thus, they may miss patients with more subtle
encephalitis presentations and those with chronic autoimmune-associated
epilepsy, but they are helpful in identifying patients with a high pretest
probability of autoantibody positivity.107-109 One such scoring system is the
Antibody Prevalence in Epilepsy (APE) and the related Antibody Prevalence in
Epilepsy and Encephalopathy (APE2) score (TABLE 5-5). A score of 4 or greater on
the APE scale showed 82.6% sensitivity and 82% specificity for the detection of
serum CNS autoantibodies in a mixed cohort of inpatients and outpatients whose
serum was sent for neuroimmunology evaluation.85 Although APE and APE2
scales will not help diagnose patients with seronegative autoimmune encephalitis
and autoimmune-associated epilepsy, their use can help avoid the detection of
neural antibodies with a less clear pathogenicity, such as non-LGI1/non-CASPR2
voltage-gated potassium channel antibodies and low-titer anti-GAD65
antibodies, and those rare neural antibodies that sometimes are present in control
populations as an expression of natural immunity.
Another scale developed to aid in determining the clinical relevance of
seropositive results is the Neuronal Autoantibody Confidence Scale.110 Although
many of the autoantibodies with intracellular targets are well characterized and
associated with specific clinical phenotypes, some of the surface neuronal
autoantibodies are less so. This is especially true of voltage-gated calcium channel
antibodies, voltage-gated potassium channel without immunoreactivity to LGI1
or CASPR2, and ganglionic nicotinic acetylcholine receptor antibodies, which are
all thought to have limited clinical relevance in the setting of seizures and
epilepsy. Therefore, this scale is particularly useful as a tool to increase the
confidence in the clinical relevance of these less specific antibodies. Clinicians
should be careful, however, to always correlate the clinical presentation to the
antibody detected and question the clinical relevance of the result if clinical-
serologic discordance is present.110
To further address the question of clinical phenotype in antibody-positive
epilepsy, another scoring model was recently published by McGinty and
colleagues.104 This scoring model was based on clinical features found in patients
presenting to an epilepsy clinic who were subsequently found to be antibody
positive. This model and scoring are shown in TABLE 5-5. In this study, the
authors distinguished patients with epilepsy from those with autoimmune
encephalitis through application of the criteria from Graus and colleagues57 and
found that a proportion of patients presenting to an outpatient epilepsy clinic
actually had mild, but clinically evident, symptoms of autoimmune encephalitis.
Ictal piloerection, low mood, age older than 54 years, and MRI abnormalities in
limbic regions were predictive of CNS autoantibody positivity in this cohort,
whereas poor attention on cognitive assessment and the presence of customary
epilepsy risk factors (eg, history of traumatic brain injury and epilepsy family
history) predicted seronegativity. This scoring model can be used in concert with
the APE2 score to identify patients with “mild encephalitis” who might benefit
from neural autoantibody testing.
Finally, another scoring system called the Antibodies Contributing to Focal
Epilepsy Signs and Symptoms (ACES) score, published in 2021, helps identify
patients presenting with seizures due to an autoimmune etiology.111 The score

TABLE 5-5 Scoring Systems to Aid Identification of Autoimmune Encephalitis and

Autoimmune Associated Epilepsy
Antibodies
Contributing to
Antibody Prevalence in Neuronal Focal Epilepsy
Epilepsy and Antibody Criteria from Signs and
Encephalopathy (APE2) Confidence McGinty and Symptoms (ACES)
scale Score (NAC) scale Score colleagues104 Score scale Score
New-onset, rapidly 1 Antibody 1 Age older than 1 Cognitive 1
progressive mental status against 54 years symptoms
changes that developed intracellular
over 1-6 weeks or new- antigen (or high
onset seizure activity clinical
(within 1 year of evaluation) relevance
surface
antibody)
Neuropsychiatric changes; 1 Movement 1 Self-reported 1 Behavioral 1

agitation, aggressiveness, disorder and/or mood changes
emotional lability stiff person disturbance
syndrome
Autonomic dysfunction 1 Cancer and/or 1 Limbic system 2 Autonomic 1

(sustained atrial smoking history lesions on MRI symptoms
tachycardia or bradycardia,
orthostatic hypotension
[≥20 mm Hg fall in systolic
pressure or ≥10 mm Hg fall
in diastolic pressure within
3 minutes of quiet
standing], hyperhidrosis,
persistently labile blood
pressure, ventricular
tachycardia, cardiac
asystole, or gastrointestinal
dysmotility)
Viral prodrome (rhinorrhea, 2 Inflammatory 1 Ictal piloerection 2.5 Speech problems 1

sore throat, low-grade CSF (either high
fever) to be scored in the cell count, IgG
absence of underlying index and/or
systemic malignancy within positive
5 years of neurologic oligoclonal
symptom onset bands)
Faciobrachial dystonic 3 Serum 1 Addenbrooke’s -1.5 History of other 1

seizures hyponatremia Cognitive autoimmune
Examination disease
attention
score ≥ 16
Facial dyskinesias, to be 2 Chronic course -1 Epilepsy risk -1.5 Temporal MRI 1

scored in the absence of (>3 months) factors hyperintensities
faciobrachial dystonic
seizures
384 APRIL 2022

Antibodies
Contributing to
Antibody Prevalence in Neuronal Focal Epilepsy
Epilepsy and Antibody Criteria from Signs and
Encephalopathy (APE2) Confidence McGinty and Symptoms (ACES)
scale Score (NAC) scale Score colleagues104 Score scale Score
Seizure refractory to at 2
least two antiseizure
medications
CSF findings consistent 2

with inflammation
(elevated CSF protein
>50 mg/dL and/or
lymphocytic pleocytosis >5
cells/mm3, if the total
number of CSF red blood
cells is <1000 cells/mm3)
Brain MRI suggesting 2

encephalitis (T2/FLAIR
hyperintensity restricted to
one or both mesial
temporal lobes, or
multifocal in gray matter,
white matter, or both,
compatible with
demyelination or
inflammation)
Systemic cancer diagnosed 2

within 5 years of neurologic
symptom onset (excluding
cutaneous squamous cell
carcinoma, basal cell
carcinoma, brain tumor,
cancer with brain
metastasis)
Maximum score 18 5 6.5 6
Cutoff score predicting ≥4 a

≥2 b
≥0 c
≥2d
antibody positivity or
autoimmune etiology
CSF = cerebrospinal fluid; FLAIR = fluid-attenuated inversion recovery; IgG = immunoglobulin G; MRI = magnetic resonance imaging.
a
Sensitivity = 82.6% and specificity = 82%.
b
Sensitivity = 77% and specificity = 94%.
c
Sensitivity = 66.7% and specificity = 84.9%.
d
Sensitivity = 100% and specificity = 84.9%.

was based on antibody assessment performed in patients referred for evaluation

of epilepsy of unknown cause who had a low clinical suspicion for an
autoimmune etiology. The 6-point ACES scoring system derived by this study
gives 1 point each for the following features: cognitive symptoms, behavioral
changes, autonomic symptoms, speech problems, autoimmune diseases, and
mesial temporal lobe MRI hyperintensities. In this study, which was validated in
an additional cohort, the sensitivity of an ACES score of 2 or greater was 100%,
and specificity 84.9%, for the presence of neuronal cell surface antibodies or
high-titer anti-GAD65 antibodies.
TREATMENT IN ANTIBODY-MEDIATED AUTOIMMUNE ENCEPHALITIS

AND AUTOIMMUNE-ASSOCIATED EPILEPSY
Treatment in autoimmune encephalitis and autoimmune-associated epilepsy is
primarily focused on addressing the underlying etiology with immunotherapy
and can be considered in alignment with the phases of illness. The potential
benefit of adjunct use of antiseizure medications should also be evaluated,
especially during the acute phase.
Antiseizure Medication Therapy in Acute Symptomatic Seizures Secondary

to Autoimmune Encephalitis
Seizure control is infrequently achieved with antiseizure medication therapy
alone in patients with seizures secondary to autoimmune encephalitis.28,112 In
studies evaluating the efficacy of antiseizure medication therapy in this setting,
seizure control with antiseizure medication alone occurred in 15%.22,28
Importantly, some antiseizure medications appear to be more effective than
others. Higher responder rates have been reported with sodium channel
blockers, particularly carbamazepine and lacosamide compared with
levetiracetam, for example.28 Although the reasons for this difference in efficacy
are unclear, it is interesting that certain antiseizure medications, including
carbamazepine, have immunosuppressive effects.113 If carbamazepine or like
agents are used in this setting, however, it should be noted that the rate of
hypersensitivity reactions is greater in patients with autoimmune encephalitis
than in the general population. In addition, hyponatremia, which is a relatively
common adverse effect of carbamazepine and oxcarbazepine, is also common in
autoimmune encephalitis, so sodium concentrations must be watched carefully if
these agents are used in this setting.
The risk of ongoing seizures after recovery from the acute phase of the
encephalitic illness is reported to be higher in older patients, those with severe
seizures and status epilepticus, the presence of cortically based lesions on
neuroimaging, and patients with focal neurologic deficits.114 Seizure control
often occurs after immunotherapy in patients with neuronal cell surface
antibodies, in which case the question of antiseizure medication discontinuation
often arises.114 In this setting, it is important to take the specific neural
autoantibody into account when deciding on the necessity of long-term
antiseizure medication therapy. For example, seizures usually resolve after
resolution of anti–NDMA receptor encephalitis, eventually allowing successful
antiseizure medication discontinuation. However, the rate of persistent seizures
and postencephalitic epilepsy after acute anti–GABAB receptor encephalitis
appears higher. Recurrent seizures and the need for long-term antiseizure
medication administration are also more likely in patients initially presenting
386 APRIL 2022

with status epilepticus regardless of the autoantibody present.115 Therefore, an KEY POINTS
individualized approach to the timing of antiseizure medication discontinuation
● If used alone, antiseizure
needs to be applied in these patients as in epilepsy due to other etiologies. medications are rarely
Long-term antiseizure medication administration is not always necessary in effective in the setting of
many patients after resolution of acute encephalitis, and discontinuation can be symptomatic seizures
considered after 6 months or a greater period of seizure cessation. secondary to autoimmune
encephalitis. They also may
not be required after
Immunotherapy resolution of the acute
Immunotherapy plays a central role in the management of seizure due to illness, so cessation should
autoimmune etiology, particularly in acute symptomatic seizures secondary to be considered after
6 months or a greater period
autoimmune encephalitis. Seizure freedom occurs in 62% to 89% of patients
of sustained seizure
affected by seizures, and the median time to seizure freedom after initiation of freedom.
immunotherapy is 28 days.116 In addition, the benefits are not limited to seizure
cessation; they extend to cognitive and functional outcomes. When the use of ● Immunotherapy is the
immunotherapy is uncertain, the Response to Immunotherapy in Epilepsy mainstay of treatment for
autoimmune seizure
(RITE) score (TABLE 5-6) can be used to help select patients for treatment. In this etiologies and should be
scoring system, a score of 7 or greater is predictive of a positive response.85 administered early in the
Treatment options are listed in TABLE 5-7.117 It is important to note that none of course of the illness. Eighty
these treatment strategies have been subject to placebo-controlled clinical trials, percent to 90% of patients
may achieve seizure
except for a single-center study comparing IVIg to placebo in anti-LGI1 antibody freedom depending on the
encephalitis.118 Also, no prospective head-to-head studies have been done to specific etiology, and it may
allow for comparison of efficacy. Treatment is generally conceptualized as initial lead to improvements in
induction therapy with first-line treatments that include IV corticosteroids, IVIg, cognitive and functional
outcomes.
or plasma exchange, used individually or in combination. Second-line agents,
usually rituximab or cyclophosphamide, are typically initiated if the response to
first-line therapy is inadequate; however, these may also be used if a protracted
course is expected, such as in anti–NMDA receptor antibody encephalitis.
Induction therapy is followed by a maintenance phase, where administration of
first-line therapy or therapies continues weekly to every other week with
gradually increasing intervals between treatments. Initiation of maintenance
immunosuppressive medication may be used if a patient has a significant
response to induction therapy, establishing immunotherapy responsiveness. One
reason for the use of maintenance immunosuppressive therapies is to facilitate
eventual cessation of first-line treatment. Another rationale is to prevent relapse
of encephalitis, which can occur in up to 35% of cases.27
Acute Treatment Strategy

Once an autoimmune diagnosis is considered likely, treatment should ideally be
commenced in consultation with an autoimmune neurology specialist. The most
common approach to first-line therapy for patients in the inpatient setting
involves the use of a combination of agents, typically methylprednisolone and
IVIg.110 In anti-LGI1 encephalitis, high-dose steroids alone are often effective,
and oral (as opposed to IV) administration is often successful. A favorable seizure
response in anti-LGI1 encephalitis may be noted within a few days. IVIg was
shown to be more effective than placebo in anti-LGI1 antibody encephalitis in
one single-center study,118 so it can be tried in patients with a contraindication to
steroid therapy and when the response to corticosteroids is inadequate. If a
patient has no response to corticosteroids or IVIg, plasma exchange is commonly
recommended as an option. Corticosteroids and IVIg are often continued after
the resolution of the induction period if the response was favorable, and they are

continued over the ensuing 6 to 12 months depending on the clinical course on a

gradual tapering schedule.
Second-line immunosuppressant therapy may be administered empirically
during the induction phase in acute inpatient situations.38,119 This is the typical
approach in hospitalized patients with severe anti–NDMA receptor, anti–GABAA
receptor, anti–GABAB receptor, and anti–AMPA receptor encephalitis in
which it is a priority to suppress the inflammatory response and eliminate
circulating neural autoantibodies as quickly as possible. The second-line
immunosuppressant most commonly used is rituximab. When it is decided
that rituximab is necessary, it is usually instituted early because the reduction
in antibody production achieved is usually delayed for 2 to 4 weeks from
administration.110 Rituximab needs to be readministered every 6 months if
TABLE 5-6 Response to Immunotherapy in Epilepsy Scorea
Score
New-onset, rapidly progressive mental status changes that developed over 1-6 weeks or new-onset seizure activity 1
(within 1 year of evaluation)
Neuropsychiatric changes: agitation, aggressiveness, emotional lability 1
Autonomic dysfunction (sustained atrial tachycardia or bradycardia, orthostatic hypotension [≥20 mm Hg fall in 1
systolic pressure or ≥10 mm Hg fall in diastolic pressure within 3 minutes of quiet standing], hyperhidrosis, persistently
labile blood pressure, ventricular tachycardia, cardiac asystole, or gastrointestinal dysmotility)
Viral prodrome (rhinorrhea, sore throat, low-grade fever), only to be scored in the absence of underlying malignancy 2
Faciobrachial dystonic seizures 3
Facial dyskinesias, to be scored in the absence of faciobrachial dystonic seizures 2
Seizure refractory to at least to two antiseizure medications 2
CSF findings consistent with inflammation (elevated CSF protein >50 mg/dL and/or lymphocytic pleocytosis 2
>5 cells/mm3, if the total number of CSF red blood cells is <1000 cells/mm3)
Brain MRI suggesting encephalitis (T2/FLAIR hyperintensity restricted to one or both mesial temporal lobes, or 2
multifocal in gray matter, white matter, or both compatible with demyelination or inflammation)
Systemic cancer diagnosed within 5 years of neurologic symptom onset (excluding cutaneous squamous cell 2
carcinoma, basal cell carcinoma, brain tumor, cancer with brain metastasis)
Initiation of immunotherapy within 6 months of symptom onset 2
Neural plasma membrane autoantibody detected (N-methyl-D-aspartate [NMDA] receptor antibody, γ-aminobutyric acid A 2
[GABAA] receptor antibody, γ-aminobutyric acid B [GABAB] receptor antibody, α-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid [AMPA] receptor antibody, dipeptidyl-peptidase–like protein 6 [DPPX], metabotropic glutamate
receptor 5 [mGlur1], mGluR2, mGluR5, leucine-rich glioma inactivated protein 1 [LGI1] antibody, IgLON5, contactin-
associated proteinlike 2 [CASPR2] antibody or myelin oligodendrocyte glycoprotein [MOG])
Maximum score 22
Cutoff score predicting favorable seizure outcome ≥7b
CSF = cerebrospinal fluid; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
a
Modified with permission from Dubey D, et al, Epilepsia.85 © 2017 International League Against Epilepsy.
b
Sensitivity = 87.5% and specificity = 83.8%.
388 APRIL 2022

effective because the CD20-expressing lymphocytes targeted by the medication
begin to recover after that timeframe. Cyclophosphamide can be used as an
alternative to rituximab; however, it has risks of infertility, hemorrhagic cystitis,
and malignancy, so it is typically reserved for cases refractory to rituximab.
Maintenance
Corticosteroids are typically continued after the induction phase if a response has
occurred. This may continue to be administered as a 1-g IV methylprednisolone
infusion every 7 to 14 days with gradually increasing intervals as allowed by the
clinical course. Daily oral prednisone may also be used if IV preparations are not
easily accessible. Treatment is typically continued for 6 to 12 months, and oral
dosages are reduced gradually every few weeks. If IVIg was used in induction and
was deemed effective, it can be continued with gradually increasing interdose
intervals while response is monitored, most commonly monthly over the
following 6 to 12 months.
If rituximab was used at induction, and a response was determined to have
been achieved, it usually needs to be readministered every 6 months to prevent
relapse, given that B cells will regenerate eventually and antibody production will
resume. During this time, CD20 levels can be monitored to assess for B-cell
recovery. If cyclophosphamide was used during the initial treatment phase, it is
typically continued as part of the maintenance therapy for 6 months.
Mycophenolate mofetil and azathioprine are sometimes used, if a response to
induction therapy was achieved, to maintain remission and facilitate eventual
discontinuation of first-line therapies. They are also used to prevent relapses,
which can occur in 35% of patients with autoimmune encephalitis. They have also
been used to augment induction therapy in some cases. The use of these
medications has not been established for any of these indications in prospective
trials to date. The duration of treatment is also unclear. It is best to seek advice
through an autoimmune neurologist to determine if these agents are warranted
and clarify duration of treatment.
Monitoring
It is essential to monitor for response and relapse after initial treatment. Seizure
frequency should be recorded and evaluation of treatment response made
6 weeks after commencing induction therapy. A complete response is clearly
desired when immunotherapy is used; however, a 50% reduction in seizure
frequency after initiation of treatment is typically considered a sign of
immunotherapy responsivity. If no improvement in seizure control is seen but a
high degree of suspicion for an autoimmune etiology remains, administration of
another agent or second-line therapy should be considered. Clinicians should also
be mindful that recovery may be slow, such as in anti–NDMA receptor
encephalitis, which may take months.
Precautions and Additional Considerations

Clinicians should have a good understanding of the clinical relevance of
autoantibody test results. For example, voltage-gated potassium channel
antibodies without LGI1 or CASPR2 immunoreactivity and low-titer anti-GAD65
antibodies generally do not justify the use of immunotherapy. Also, the
likelihood of a favorable response to immunotherapy is low with certain
antibodies, such as onconeural antibodies and even high-titer anti-GAD65

TABLE 5-7 Immunotherapy for Symptomatic Seizures Secondary to Autoimmune

Encephalitisa
Drug Dose Duration Precaution Potential side effects

First-line therapies
IV methylprednisolone 1000 mg daily 3-5 days, then Monitor for Infection, avascular
weekly for hyperglycemia if the necrosis hip, peptic ulcer,
5 weeks, then patient has diabetes or insomnia, psychosis,
every 7-14 days is at risk; consider depression, hypertension,
for 6 weeks baseline bone density edema
(12 weeks total) scan at inception
Oral prednisone (if IV 1250 mg daily 3-5 days, then

preparation is not 60 mg daily for
available) 3 months
IVIg 0.4 g/kg/d 3-5 days, then Measure IgA because Headache, aseptic
weekly for deficiency has a risk of meningitis, renal failure,
5 weeks, then anaphylaxis (or use myocardial infarct
every 7-14 days non-IgA formulation); (avoid in at-risk
for 6 weeks consider non–sucrose- patients), venous
(12 weeks total) containing formulations thromboembolism
in renal impairment
Plasma exchange 1 body volume 5 to 7 May need to Anemia, muscle

exchange with treatments discontinue or cramps, electrolyte
albumin every other substitute angiotensin- abnormalities,
replacement day converting enzyme complications of
inhibitors, consult central line insertion
internist for options; (thrombosis, infection)
monitor blood counts
and electrolytes
Second-line therapies 1000 mg IV for 2 Repeat every Exclude tuberculosis, Infusion reactions,
doses 2 weeks apart 6 months or at hepatitis B and hepatitis hypogammaglobulinemia
Rituximab
recovery of C infection before resulting in chronic
OR CD20 count initiation; monthly sinopulmonary infections
blood counts; (can be treated with IVIg),
375 mg/m2 weekly pregnancy test before other infections including
for 4 weeks commencement rare risk of progressive
multifocal
leukoencephalopathy
390 APRIL 2022


Cyclophosphamide Oral: 1-2 mg/kg/d 6 months Suggest consultation Teratogenicity, infection,
with an oncologist, malignancy (lymphoma,
OR rheumatologist to assist skin cancers, and others),
with dosing; encourage hemorrhagic cystitis,
IV: 500 mg/m2 to liberal hydration and infertility, alopecia, and
1000 mg/m2 consider mesna use for nausea/vomiting
monthly IV to prevent
hemorrhagic cystitis;
baseline urinalysis,
complete blood cell
count, creatinine and
liver function
performed weekly for
1 month and every
2 weeks for 2 months
and monthly thereafter
for IV; adjust dose
based on results;
pregnancy test before
commencement
Maintenance therapies
IV methylprednisolone 1000 mg weekly After Monitor for metabolic Infection, osteoporosis,

induction, complications peptic ulcer, cushingoid
gradually appearance, skin thinning,
increase easy bruising, insomnia,
intervals over depression, cataracts,
ensuing hypertension, weight gain,
6-12 months edema; caution when
discontinuing to avoid
Oral prednisone 1 mg/kg/d (adult, After 3 months, addisonian crisis
60 mg daily gradually
maximum) reduce the
dose over
ensuing
6-12 months
IVIg 0.4 g/kg once After Measure IgA because Headache, aseptic
weekly induction, deficiency has a risk of meningitis, renal failure,
gradually anaphylaxis (or use myocardial infarct (avoid
increase non-IgA formulation); in at-risk patients), venous
intervals over consider non–sucrose- thromboembolism
ensuing containing formulations
6-12 months in renal impairment

Oral mycophenolate After establishment 3-5 years Blood cell counts, renal Teratogenicity, infection,
mofetil of response to and liver function tests malignancy (lymphoma,
induction therapy: at baseline, weekly for skin cancers, and others),
500 mg 2 times a day 1 month, every other diarrhea, hypertension,
by mouth for 2 weeks week for 2 months hepatitis,
then 1000 mg 2 times then monthly; myelosuppression,
a day mycophenolate mofetil renal failure, bleeding of
serum levels; pregnancy gastric ulcer
test, ensure
contraception; avoid
antacids containing
magnesium or
aluminum; pregnancy
test before
commencement
Oral azathioprine 2-3 mg/kg/d once 3-5 years Measure thiopurine Infection, malignancy
daily or in divided S-methyltransferase (lymphoma, skin cancers,
doses enzyme activity before and others), nausea,
initiation; blood cell macrocytic anemia,
counts, renal function skin rash, hypersensitivity
and liver function at reaction, pancreatitis and
baseline then weekly for elevated liver function
1 month, every other tests
week for 2 months, and
monthly thereafter;
consider monitoring
mean corpuscular
volume (MCV) as
increases of >5 points
may correlate with
improved efficacy;
pregnancy test before
commencement
IgA = immunoglobulin A; IV = intravenous; IVIg = intravenous immunoglobulin.

a
Modified with permission from Britton JW, et al, John Wiley & Sons.117 © 2021 John Wiley & Sons.
antibodies. In such settings, patient and family expectations may need to be

tempered. In addition, the absence of a neural antibody does not necessarily
exclude the diagnosis of autoimmune encephalitis, and up to 50% of such
patients may be seizure free after immunotherapy.120 Seronegative disease
should, therefore, be considered in the context of an appropriate clinical
syndrome, especially in the presence of status epilepticus or cryptogenic seizures
where paraclinical markers support the presence of CNS inflammation.
Careful consideration of the differential diagnosis is also prudent to ensure
other causes of encephalitis are excluded. This is especially the case for infectious
etiologies because immunosuppression is contraindicated in this context.
Similarly, metabolic and structural causes of seizures also warrant exclusion.
Paraneoplastic causes should be considered and a search for underlying
malignancies pursued, particularly with certain autoantibodies. Importantly,
392 APRIL 2022

treatment of the underlying neoplasm in these cases can result in clinical
improvement, especially in the case of anti–NMDA receptor encephalitis where
resection of an ovarian teratoma can result in improvement.
Before immunosuppression, clinicians should ensure chronic and latent
infections have also been excluded or treated adequately. Screening should be
performed to exclude occult disease including Mycobacterium tuberculosis, viral
hepatitis, and human immunodeficiency virus (HIV) infection. Vaccinations should
also be up to date. Prophylaxis for Pneumocystis jirovecii with sulfamethoxazole/
trimethoprim or dapsone is recommended. Similarly, it is prudent to be mindful
of corticosteroid-related complications, and prophylaxis for osteoporosis with
vitamin D and calcium and for gastritis and ulcers with proton pump inhibitors
or histamine receptor 2 (H2) antagonists is advisable. This is especially important
in cases where these are preexisting conditions, and care should also be taken
with other medical comorbidities, particularly diabetes mellitus.
CONCLUSION
Seizures due to an autoimmune etiology are increasingly encountered in clinical
practice and can take the form of autoimmune-associated epilepsy or acute
symptomatic seizures due to autoimmune encephalitis. Seizures of an immune
etiology are often resistant to antiseizure medications but are usually responsive
to immunotherapy. It is critical that clinicians recognize immune etiologies early
in their course because treatment delays can result in poorer outcomes, and
currently, it is not uncommon for autoimmune-associated seizure disorders to
remain undiagnosed, resulting in missed opportunities to administer effective
therapies. Although autoimmune seizures are caused by a heterogeneous group
of autoantibodies, key features should raise suspicion for the possible diagnosis.
Diagnostic accuracy requires an understanding and integration of the
spectrum of clinical and paraclinical presentations. Clinicians should also become
familiar with the specificity of the various CNS autoantibodies to determine
whether their presence can be considered indicative of an immune etiology and if
antibody positivity might justify the use of immunotherapy. Several scoring
systems have been developed that may be useful in identifying autoimmune
seizures and can be applied in clinical practice to improve the certainty of
diagnostic and therapeutic decision making. Current recommendations
regarding patient selection for autoimmune antibody evaluation and the
approach to immunotherapy are largely based on data derived from autoimmune
encephalitis, and efforts to better understand autoimmune seizure
manifestations and treatment strategies are ongoing.
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Autoimmune-Associated Seizures

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Autoimmune-Associated Seizures

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Autoimmune-Associated REVIEW ARTICLE

presentations of autoimmune-associated epilepsy and acute symptomatic

RECENT FINDINGS: Although autoimmune seizures are caused by a

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In current practice, it is unfortunately not uncommon for autoimmune-

PATHOPHYSIOLOGY AND DIAGNOSIS

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ACUTE SYMPTOMATIC SEIZURES SECONDARY TO AUTOIMMUNE

Seizure and Clinical Characteristics

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hippocampal sclerosis and seizures secondary to autoimmune encephalitis, those

Anti–Leucine-Rich Glioma Inactivated Protein 1 Antibody Encephalitis

Antibodies with definite association with autoimmune encephalitis

366 APRIL 2022

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Experiential and perceptive

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more common in men than women (66%). Hyponatremia is relatively

Anti–N-methyl-D-aspartate Receptor Encephalitis

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Seizure Manifestations in Other Antibody-Mediated Encephalitides

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COMMENT This patient had acute symptomatic seizures secondary to anti-LGI1

anti–α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor,

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Main presenting FDG-PET Cancer

N-methyl-D- Psychiatric Focal aware Normal or transient Increased Ovarian teratoma,

Leucine-rich Seizures, memory Faciobrachial Hyperintense T2 Basal ganglia Rare: thymoma,

γ-Aminobutyric Seizures Focal or focal to Normal or Increased Small cell lung

CONTINUED ON PAGE 375

374 APRIL 2022

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α-Amino-3- Psychiatric, Focal seizures, Bilateral mesial Increased Thymoma, small

Metabotropic Psychiatric Focal, secondary Normal or Normal or Hodgkin

CONTINUED ON PAGE 376

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CONTINUED FROM PAGE 375

Main presenting FDG-PET Cancer

Ma/Ta Encephalitis Focal impaired Brainstem FLAIR Normal or Testicular, non–

teratoma. One-third of cases are associated with the presence of additional

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Seronegative Autoimmune Limbic Encephalitis ● Examples of autoimmune-

SEIZURE AND CLINICAL CHARACTERISTICS IN AUTOIMMUNE-

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up to 37% of cases of autoimmune encephalitis, and additional immunotherapy

Anti–Glutamic Acid Decarboxylase 65 Antibody–Associated Epilepsy

378 APRIL 2022

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A 35-year-old right-handed woman presented for epilepsy management CASE 5-2

This patient has epilepsy as defined as an enduring predisposition to COMMENT

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No EEG findings are specific to anti-GAD65 antibody–associated epilepsy. The

380 APRIL 2022

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Patient Selection for Immune Etiology Evaluation

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