Neuro-inflammation

Review

Autoimmune encephalitis: proposed best practice

recommendations for diagnosis and acute
management
Hesham Abboud ,1,2 John C Probasco,3 Sarosh Irani ,4 Beau Ances,5
David R Benavides, Michael Bradshaw, Paulo Pereira Christo,9 Russell C Dale,10
6 7,8

Mireya Fernandez-Fournier,11 Eoin P Flanagan ,12 Avi Gadoth,13 Pravin George,14

Elena Grebenciucova,15 Adham Jammoul,14 Soon-Tae Lee,16 Yuebing Li,14
Marcelo Matiello,17,18 Anne Marie Morse,19 Alexander Rae-Grant,14 Galeno Rojas,20,21
Ian Rossman,22 Sarah Schmitt,23 Arun Venkatesan,3 Steven Vernino,24
Sean J Pittock ,12 Maarten J Titulaer ,25 Autoimmune Encephalitis Alliance
Clinicians Network

► Additional material is
published online only. To view, ABSTRACT antibodies against intracellular onconeuronal anti-
please visit the journal online The objective of this paper is to evaluate available gens such asANNA-1/anti-Hu.5 6 These ‘classical’
(http://dx.doi.org/10.1136/ evidence for each step in autoimmune encephalitis antibodies are non-pathogenic but represent markers
jnnp-2020-325300).
management and provide expert opinion when of T-cell-mediated immunity against the neoplasm
For numbered affiliations see evidence is lacking. The paper approaches autoimmune with secondary response against the nervous
end of article. encephalitis as a broad category rather than focusing on system. In recent years, an increasing number of
individual antibody syndromes. Core authors from the antibodies targeting neuronal surface or synaptic
Correspondence to Autoimmune Encephalitis Alliance Clinicians Network antigens have been recognised such as N-MethylD-
Dr Hesham Abboud, Neurology,
reviewed literature and developed the first draft. Where Aspartate Receptor (NMDAR)-antibody and
Case Western Reserve
University, Cleveland, Ohio, evidence was lacking or controversial, an electronic Leucine-richglioma inactivated (LGI1)-antibody.1
USA; hesham.abboud@ survey was distributed to all members to solicit individual Most of these surface antibodies have been shown
uhhospitals.org responses. Sixty-eight members from 17 countries to be likely pathogenic and are thought to mediate
answered the survey. Corticosteroids alone or combined more immunotherapy-responsive forms of AE and
SJP and MJT are joint senior
authors. with other agents (intravenous IG or plasmapheresis) have less association with tumours. Specific types
were selected as a first-line therapy by 84% of of encephalitis can occur in the setting of
Received 2 October 2020 responders for patients with a general presentation, antibodies against oligodendrocytes (eg, anti-
Revised 22 December 2020 74% for patients presenting with faciobrachial dystonic myelin oligoden- drocyte glycoprotein (MOG)
Accepted 10 January 2021
Published Online First 1 March seizures, 63% for NMDAR-IgG encephalitis and 48.5% brainstem enceph- alitis) or astrocytes (eg, anti-
2021 for classical paraneoplastic encephalitis. Half the aquaporin-4 (AQP4) diencephalic encephalitis,
responders indicated they would add a second-line anti-glial fibrillary acidic protein (GFAP)
agent only if there was no response to more than one meningoencephalitis). In addition, some AE
first-line agent, 32% indicated adding a second-line patients do not have any identifiable anti- bodies
agent if there was no response to one first-line agent, (seronegative) representing a disease cate- gory
while only 15% indicated using a second-line agent in with novel, yet to be identified antibodies or T-
all patients. As for the preferred second-line agent, 80% cell mediated disease. Online supplemental
of responders chose rituximab while only 10% chose appendix S1 contains a list of the commercially
cyclophosphamide in a clinical scenario with unknown available neuronal autoantibodies (NAAs).
antibodies. Detailed survey results are presented in Recent epidemiological studies suggest that AE is
► http://dx.doi.org/10.1136/ the manuscript and a summary of the diagnostic and possibly as common as infectious encephalitis with
jnnp-2021-326096
therapeutic recommendations is presented at the an estimated prevalence rate of 13.7/100 000. 7 The
conclusion. rapidly advancing knowledge of new antibodies
and their associated syndromes has created a new
© Author(s) (or their and growing field of autoimmune neurology.8
employer(s)) 2021. Re-use However, advances from the laboratory bench have
permitted under CC BY-NC. No
commercial re-use. See rights INTRODUCTION not been paralleled by advancement in clinical
and permissions. Published Autoimmune encephalitis (AE) comprises a group prac- tice, leading to a large knowledge gap and
by BMJ. of non-infectious immune-mediated inflammatory many unanswered questions regarding the acute
and long-term management of AE. The
To cite: Abboud H, Probasco disorders of the brain parenchyma often involving
JC, Irani S, et al. J Neurol the cortical or deep grey matter with or without heterogeneity of AE presentation and findings on
Neurosurg Psychiatry involvement of the white matter, meninges or ancillary testing hinder large-scale clinical trials
2021;92:757–768. the spinal cord.1–4 The original description of AE and limit the quality of evidence behind AE
was based on paraneoplastic conditions related to management.
The objective of this paper is to evaluate avail-
able evidence for each step in AE management and
 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325300 on 1 March 2021. Downloaded from http://jnnp.bmj.com/ on February 9, 2023 by guest. Protected by copyright.
757
Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300
 Neuro-inflammation

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325300 on 1 March 2021. Downloaded from http://jnnp.bmj.com/ on February 9, 2023 by guest. Protected by copyright.
provide expert opinion when evidence is lacking. Although the
of 7.3 AE subtypes (range 1–13 subtypes, median 8 subtypes).
turnaround time of commercial NAAs panels may improve in
In total, 9% of the participating members were affiliated with
the near future, currently these results are often unavailable at
refer- ence neuroimmunology laboratories with NAAs testing
the time of early evaluation and management. Moreover,
capabil- ities. The results of individual survey questions are
current commercial NAAs panels are inherently limited in
presented under the corresponding sections of AE management.
their ability to diagnose AE, given the ever-growing numbers of
The final draft was approved by all participating AEACN
antibodies identified and the likelihood of T-cell mediated
members after four rounds of revisions. The paper aimed to
pathogenesis in some cases. Consequently, clinicians have to
answer prespeci- fied clinical questions as detailed below.
approach AE initially as a clinical entity when deciding on
investigations and treatment.1 Long-term management can then
be modified according to the type of antibody identified, if any. DATA AVAILABILITY STATEMENT
Therefore, the aim of this paper is to emphasise the practical The results of the survey are partially summarised in figure 1
acute and long- term management of AE as a broad category and the detailed responses of all survey questions are published
rather than focusing on individual antibody syndromes. as online supplemental document 2.
Another important goal is to represent the practice of
experienced clinicians from different clinical and geographical
SECTION 1: DIAGNOSIS OF AE
backgrounds.
When to suspect AE clinically?
A detailed history and examination is the first and most
METHODS important step in AE diagnosis. The immune reaction in AE
Core authors from the Autoimmune Encephalitis Alliance often results in acute or subacute presentation of a duration
Clinicians Network (AEACN) developed the first draft of this less than 3 months.1 Chronic presentations are only seen
paper (HA, JCP, SI, RCD, EPF, PG, AJ, YL, AR-G, IR, SJP and in some of these conditions, especially LGI1, Contactin-
MJT). The AEACN is comprised of self-identified clinicians with associatedprotein-like 2 (CASPR2), Dipeptidyl-peptidase-
interest and clinical expertise in AE management listed by the likeprotein 6 (DPPX) and Glutamicacid decarboxylase 65
AE Alliance, a non-profit organisation founded by AE patients (GAD65)-antibody encephalitis, and should otherwise raise
and families to establish a supportive community for patients suspicion of a neurodegenerative disease or other etiolo-
and caregivers, enhance clinical collaboration, and facilitate AE gies.9 Likewise, hyperacute presentations are also atypical
scientific research. The AEACN includes a multidisciplinary and a vascular aetiology should be considered in those cases.
international group of adult and paediatric neurologists, rheu- A recurrent course may point towards an autoimmune aeti-
matologists, psychiatrists, neuropsychologists and other special- ology but unlike the typical relapsing-remitting course of
ists with real-life experience in AE management. The authors of multiple sclerosis and systemic inflammatory disorders, AE
the first draft reviewed available literature to compile existing relapses are rare and often result from insufficient treatment
evidence for every step in AE management. Where evidence was or rapid interruption of immunotherapy. A monophasic
lacking or controversial, an electronic survey was distributed to course is more common in idiopathic AE while a progres-
all AEACN members to solicit individual responses. The survey sive course may be seen in some paraneoplastic syndromes
questions were strategically planned to look at initial treatment, especially paraneoplastic cerebellar degeneration, which
continued care and finally long-term management. After adding tends to plateau after the cancer is treated. Patients with
survey results to the manuscript, the updated version was circu- known cancer or those at increased cancer risk (smokers,
lated to all participating AEACN members for edits and further the elderly, and patients with rapid unintentional weight
suggestions. loss) are prone to paraneoplastic AE, while patients with
personal or family history of other autoimmune disorders
are at increased risk of idiopathic AE.10 A preceding viral
SURVEY RESULTS
infection, fever or viral-like prodrome is common.11 AE may
The survey was distributed to 147 Clinical members. Sixty-eight
be triggered by herpes simplex virus (HSV) encephalitis or
(46%) members responded including the core authors. The
certain immune-modulating therapies such as TNF inhib-
most represented specialty/subspecialty of the respondents was
itors, and immune-checkpoint inhibitors (ICIs)—the latter
neuroimmunology (66%), followed by general neurology
can cause an accelerated form of paraneoplastic encephalitis
(21%), paediatric neurology (16%), epilepsy (9%),
in patients with advanced cancer.1 12 Table 1 shows practical
behavioural/cogni-
classification concepts in AE.
tive neurology (6%), hospital neurology-neurohospitalist (6%),
The immune reaction in AE is usually diffuse, resulting in
neuromuscular neurology (6%), paediatric rheumatology (6%),
multifocal brain inflammation and occasionally additional
neurocritical care (4%), psychiatry (4%), movement disorders
involvement of the meninges, spinal cord and/or the periph-
(3%), general paediatrics (3%) and one specialist (1.5%) each
eral nervous system.3 6 This diffuse inflammation may or may
of the following: autonomic disorders, adult rheumatology and
not be detectable on ancillary testing but it usually results in a
paediatric critical care. Twenty-five members (37%) indicated
polysyndromic presentation which is a clinical hallmark of AE.
more than one subspecialty.
Although some antibodies have been linked to stereotypical
Clinicians from 17 countries participated including USA
symptoms (eg, oromandibular dyskinesia, cognitive/behavioural
(69%), Brazil (4%), Canada (3%), China (3%), Spain (3%),
changes, and speech and autonomic dysfunction in NMDAR-
Argentina, Australia, Indonesia, Israel, Italy, the Netherlands,
antibody encephalitis, faciobrachial dystonic seizures in LGI1-
the Philippines, Singapore, South Korea, Switzerland, Turkey
antibody encephalitis, etc), there is significant symptom overlap
and the UK (countries listed in a descending order based on the
between all antibodies and all forms of AE.1 11 Symptoms vary
number of responders and alphabetically when the number of
according to the anatomical localisation of inflammation and
responders was equal). Of the total participating members,
there are several clinical-anatomical syndrome categories in AE
88% practiced at academic tertiary referral centres and 76%
as summarised in table 2.
were active in AE clinical research or scholarly publications.
The participating members indicated personal clinical
experience with an average
758 Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300
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Figure 1 AEACN survey results for acute and bridging therapy. AE, autoimmune encephalitis; AEACN, Autoimmune Encephalitis Alliance Clinicians
Network; IVMP, intravenous methylprednisolone; IVIg, intravenous Ig; PLEX, plasma exchange.

What investigations should be ordered when AE is suspected? one or more of the AE anatomical syndromes (table 1 and
After AE is suspected clinically, a detailed workup is needed to
figure 3). According to the 2016 AE clinical criteria by Graus
confirm the diagnosis and exclude competing possibilities like
et al, the presence of bilateral limbic encephalitis is the only
infective encephalitis or systemic/metabolic causes. In most
MRI finding sufficient to diagnose definite AE in the correct
cases, the workup starts with brain imaging and cerebrospinal
clinical setting (eg, negative CSF viral studies) even in
fluid (CSF) analysis. The diagnostic algorithm follows the struc-
absence of NAAs.1 All other MRI patterns (cortical/subcor-
ture summarised in figure 2 and detailed below:
tical, striatal, diencephalic, brainstem, encephalomyelitis
and meningoencephalitis) can support possible or probable
Aim 1: confirming the presence of focal or multifocal brain AE unless the NAAs panel is positive for a clinically relevant
abnormality suggestive of encephalitis antibody.1 2 Diffuse or patchy contrast enhancement sugges-
Brain MRI tive of inflammation is seen in a few patients while intense
In addition to ruling out alternative diagnoses, standard enhancing lesions are unlikely in AE.3 9 Rare findings include
Brain MRI with contrast can show changes consistent with focal or extensive demyelination, meningeal enhancement,

Table 1 Proposed classification concepts in autoimmune encephalitis

Anatomical classification Serological classification Aetiological classification
1. Limbic 1. Antibodies to intracellular antigens (classical onconeuronal antibodies).* 1. Idiopathic
2. Cortical/subcortical 2. Antibodies to surface antigens and other antigens with high clinical 2. Paraneoplastic
3. Striatal relevance (eg, NMDAR, AMPAR, LGI1, CASPR2, GABAR A/B, DPPX, glycine 3. Postinfectious
4. Diencephalic receptor, AQP4, MOG, GFAP†). 4. Iatrogenic (eg, in the setting of immune check point
5. Brainstem 3. Antibodies to surface antigens with low clinical relevance (eg, VGKC, inhibitors or other immune-modulating agents).
6. Cerebellar VGCC).‡
7. Encephalomyelitis 4. Seronegative autoimmune encephalitis.
8. Meningoencephalitis
9. Combined
*GAD65 antibody is directed against an intracellular antigen but in high titers, it mediates an autoimmune encephalitis phenotype similar to surface antibodies with high clinical
relevance, and in low titers is usually clinically irrelevant to neurological symptoms.
†GFAP is a cytoplasmic antigen associated with intermediate filaments. Considered clinically relevant in patients presenting with typical radiological findings (perivascular radial
enhancement).
‡Clinical relevance of these antibodies varies according to presentation. Although they may not be clinically relevant in certain patients with typical autoimmune encephalitis,
some of these antibodies have higher clinical relevance to other neurological presentations (eg, VGCC is likely relevant in patients with Lambert-Eaton myasthenic syndrome and
acquired autoimmune ataxia).
AMPAR, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ; AQP4, aquaporin-4; CASPR2, Contactin-associated protein-like 2 ; DPPX, Dipeptidyl-peptidase-like
protein 6 ; GABAR, Gamma-Amino butyric acid Receptor ; GFAP, glial fibrillary acidic protein; LGI1, Leucine-rich glioma inactivated ; MOG, Myelin oligodendrocyte glycoprotein ;
VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel .

Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300 759

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Table 2 Anatomical-clinical syndromes of autoimmune encephalitis
Anatomical classification of autoimmune encephalitis Corresponding clinical syndromes Possible associated antibodies
Limbic encephalitis ► Cognitive presentation Hu, CRMP5/CV2, Ma2, NMDAR, AMPAR, LGI1, CASPR2,
► Psychiatric presentation GAD65, GABABR, DPPX, mGluR5, AK5, Neurexin-3
► Epileptic presentation antibodies
Cortical/subcortical encephalitis ► Cognitive presentation PCA-2 (MAP1b), NMDAR, GABA A/B R, DPPX, MOG
► Seizure presentation antibodies
Striatal encephalitis ► Movement disorder presentation CRMP5/CV2, DR2, NMDAR, LGI1, PD10A antibodies
Diencephalic encephalitis ► Autonomic presentation Ma 1–2, IgLON5, DPPX, AQP4 antibodies
► Sleep disorder presentation
Brainstem encephalitis ► Cognitive presentation Ri, Ma 1–2, KLHL11, IgLON5, DPPX, AQP4, MOG, GQ1b
► Movement disorder presentation antibodies
► Cranio-bulbar presentation
Cerebellitis or cerebellar degeneration ► Ataxic presentation Hu, Ri, Yo, Tr, CASPR2, KLHL11, NIF, mGluR1, GAD65,
VGCC antibodies
Meningoencephalitis ► Cognitive presentation GFAP antibody or seronegative AE
► Seizure presentation
► Meningeal presentation
Encephalomyelitis ► Movement disorder presentation including PERM GAD65, amphyphysin, glycine receptor, PCA-2 (MAP1B),
and SPS GABA A/B R, DPPX, CRMP5/CV2, AQP4, MOG antibodies
► Spinal presentation
► Opticospinal presentation
Possible associated peripheral syndromes
Neuropathy/neuronopathy ► Ataxic presentation Hu, PCA-2 (MAP1B), CRMP5, Amphiphysin, CASPR2,
► Sensoriomotor presentation CASPR1, CONTACTIN1, NIF155 antibodies
Autonomic neuropathy/ganglionopathy ► Autonomic presentation Hu, CRMP5, anti-ganglionic AChR antibodies
Neuromuscular junction dysfunction ► Myasthenic presentation VGCC, AchR antibodies
Myopathy ► Motor presentation Striational antibodies
AchR, Acetyl Choline Receptor; AE, autoimmune encephalitis; AK5, Adenylate kinase 5 Ab ; AMPAR, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ; AQP4,
aquaporin-4; CASPR, Contactin-associated protein-like ; CRMP5, Collapsin response mediator protein 5 ; DPPX, Dipeptidyl-peptidase-like protein 6 ; GABAR, Gamma-Amino
butyric acid Receptor ; GAD65, Glutamic acid decarboxylase 65 ; GFAP, glial fibrillary acidic protein; GQ1b, ganglioside Q1B antibody; IgLON5, immunoglobulin-like cell adhesion
molecule 5; KLHL11, kelch-like protein 11 ; LGI1, Leucine-rich glioma inactivated ; mGluR1, Metabotropic glutamate receptor 1 ; mGluR5, Metabotropic glutamate receptor ;
MOG, myelin oligodendrocyte glycoprotein; NIF, Neuronal intermediate filament ; NMDAR, N-Methyl D-Aspartate Receptor ; PCA2, Purkinje Cell Cytoplasmic Ab Type 2 ; PERM,
progressive encephalomyelitis with rigidity and myoclonus; SPS, stiff person syndrome ; VGCC, voltage gated calcium channel.

Figure 2 Diagnostic algorithm for autoimmune encephalitis. *EEG can confirm focal or multifocal brain abnormality and rule out subclinical seizures.
**In addition to neuronal autoantibodies, cerebrospinal fluid should be tested for infections, inflammatory markers (IgG index and oligoclonal bands), and
in some cases cytology. ***In addition to neuronal autoantibodies, the differential diagnosis generated based on MRI results will guide what blood tests
to send. ****In most cases, general neoplasm screening starts with CT then other screening modalities are added until a neoplasm is found or eventually
ruled out. If the clinical picture is highly suggestive of a specific neoplasm, a targeted screening approach could be implemented (eg, starting with pelvic
ultrasound if the clinical picture is suggestive of anti-NMDAR encephalitis). AE, autoimmune encephalitis; EEG, electroencephalogram; MRI WWO, MRI with
or without contrast; PET, positron emission tomography.
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gradient echo sequence is more common in herpetic
encephalitis than AE although this difference did not reach
statistical signif- icance in one underpowered study comparing
the two types of encephalitis.14
In some related immune-mediated conditions, the diagnosis
can be inferred from typical MRI patterns such as radial peri-
vascular enhancement in autoimmune GFAP astrocytopathy and
punctate brainstem/cerebellar enhancement in chronic lympho-
cytic inflammation with pontine perivascular enhancement
responsive to steroids (CLIPPERS).15 16

Electroencephalogram
Electroencephalogram (EEG) is commonly performed in
patients with suspected AE to exclude subclinical status
epilepticus in encephalopathic patients or to monitor treatment
response in patients with seizures. AE is a major cause of new
onset refrac- tory status epilepticus (NORSE), which can be
convulsive or non-convulsive.17 EEG can also provide evidence
of focal or multifocal brain abnormality when MRI is negative
which would support encephalitis over metabolic
Figure 3 Anatomical subtypes of autoimmune encephalitis. (A) Limbic encephalopathy.1 Findings suggestive of AE include focal
encephalitis, (B) cortical/subcortical encephalitis, (C) striatal encephalitis, slowing/seizures, later- alised periodic discharges and/or
(D) diencephalic encephalitis, (E) brainstem encephalitis (arrow), (F) extreme delta brush, which is occasionally seen in NMDAR-
meningoencephalitis (arrow). antibody encephalitis.18 Frequent subclinical seizures are
commonly identified in LGI1-antibody encephalitis but patients
may also have a normal EEG including those with classical
and rarely cortical diffusion restriction (often related to faciobrachial dystonic seizures (FBDS). 19 20 Although a normal
secondary seizures). Brain MRI may also be normal. Patients EEG does not exclude AE, it can support primary psychiatric
with initially negative MRI may show changes suggestive of disorders when investigating patients with isolated new
AE on repeat MRI a few days later. Gadolinium should be psychiatric symptoms. EEG can also help differen- tiate AE from
avoided during pregnancy. Table 3 shows the main differen- CJD.
tial diagnoses for each of the AE anatomical syndromes.
Importantly, brain MRI can also help exclude alternative
diagnoses such as acute stroke, neoplasm or Creutzfeldt-Jacob Brain fluorodeoxyglucose positron emission tomography
disease (CJD), although AE MRI changes can sometimes mimic In the event of a negative brain MRI and clinical uncertainty
some of these entities. Unilateral, and to a lesser extent despite high suspicion of AE, obtaining a brain fluorodeoxyglu-
bilateral, inflammation of the mesial and non-mesial temporal cose positron emission tomography (FDG-PET) can confirm
lobe as well as the orbitofrontal cortex on FLAIR or DWI focal or multifocal brain abnormality in the correct clinical
sequences supports herpetic encephalitis over AE.13 setting.21 It can also substitute for MRI when MRI is contrain-
Parenchymal haemorrhage on dicated. In case series, brain FDG-PET was more sensitive than

Table 3 Differential diagnosis of autoimmune encephalitis anatomical syndromes and suggested additional testing
Anatomical Classification of autoimmune
encephalitis Differential diagnosis Possible Additional testing as appropriate
Limbic encephalitis HSV, VZV, HHV6 CSF viral PCR, CSF VZV IgG/IgM
Cortical/subcortical encephalitis ADEM, AHL, tumefactive MS, Marburg, PML, CJD, lupus MOG-IgG, CSF JCV PCR, CSF prion panel (RTQuIC), ANA/
cerebritis, Behcet, neurosarcoidosis, neurosyphilis, lymphoma, ENA, HLA-B51, ACE, CT chest (to rule out sarcoidosis),
anoxic injury, seizure-related changes treponemal antibodies, CSF cytology and flow cytometry
Striatal encephalitis CJD, WNV, toxic encephalopathy, anoxic injury, hyperglycaemic Prion panel, WNV IgM, CSF viral PCR, toxicology screen,
injury, uraemia metabolic panel
Diencephalic encephalitis Neurosarcoidosis, Behcet, Wernicke, Whipple ACE, CT chest (to rule out sarcoidosis), HLA-B51, thiamine
level
Brainstem encephalitis Rhombencephalitis (listeria), viral, CLIPPERS, neurosarcoidosis, CSF bacterial culture, CSF viral PCR, HLA-B51, CSF cytology
Behcet, lymphoma, PML, CPM, Erdheim-Chester, Whipple and flow cytometry, CSF JCV PCR, bone scan
Cerebellitis or cerebellar degeneration Viral or post-viral cerebellitis, coeliac disease, Miller Fisher Viral PCR, coeliac antibodies, anti-GQ1b, vitamin E level,
syndrome, vitamin E deficiency, MSA-C, SCA DaT scan
Meningoencephalitis Tuberculosis, neurosarcoidosis, Behcet, bacterial or viral infection, Bacterial PCR, ACE, CT chest, HLA-B51, CSF bacterial
leptomeningeal carcinomatosis, GPA, IgG4-related disease culture, CSF viral PCR, CSF cytology and flow cytometry
Encephalomyelitis and/or opticospinal syndrome ADEM, WNV MOG-IgG, WNV IgM, CSF viral PCR
ADEM, acute disseminated encephalomyelitis; AHL, acute haemorrhagic leukoencephalitis; ANA, antinuclear antibody; AQP4, aquaporin-4; CJD, Creutzfeldt-Jacob disease;
CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CPM, central pontine myelinolysis; CSF, cerebrospinal fluid; DaT scan,
dopamine transporter scan; ENA, extractable nuclear antigens; GFAP, glial fibrillar acidic protein; GPA, gliomatosis with polyangitis; GQ1b, anti-ganglioside Q1B antibody; HHV6,
human herpes virus-6; HSV, herpes simplex virus; JCV, John Cunningham virus; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; MSA-C, cerebellar multiple
system atrophy; NMOSD, neuromyelitis optica spectrum disorder; PML, progressive multifocal leukoencephalopathy; SCA, spinocerebellar ataxia; VEP, visual evoked potentials;
VZV, varicella zoster virus; WNV, West Nile virus.

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 Neuro-inflammation
MRI and may reveal brain abnormalities at an earlier stage of
significant syndromic overlap between most of these antibodies
the disease.22 Bilateral temporal hypermetabolism (in seroposi-
and because more than one antibody can coexist in the same
tive or seronegative limbic encephalitis) and bilateral occipito-
patient.24 Notably, routine CSF studies may be normal in some
parietal hypometabolism (in NMDAR-antibody encephalitis) are
AE patients and this does not exclude the diagnosis when other
among the most common patterns seen and may prove useful
parameters are consistent with AE; therefore, testing NAAs
biomarkers for specific syndromes. Importantly, further studies
panels is recommended in case of high clinical suspicion even if
are needed to better differentiate AE metabolic patterns from
the CSF is normal.25
neurodegenerative and neuroinfectious syndromes. In addition,
immunosuppressants, anaesthetics and antiseizure therapies,
commonly administered to AE patients, can also alter cortical Blood tests
metabolism. Seizures can also cause hypermetabolic changes on In addition to testing NAAs in the serum, several blood tests are
FDG-PET. The lack of specificity and the limited availability of often needed to exclude other competing etiologies. Test selec-
FDG-PET are barriers against the wide utilisation of this tech- tion can be guided by the MRI anatomical pattern as shown in
nique in AE diagnosis. table 3 but some tests may be useful in case of negative MRI
such as antithyroid antibodies, toxicology screen, ammonia,
vitamin B1/B12 levels, HIV, inflammatory markers, antinuclear
Aim 2: confirming an autoimmune inflammatory etiology and antibodies, extractable nuclear antigen antibodies, antiphospho-
excluding other possibilities lipid and lupus anticoagulant antibodies, immunoglobulins and
Following assessment for focal or multifocal brain abnormality metabolic and hormonal panels when appropriate. 1 Monitoring
by MRI or other studies, additional investigations are indicated sodium level is important since hyponatraemia is common with
to confirm AE and exclude other possibilities. Testing can be certain AE subtypes such as LGI-1 antibody encephalitis.19 Blood
guided by the clinical-anatomical syndrome to narrow down the samples should be collected prior to treatment with intravenous
scope of investigations as shown in table 3. immunoglobulins or plasmapheresis to avoid false positive or
false negative results.
CSF analysis
This is the most important test in AE evaluation and is usually Brain biopsy
the second step in the workup after brain MRI. Regardless of Most AE cases with normal brain MRI or typical MRI patterns
MRI findings, all patients with suspected encephalitis require a (limbic, striatal, etc) do not require a brain biopsy. Rarely, a
lumbar puncture (LP) unless there is a significant contraindica- brain biopsy may be needed for atypical or mass-like lesions to
tion (eg, risk of herniation on brain imaging). In some cases, exclude neoplastic or other possibilities especially when all
inflammatory CSF may be the only abnormality found on initial other investi- gations point away from autoimmunity.1
testing serving as the sole indication for empiric Pathological findings in AE are nonspecific and include T-cell
immunotherapy after infection is excluded. If timely brain and/or B-cell perivascular and parenchymal infiltrates along
MRI is not possible due to patient agitation or lack of access, with secondary gliosis.26
clinicians should proceed with LP after a screening head CT so
as not to delay immunotherapy. CSF analysis should include cell
Aim 3: screening for an associated neoplasm
count and differential, protein, glucose, CSF/serum glucose
It is nearly impossible to predict whether AE is paraneoplastic
ratio, albumin quotient, IgG index and synthesis rate, oligoclonal
or non-paraneoplastic based on symptoms as both AE subtypes
bands, broad viral studies including HSV1/2 PCR and varicella
present similarly. Therefore, cancer screening should be consid-
zoster virus (VZV) PCR and IgG/IgM, bacterial/fungal cultures
ered in most adult AE patients at time of presentation. 24 If the
when appro- priate, cytology, flow cytometry, NAAs panel (eg,
patient has a known history of cancer typically associated with
Autoimmune encephalopathy/encephalitis panel, etc), and in some
paraneoplastic syndromes then a paraneoplastic aetiology is
cases, prion disorder panel (preferably RTQuIC when available).
presumed, and repeat cancer screen is indicated to identify recur-
Common CSF findings in AE include mild to moderate
rence or progression. In patients with cancer history not typi-
lymphocytic pleo- cytosis (commonly 20–200 cells but can be as
cally associated with paraneoplastic neurologic syndromes (eg,
high as 900 cells with some antibodies), hyperproteinorrachia,
basal cell skin cancer, prostate cancer), repeat cancer screen
and in some cases, elevated IgG index and/or IgG synthesis rate
may unmask a new different tumour. The most common
and positive intra- thecal oligoclonal bands (unmatched in the
neoplasms associated with AE include small cell lung cancer,
serum).1 23 These findings in the setting of negative infectious
thymic neoplasm, breast cancer, ovarian teratoma or carcinoma,
and cytological studies support an immune-mediated aetiology
testic- ular teratoma or seminoma, neuroblastoma and
but would not differentiate AE from other immune-mediated
lymphoma.24 In some patients, the suspicion of associated
conditions (eg, neurosarcoidosis) so clinical correlation is
neoplasm may be high based on certain demographic factors
always needed. In many patients, testing NAAs in both CSF and
(eg, smoking history or advanced age) or typical clinical picture
serum is needed because CSF detection is more sensitive for
(NMDAR-antibody encephalitis associated with ovarian
some antibodies (eg, NMDAR and GFAP antibodies) while
teratoma). Although some antibodies have stronger cancer
serum is more sensitive for other antibodies (eg,
association than others (eg, anti- bodies against intracellular
onconeuronal, LGI1, and AQP4 anti- bodies).1 If the clinical
antigens), the implicated antibody is usually unknown at the
picture is highly suggestive of an antibody with a higher serum
time of first presentation. The following screening modalities
sensitivity (eg, FBDS suggestive of LGI1- antibody encephalitis),
are available:
then it might be reasonable to avoid CSF testing in clinical
situations where CSF sampling is challenging. Although
symptomatology can guide which neuronal antibodies (or CT chest, abdomen and pelvis
antibody panels) to test for in some patients, it may be most Initial screening with CT of the chest, abdomen and pelvis with
practical to send the most comprehensive panel especially in contrast is a reasonable approach given its lower cost compared
patients with less defined presentations. This is because there is a with FDG-PET and since it provides more structural details of
the neoplasm (if present) to guide biopsy and further surgical
inter- vention if indicated. A major limitation of CT-based
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Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300
screening
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is its low sensitivity for early breast and testicular cancers. 24 In subject to high doses of sedation, antiseizure medications, and
addition, CT is not preferred in children and pregnant women; other symptomatic therapies so monitoring for drug toxicity in
and pelvic CT is not preferred for women in childbearing age in the ICU is imperative.
general. Moreover, CT contrast dye may be contraindicated due
to renal impairment or dye allergy. In these situations,
additional or alternative means (eg, MRI) of cancer screening Empiric antimicrobial treatment
are required. It is to be noted, however, that CT iodine-based In many encephalitis patients, differentiating infectious from
dye is relatively safer in pregnant women compared with MRI autoimmune aetiologies may be difficult prior to CSF analysis
gadolinium-based dye. and therefore starting empiric antimicrobials with CNS
coverage is always recommended until infection is excluded.
The common practice is to start CNS doses of intravenous
Mammogram and breast MRI
acyclovir and stan- dard coverage for bacterial meningitis.
Breast cancer is a common source of paraneoplastic syndromes
Antibiotics and acyclovir can later be discontinued if CSF
in females, and a mammogram should be performed if the initial
bacterial and HSV/VZV studies return negative.
CT screen is negative. 24 Patients with a strong family history of
breast cancer and those who are not up to date with their
regular mammograms are a special concern. If mammogram is Acute immunotherapy
negative but the suspicion of breast cancer is high, then breast Several retrospective studies have shown that early and aggres-
MRI may improve sensitivity of cancer detection. sive immunotherapy is associated with better outcomes in AE
patients.1 29 The 2016 AE clinical criteria emphasise the impor-
tance of starting immunotherapy once AE is highly suspected
Pelvic or testicular ultrasound or MRI
and infectious etiologies are excluded based on CSF results
Young and middle age adults with a typical clinical picture of
(cell-count, glucose, viral PCR, gram stain). It is impractical
NMDAR-antibody encephalitis should be specifically screened
and potentially hazardous to delay immunotherapy until AE
for teratoma by a transvaginal or transabdominal pelvic ultra-
is confirmed by a positive antibody. There are no robust clin-
sound (or testicular ultrasound in males). 24 In female patients
ical trials comparing the different modalities of acute immu-
with ataxic presentation (suggestive of PCA1/Yo antibody),
notherapy; therefore, the choice of the initial therapy may be
pelvic ultrasound can screen for ovarian carcinoma. Likewise, in
based on anecdotal evidence and factors related to the specific
males with ataxia and other brainstem symptoms (suggestive of
syndromic presentation and comorbidities as shown in figure 4
Ma and Kelch-like Protein-11 Antibodies), testicular ultrasound
and detailed below:
may reveal the associated neoplasm.27 Pelvic MRI may be useful
if ultrasound is equivocal. Extraovarian and extratesticular
germ cell tumours may be detected on CT-based or MRI-based High-dose corticosteroids
general cancer screening. Empiric treatment with intravenous methylprednisolone at a dose
of 1 g per day for 3–7 days is a common reasonable approach to
Whole body FDG-PET scan achieve initial immunosuppressive and anti-inflammatory effect
Whole body FDG-PET can be more sensitive for early neoplasms in AE patients.1 It is also the preferred approach in presenta-
when initial CT screen is negative or inconclusive and the tions known to be specifically corticosteroid-responsive namely
suspicion of cancer is high (eg, smoker elderly patient, classic demyelinating pattern on MRI (suggestive of AE overlap with
paraneoplastic presentation).24 It can also be used as the initial demyelinating syndromes),30 or dotted or radial enhancement
screening tool when there is a contraindication to high (suggestive of CLIPPERS or autoimmune GFAP astrocytop-
resolution CT or iodine contrast. Insurance coverage can be an athy, respectively).15 16 Patients with FBDS suggestive of LGI1-
obstacle and insurers should consider fewer restrictions on antibody encephalitis may also show a dramatic response to
FDG-PET in AE patients given the high likelihood of a coexisting corticosteroids.19 Patients with known or highly suspected para-
cancer in those patients. neoplastic AE associated with classical onconeuronal antibodies
are thought to have a primarily T-cell mediated inflammation
making corticosteroids, theoretically, a preferred option for
SECTION 2: ACUTE TREATMENT immunosuppression over intravenous IG or plasma exchange
Intensive care unit needs (PLEX). However, paraneoplastic conditions associated with
The main indications for intensive care unit (ICU) admission in classical onconeuronal antibodies are often resistant to immu-
AE include refractory status epilepticus, severe dysautonomia nosuppression and tend to respond best to cancer therapy. A
and respiratory compromise (eg, from brainstem involvement, notable exception are patients who develop accelerated parane-
associated neuromuscular syndrome or medication-induced oplastic AE in the setting of ICI treatment. These patients may
hypoventilation).28 It is important for ICU clinicians to distin- be particularly responsive to corticosteroids given their
guish central non-infectious fevers caused by the primary disease inhibitory effect on T-cell overactivity which is the
from infectious processes. Careful monitoring and manage- pathogenic hallmark of ICI-associated immune adverse events;
ment of blood pressure and heart rate fluctuations is critical in however, second-line therapies may also be needed in some
patients with severe dysautonomia. A temporary pacemaker cases.12
may be needed in patients with severe dysrhythmia until the On our AEACN survey, 84% of responders chose corticoste-
dysau- tonomia improves. Patients with severe hyponatraemia roids alone (65%) or in combination with other agents (19%)
may require controlled slow correction of sodium levels to for initial immunotherapy in patients with a general AE presen-
avoid central pontine myelinolysis. In most cases, tation. Likewise, 74% of responders chose corticosteroids
hyponatraemia is related to inappropriate antidiuretic hormone for initial immunotherapy for patients presenting with FBDS
secretion and fluid restriction is sufficient. In rare occasions suggestive of LGI1-antibody encephalitis, alone (58%) or in
with massive inflammation and brain oedema, intracranial combination with other agents (16%). For NMDAR-antibody
pressure moni- toring and management may be indicated. AE encephalitis, corticosteroids remained the most popular choice
patients are often on the survey. However, the percentage was lower selected only
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Figure 4 Therapeutic algorithm for autoimmune encephalitis. *Relative contraindications to steroids include uncontrolled hypertension, uncontrolled
diabetes, acute peptic ulcer and severe behavioural symptoms that worsen with corticosteroid therapy. **Steroid-responsive conditions include faciobrachial
dystonic seizures suggestive of LGI1-antibody encephalitis, autoimmune encephalitis in the setting of immune checkpoint inhibitors, central demyelination,
autoimmune GFAP astrocytopathy, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, and steroid-responsive
encephalopathy associated with autoimmune thyroiditis. ***High thromboembolic risk includes patients with known or suspected cancer, smoking
history, hypertension, diabetes, hyperlipidaemia and hypercoagulable states. Ab, antibody; AE, autoimmune encephalitis; Ag, antigen; IVMP,
intravenous methylprednisolone; IVIg, intravenous Ig; IL-6: interleukin 6; NORSE, new-onset refractory status epilepticus; PLEX, plasma exchange.

764 Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300

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by 63% of responders either alone (35%) or combined with
Box 1 Best practice recommendations summary for acute other agents (28%) indicating a larger diversity among special-
management of autoimmune encephalitis (AE) ists when selecting first-line therapy in those patients. Similar
diversity was present for treatment of known or highly
1. Evaluate the likelihood of AE relative to the patient’s clinical suspected paraneoplastic AE; whereas corticosteroids remained
picture. the most popular choice, it was chosen by only 48.5% of
2. Perform brain MRI and/or EEG to look for focal or multifocal responders, alone (29%) or combined with other agents (19%)
brain abnormality. (see online supplemental document S2).
3. Perform lumbar puncture to support inflammatory aetiology One theoretical disadvantage to corticosteroids in AE is their
and rule out infective/neoplastic causes. Test oligoclonal potential for causing initial worsening of behavioural/psychiatric
bands, IgG index, IgG synthesis rate and neuronal symptoms hampering a timely evaluation of treatment response
autoantibodies in the cerebrospinal fluid (CSF). although in most cases, corticosteroids may actually improve
4. Send blood tests to rule out other potential causes these symptoms. The use of corticosteroids may also be diffi-
guided by neuroanatomical and clinical data. Test neuronal cult in patients with common comorbidities such as
autoantibodies in the serum. uncontrolled hypertension or diabetes. Some experts
5. Consider brain FDG-PET when there is a high recommend avoiding corticosteroids in patients with known
clinical suspicion of AE and other paraclinical studies GAD65-antibody associ- ated neurological syndromes for fear of
are uninformative. inducing type-1 diabetes but this concern remains theoretical
6. Perform cancer screening with CT chest, abdomen, and without confirmatory studies. In patients with atypical or mass-
pelvis with contrast in relevant cases (or MRI when CT like lesions on brain MRI in whom primary CNS lymphoma is on
is contraindicated or not preferred). If negative, consider the differential diagnosis, corticosteroids should be delayed so
further testing with mammogram/breast MRI, pelvic as not to interfere with pathology results if a biopsy is
ultrasound, and/or whole body FDG-PET guided by the considered during hospital- isation. Similar precautions are
clinical presentation and each patient’s specific cancer risk advisable when systemic autoim- munity such as sarcoidosis is
factors. on the differential.
7. Once infection is ruled out based on basic CSF results (eg,
number of cells) and if biopsy for primary CNS lymphoma
Intravenous Ig
or neurosarcoidosis is not a consideration, start acute
Intravenous Ig (IVIg) at a dose of 2 g/kg over 2–5 days is a rela-
immunotherapy with high dose corticosteroids (or IVIG or
tively easy-to-use and timely option for fast immunomodulation
PLEX if steroids are not preferred or contraindicated).
when corticosteroids are contraindicated or when the clinical
8. If there is no clinical, radiological or electrophysiological
picture is suggestive of or known to be related to antibody-
improvement by the end of the initial treatment cycle, add
mediated disease (eg, probable or definite NMDAR-antibody
IVIG or PLEX. Consider IVIG first in agitated patients and
encephalitis).29 IVIg can be more readily available than PLEX
in those with bleeding disorders. Consider PLEX first in in some centres and it does not require a central line. A recent
patients with severe hyponatraemia, high thromboembolic randomised blinded study showed IVIg efficacy over placebo in
(or cancer) risk, and if there is associated brain or spinal controlling seizures in a small number of patients with LGI1-
demyelination. antibody and CASPR2-antibody AE.31 On our AEACN survey,
9. Consider starting with a combination therapy of steroids/ IVIg was the most popular acute immunotherapy if corticoste-
IVIG or steroids/PLEX from the beginning (as opposed to roids are contraindicated chosen by 41% of responders. Also
sequentially) in patients with severe initial presentation (eg, 40% of responders indicated choosing IVIg alone or in combi-
severe NMDAR-antibody presentation, new onset refractory nation with corticosteroids and other immunotherapies for
status epilepticus, severe dysautonomia, etc). acute therapy if the clinical picture was suggestive of NMDAR-
10. If there is no clinical or radiological improvement 2–4 antibody encephalitis.
weeks after completion of combined acute therapy, consider A downside to IVIg is its association with increased throm-
starting a second-line agent when the clinical suspicion is boembolic risk. Therefore, IVIg should be used with caution in
high and/or a clinically relevant antibody is present. patients with known or suspected paraneoplastic AE or other
11. Consider rituximab in known or highly suspected risk factors for thrombosis (eg, heavy smokers and the elderly).
antibody-mediated autoimmunity (eg, NMDAR-antibody In addition, the aetiology of paraneoplastic AE associated with
encephalitis) and consider cyclophosphamide in known antibodies against intracellular antigens is thought to be cell-
or mediated rather than antibody-mediated rendering the use of
highly suspected cell-mediated autoimmunity (eg, classical IVIg in this setting potentially ineffective. On our survey only
paraneoplastic syndrome). 25% of responders indicated using IVIg in known or suspected
12. If no clear objective or subjective evidence of improvement paraneoplastic AE. The use of IVIg may also worsen coexisting
with conventional second-line therapies, consider novel hyponatraemia due to volume expansion, which may potentially
approaches such as tocilizumab or bortezomib although predispose to brain oedema and worsening mental status.32
there is only minimal evidence to support their use.
13. Start bridging therapy with gradual oral prednisone taper
or monthly intravenous Ig or intravenous Plasma exchange
PLEX (5–10 sessions every other day) is an effective option for
methylprednisolone. Avoid steroid taper or implement a
acute immunomodulation when corticosteroids are contraindi-
shorter taper in vague cases with poor response to initial
cated or ineffective. In a small retrospective study, patients with
immunosuppressive therapy or when immunosuppression
NMDAR-antibody encephalitis treated with both corticosteroids
may impose higher risks than benefits (eg, patients with
and PLEX had better improvement in the modified Rankin
cancer or active infection).
score than those treated with corticosteroids alone,33 which
is similar to the results in other antibody-mediated conditions
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like NMOSD.34 PLEX may be particularly effective in AE cases refractory AE. A clinical trial of ocrelizumab (a humanised anti-
with associated central demyelination or coexisting NMOSD. It CD20 monoclonal antibody with a similar mechanism of action
provides a potentially faster immunomodulation in patients to rituximab) is currently recruiting, and a clinical trial of borte-
with severe or fulminant presentations. It has no known zomib is underway (www.clinicaltrials.gov, accessed 13 April
psychiatric side effects and does not increase the risk of 2020).
thromboembolism except for line-related thrombosis. Major When a second-line agent is used in the acute setting, it also
limitations include increased bleeding risk, volume shifts serves as a bridging therapy to prevent early relapses that
(which can be problematic in dysautonomic patients), and the might happen if immunosuppression is abruptly discontinued. 38
need for central line place- ment (in some institutions) with its Prog- nostication and clinical severity tools are being developed
associated risks. In addition, it is less suitable for agitated to help select patients who would benefit from conventional and
patients. non-conventional second-line agents such as the anti-NMDAR
Encephalitis 1-year Functional Status score and the Clinical
Combined first-line therapies Assessment Scale in Autoimmune Encephalitis.39 40
If the initial clinical picture is severe (eg, NMDAR-antibody On the AEACN survey, 50% of responders indicated they
encephalitis, NORSE, severe dysautonomia), clinicians may would consider adding a second-line agent in the acute setting
consider using combined first-line therapies from the beginning only if there was no response to more than one first-line agent,
despite the lack of high quality evidence to support this 32% indicated adding a second-line agent if there was no
practice. On our AEACN survey, combination therapy was the response to one first-line agent, while only 15% indicated using
second most popular choice after corticosteroids alone if the a second-line agent in the acute setting on all patients
clinical picture was suggestive of NMDAR-antibody encephalitis regardless of the response to first-line therapy. As for the
chosen by 28% of responders, and for unspecified AE (19%). preferred second- line agent, 80% of responders chose
More commonly, combination therapy is done sequentially if rituximab while only 10% chose cyclophosphamide in a clinical
there is no meaningful response to the initial agent (eg, adding scenario with unknown antibodies and no clinical clues for
IVIg and/ or PLEX after completing corticosteroids). On the aetiology.
survey, 62% of responders chose adding a different first-line
therapy if the initial agent was ineffective while 26% chose
going directly to a second-line agent. Other options like CONCLUSION
adding a second round or prolonging the duration of the same In this first part of the best practice recommendations, we
first-line agent were less popular. covered the clinical presentation, diagnostic workup and acute
management of AE guided by published studies and the results
of the AEACN survey providing updated recommendations for
Second line agents
management of patients with suspected AE. The second part
If there is no meaningful clinical or radiological response to
will follow with a focus on bridging therapy, symptomatic
optimised first-line therapy after 2–4 weeks, the addition of a
treatment and maintenance immunotherapy. A discussion of the
second-line agent with both rapid and sustained immunosuppres-
sive effects can improve the outcome. 29 However, the exact defi- limitations will be presented at the end of the second part. A
nition and timing of treatment responsiveness is not well summary of the best practice recommendations for AE
defined and some clinicians may anecdotally choose earlier diagnosis and acute management is presented in box 1.
initiation of second-line agents. Both rituximab and
Author affiliations
cyclophosphamide have been used as second-line agents for 1
Neurology, Case Western Reserve University, Cleveland, Ohio, USA
rescue therapy in AE with good results.29 Rituximab is less toxic 2
Multiple Sclerosis and Neuroimmunology Program, University Hospitals of
than cyclophosphamide and therefore is preferentially Cleveland, Cleveland, Ohio, USA
considered by most clinicians although it may not be as effective 3
Neurology, Johns Hopkins Medicine, Baltimore, Maryland, USA
for cell-mediated inflamma- tion as in the case of antibodies
4
Oxford Autoimmune Neurology Group, John Radcliffe Hospital, Oxford, UK
against intracellular antigens. However, although rituximab acts
5
Neurology, Washington University in St Louis, St Louis, Missouri, USA
6
Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
mainly on B-cells, it indirectly suppresses T-cell activity by 7
Neurology, Rosalind Franklin University of Medicine and Science, North Chicago,
reducing B-cell drive to T-cells. In most newly diagnosed cases, Illinois, USA
it is hard to determine clinically whether AE is antibody or cell- 8
Billings Clinic, Billings, Montana, USA
mediated before the antibody results are available. Some clues
9
Neurology, Minas Gerais Federal University Risoleta Tolentino Neves Hospital, Belo
may help the clinician come to a preliminary hypothesis Horizonte, MG, Brazil
10
Neuroimmunology Group, The University of Sydney Faculty of Medicine and Health,
regarding aetiology (eg, FBDS or typical NMDAR-antibody Sydney, New South Wales, Australia
encephalitis presentation suggest antibody- mediated AE while 11
Neurology, La Paz University Hospital General Hospital Department of Neurology,
patients with known or increased cancer risk are more likely to Madrid, Madrid, Spain
have cell-mediated AE). Based on these clues, clinicians may 12
Neurology, Mayo Clinic, Rochester, Minnesota, USA
decide to use rituximab or cyclophosphamide as a second-line
13
Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
14
Neurology, Cleveland Clinic, Cleveland, Ohio, USA
agent if antibody results are delayed or if there is no access to 15
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
antibody testing. Common rituximab dosing regimens include 16
Neurology, Seoul National University College of Medicine, Seoul, Republic of Korea
375 mg/m2 weekly for 4 weeks or two doses of 1000 mg 2 17
Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
weeks apart. Common dosing regimen of cyclophospha- mide 18
Neurology, Harvard Medical School, Boston, Massachusetts, USA
include 600–1000 mg/m2. A few case series have shown
19
Pediatric Neurology, Geisinger Commonwealth School of Medicine, Scranton,
response to proteasome inhibitors that block plasma-cell gener- Pennsylvania, USA
20
Neurology, Sanatorio de La Trinidad Mitre, Buenos Aires, Argentina
ation (bortezomib), interleukin (IL)-6 inhibition (tocilizumab),
22Neurology, Favaloro Foundation, Buenos Aires, Argentina
21

or low dose IL-2 in patients who35–37did not respond quickly to Neuro-developmental Science Center, Akron Children’s Hospital, Akron, Ohio, USA
conventional second-line agents. However, the evidence 23
Neurology, MUSC, Charleston, South Carolina, USA
behind these non-conventional rescue therapies remains limited 24
Neurology, UT Southwestern, Dallas, Texas, USA
and more research is needed to confirm their effectiveness in 25
Neurology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
766 Abboud H, et al. J Neurol Neurosurg Psychiatry 2021;92:757–768. doi:10.1136/jnnp-2020-325300
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Correction notice This article has been correcte since it appeared Online First.
Sean J Pittock http://orcid.org/0000-0002-6140-5584
In the Contributors and Collaborators sections, author Jonathan Santoro has been Maarten J Titulaer http://orcid.org/0000-0002-1033-3840
updated to Jonathan D Santoro.
Twitter Sarosh Irani @ANG_Oxford and Galeno Rojas @Dr_GalenoRojas
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