Pediatric Neurology 132 (2022) 56e66

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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Topical Review

Autoimmune Encephalitis in Children

Duriel Hardy, MD *
Department of Neurology, Dell Medical School, University of Texas at Austin, Austin, Texas

a r t i c l e i n f o a b s t r a c t

Article history: Autoimmune encephalitis is a group of central nervous system (CNS) inflammatory disorders that most
Received 4 February 2022 commonly affect young adults and children. These disorders are closely associated with antibodies
Accepted 9 May 2022 against neuronal cell-surface proteins, receptors, and ion channels; however, some forms of the disorder
Available online 13 May 2022
have no known antibody at this time. In children, neurological manifestations such as seizure, movement
disorders, and focal neurological deficits are more prominent at initial presentation than psychiatric or
Keywords:
behavioral symptoms. When psychiatric symptoms do occur, they often manifest as temper tantrums,
Autoimmune encephalitis
aggression, agitation, and rarely psychosis. Prompt diagnosis and early treatment can lead to improved
N-methyl-D-aspartate receptor encephalitis
Hashimoto encephalopathy
outcomes and decreased relapses. First-line therapies include intravenous steroids, intravenous immu-
Myelin oligodendrocyte glycoprotein- noglobulin, and plasmapheresis, whereas rituximab and cyclophosphamide are utilized for refractory or
associated cortical encephalitis relapsing disease. This review highlights the different forms of this disorder, discusses approach to
Antibody-negative autoimmune diagnosis and treatment, and reviews the outcome and prognosis of children diagnosed with different
encephalitis forms of autoimmune encephalitis.
© 2022 Elsevier Inc. All rights reserved.

Introduction electroencephalography (EEG) are utilized to support a diagnosis of

AE. Early initiation of immunotherapy, and in some cases ongoing
Autoimmune encephalitis (AE) in children is rare but important long-term immunotherapy, can result in promising outcomes. This
to recognize as prompt treatment can lead to better outcomes.1 In review discusses the common forms of pediatric AE (Table 1),
1968, the first case of suspected immune-mediated limbic en- approach to diagnosis, treatment strategies, and outcomes.
cephalitis was reported in an individual with associated small cell
lung carcinoma.2 Since then, numerous antibodies associated with Epidemiology
immune-mediated encephalitis have been characterized, including
the discovery of antibodies against the N-methyl-D-aspartate AE, or immune-mediated encephalitis, accounts for a significant
(NMDA) receptor (NMDA-R) in 2005, which is now the leading proportion of all cases of encephalitis. The California Encephalitis
known cause of AE in children.3,4 In children, neurological rather Project, a study evaluating the epidemiology and etiology of en-
than psychiatric symptoms are often the most prominent initial cephalitis in adults and children, reported that more than half of
disease manifestations. Disease severity can range from mild patients with encephalitis have a noninfectious etiology, and of
behavioral changes to profound encephalopathy, status epilepticus, these patients, the most common etiology was immune-medi-
and even coma. Diagnosis is made with the identification of anti- ated.4,7 In a large, multicenter UK study of patients of all ages with
bodies to neuronal cell-surface receptors, ion channels, or proteins; symptoms of encephalitis, 4% had NMDA receptor antibodies,
however, in some cases, no antibodies are identified, and the making it the second most common etiology of immune-mediated
diagnosis is made clinically with the exclusion of alternate di- encephalitis after acute disseminated encephalomyelitis (ADEM).8
agnoses. Neuroimaging, cerebrospinal fluid (CSF) analysis, and Moreover, NMDA-R encephalitis is now more commonly identi-
fied as an etiology of encephalitis in children than any single viral
cause.7 The precise incidence and prevalence of AE is unknown, but
Disclosures: None. recent literature suggests an incidence of 1.54 children/million with
Conflicts of interest: None. a female predominance.9 AE affects individuals of all ages, with
* Communications should be addressed to: Dr. Hardy; Department of Neurology;
Dell Medical School; University of Texas at Austin; 4900 Mueller Blvd; Austin, TX
some AE syndromes more commonly affecting young adults and
78723. children. Pediatric AE is less commonly associated with an under-
E-mail address: Duriel.Hardy@austin.utexas.edu. lying neoplasm.4,9

https://doi.org/10.1016/j.pediatrneurol.2022.05.004
0887-8994/© 2022 Elsevier Inc. All rights reserved.
D. Hardy Pediatric Neurology 132 (2022) 56e66

Autoimmune encephalitis syndromes between 0 and 2) compared with 29% of patients with poorer
outcomes (mRS between 3 and 5) who did not receive first-line
Antibodies to extracellular proteins and receptors immunotherapy.17 Up to 30% to 40% of patients initially treated
with first-line therapies will not exhibit adequate recovery (with
N-methyl-D-aspartate (NMDA) receptor treatment failure considered to be no clinical improvement or
The most common form of known antibody-mediated AE is change in mRS score after 10 days to 4 weeks of treatment)3,4,17 and
NMDA-R encephalitis. NMDA-Rs are glutamate-gated ion channels require second-line therapies such as rituximab, cyclophospha-
that play significant roles in synaptic transmission and plasticity, mide, or tocilizumab. Rituximab and cyclophosphamide are the
which clinically contribute to human memory and cognition.10 most commonly used second-line therapies. There is increasing
About 40% of NMDA-R encephalitis cases occur in patients evidence to suggest that rituximab is safe and effective for re-
younger than 18 years. The incidence of pediatric NMDA-R en- fractory disease and preventing relapse.22-25 For patients refractory
cephalitis ranges from 0.07 to 0.085 per 100,000 children.11 Women to rituximab, tocilizumab might be a safe and effective option.26,27
account for about 80% of pediatric NMDA-R encephalitis.12 Risk
factors for developing NMDA-R encephalitis have not been clearly
defined; however, numerous studies have implied an association of Leucine-rich, glioma-inactivated 1 (LGI-1) and contactin-associated
NMDA-R encephalitis with viral infections, including herpes sim- protein-like 2 encephalitis
plex virus, Japanese encephalitis virus, and even the 2019 novel Both leucine-rich, glioma-inactivated 1 (LGI-1) and contactin-
coronavirus.13-15 NMDA-R encephalitis evolves through stages over associated protein-like 2 are auxiliary proteins associated with
the course of days to weeks, often beginning with a viral prodrome. voltage-gated potassium channels (VGKCs). Disease-causing anti-
About 50% of children with NMDA-R encephalitis have a viral bodies are typically found against LGI-1 or contactin-associated
prodrome consisting of fever, malaise, headache, gastrointestinal protein-like 2 protein rather than the VGKC itself. These anti-
symptoms, or upper respiratory tract infection symptoms.12,16 bodies are uncommon in children, and thus data on these disorders
Following the prodrome, initial disease manifestations in chil- is limited. About 2.7% of children being evaluated for central ner-
dren, especially young children, often include prominent neuro- vous system (CNS) autoimmunity have these antibodies. The most
logical symptoms, such as seizure or movement disorders, rather frequently described clinical presentations include subacute
than predominately psychiatric symptoms as commonly seen in cognitive decline, seizures, movement disorders, and psychiatric
adults.3,4,16,17 In one cohort study of 20 pediatric patients with manifestations.28-30 In one of the largest case series of children with
NMDA-R encephalitis, 60% presented with seizure, movement LGI-1 antibodies, no children were found to have faciobrachial
disorder, or focal neurological deficits rather than psychiatric dystonic seizures, hyponatremia, or cancers as commonly seen in
manifestations. This study also found that patients younger than adults.30 CSF profiles are often normal. MRI is abnormal in up to 33%
12 years were more likely to present with neurological features of children with these antibodies with T2 hyperintensities in the
compared with children older than 12 years.16 Irrespective of initial temporal lobes being the most common finding.28,30 Treatment
presentation, 90% of children will progress to develop at least three consists of IVMP, IVIG, and/or PLEX with most children improving
symptoms, including psychiatric features, memory disturbance, with immunotherapy.30 Outcomes are generally favorable. Fre-
seizures, dyskinesias, change in level of consciousness, or auto- quency of associated tumor in VGKC encephalitis is unknown,
nomic dysfunction within the first month of disease onset.4,12 Tu- although no isolated cases of tumor in pediatric VGKC encephalitis
mor is uncommonly identified in children; however, ovarian have been reported in contrast to adults in whom tumor is iden-
teratomas occur in about 30% of women younger than 18 years.12 In tified in about 30%.28
men, testicular tumor is exceedingly rare. Only about 30% of chil-
dren will have abnormal brain magnetic resonance imaging (MRI)
compared with 55% of adults with NMDA-R encephalitis.4 Glycine receptor antibody encephalitis
Abnormal CSF in pediatric NMDA-R encephalitis is very common, Glycine receptor antibody encephalitis has been reported in a
with up to 94% of patients having lymphocytic pleocytosis (>5 CSF few pediatric cases. Glycine receptor encephalitis most commonly
white blood cells per mm3). CSF NMDA antibody titers have been manifests with a “stiff person syndrome (SPS)” phenotype or
shown to correlate with disease course and remain present in pa- “progressive encephalomyelitis with rigidity and myoclonus
tients with clinical relapse.18 EEG is abnormal in over 90% of chil- (PERM)” phenotype both characterized by muscle rigidity, debili-
dren with NMDA-R encephalitis.4,12 Recovery can be slow, but up to tating muscle spasms, and myoclonus. Initially, both SPS and PERM
80% will demonstrate near-full recovery up to two years after initial were thought to be associated solely with antibodies against the
presentation.17 In patients with near-full recovery, autonomic glutamate deoxycarboxylase (GAD) enzyme; however, in 2008, a
instability, dyskinesias, encephalopathy, and seizure are typically patient was described with PERM without GAD antibodies but
the first symptoms to improve with immunotherapy, whereas the instead with antibodies against the glycine receptor.31 Since then,
psychiatric and cognitive symptoms can persist.4 Some studies additional patients with SPS and PERM have been described with
report ongoing cognitive symptoms for as long as three years post glycine receptor antibodies. GAD antibodies can be identified
disease onset in children.19 Clinical relapse occurs in approximately concurrently with glycine receptor antibodies, however. In one
20% to 25% of children.4,12 Acute first-line treatment includes large study of 52 patients with glycine receptor antibodies (aged 1
intravenous methylprednisolone (IVMP), intravenous immuno- to 75 years), muscles spasms (69%), excessive startle (42%), and eye
globulin (IVIG), plasma exchange (PLEX), or a combination of these movement disorders (40%) were the most frequent clinical features.
therapies.3,4,20 Although antibody testing is utilized to confirm the Limbic encephalitis and epileptic encephalopathy were also
diagnosis, testing can take days to weeks to result, and therefore recognized manifestations.31-33 Most patients had normal MRIs.
empirical treatment is recommended for cases with high index of Seventeen of 29 patients in this cohort who had electromyography
suspicion. Early and aggressive treatment is associated with better performed were abnormal. Only about one-third of patients with
neurological outcomes as measured by improvement in modified CSF testing demonstrated a pleocytosis.32 Treatment with IVMP,
Rankin scale (mRS) scores and relapse rate.17,21 In one large, multi- IVIG, or PLEX, resulted in clinical improvement; however, relapses
institutional observational study, 96% of patients who responded to did occur.32 There are reports suggesting efficacy with rituximab for
first-line therapies had good outcome (defined as mRS score refractory cases.32,34 Neoplasms are rarely identified.32
57
 TABLE 1.

D. Hardy
Clinical Features of Autoimmune Encephalitis

Subtype Typical Presentation Common CSF Findings Common Common EEG Findings Tumor Association Long-Term Treatment Outcome
Neuroimaging Findings

NMDA Seizures, orofacial Majority with 30% with abnormal MRI >90% with abnormal 30% of females with Rituximab, monthly Good outcome
dyskinesias, behavioral lymphocytic EEG; Extreme delta ovarian teratoma IVIG,
change, psychiatric pleocytosis brush cyclophosphamide
features
LGI-1 and CaspR2 Cognitive decline, Often normal Majority normal; can Variable None currently Unknown Generally favorable
seizures, movement show T2 reported in children
disorders hyperintensities in the
temporal lobes
GlyR SPS, PERM, muscle ~1/3 with pleocytosis Majority normal Variable None currently Rituximab for relapsing Variable
rigidity, myoclonus, reported in children cases
seizure
GABA-A Seizure, status Variable Majority with Often abnormal Hodgkin lymphoma Unknown Good recovery
epilepticus, alteration multifocal cortical and reported in 1 patient5
in mental status subcortical
involvement
GABA-B Seizure, alteration in Often with lymphocytic Often with T2 Often abnormal None currently Unknown Good recovery
mental status, memory pleocytosis hyperintensities in the reported in children
loss, confusion temporal lobes
Ophelia syndrome Behavioral change, Can see pleocytosis and MRI may be normal or Nonspecific Hodgkin lymphoma Treatment of Hodgkin Full recovery with
(mGluR5) confusion, memory loss elevated protein with nonspecific abnormalities can be lymphoma; unknown appropriate treatment
findings; may also seen response to
show evidence of immunotherapy
diffuse cerebellar
hyperintensities or
involvement of
58

temporal lobes
MOG Seizure, focal Often with CSF Often with multifocal Often abnormal None currently Monthly IVIG or Good outcome
neurologic deficits, pleocytosis cortical and subcortical reported in children rituximab for relapsing
alteration in mental white matter changes patients
status
GFAP Encephalopathy, Majority with Characteristic linear, Nonspecific Uncommon in children Rituximab, Good outcome
seizures, psychiatric lymphocytic radial perivascular abnormalities can be but various tumors azathioprine, or
symptoms, tremor, pleocytosis pattern of seen have been identified mycophenolate mofetil
meningeal symptoms and oligoclonal bands enhancement in (yolk sac tumor, for relapsing cases
(including headache) cerebral white matter paraganglioma)
and perilateral
ventricular regions
Hashimoto Hallucinations, Elevated CSF protein Nonspecific white Nonspecific None currently Rituximab Good outcome
encephalopathy confusion, matter changes, but abnormalities reported in children
(TPO, thyroglobulin) encephalopathy, often normal
seizure, movement
disorder
Hu Refractory seizures, Often normal Majority with T2 Often abnormal 25% associated with Consider T-cell- Poor outcome with

Pediatric Neurology 132 (2022) 56e66

psychiatric symptoms, hyperintensities in the neuroblastoma targeted therapies; cognitive decline and
alteration in mental medial temporal lobes poor response to refractory seizures
status immunotherapy
Ma Seizures, behavioral Variable T2 hyperintensities in Often abnormal One report of an Consider T-cell- Poor outcome with
change, speech the temporal lobes, adolescent with targeted therapies; refractory seizures
disturbance, dystonia hypothalamus, and mediastinal seminoma6 poor response to
midbrain immunotherapy
GAD SPS, seizure, cognitive Variable Often with T2 Often abnormal None currently Consider rituximab Variable outcome
decline, memory loss, abnormalities in the reported in children
cerebellar ataxia, temporal lobe
psychosis
Variable outcome
 D. Hardy
Rasmussen Focal seizures, 50% with normal CSF EEG often with MRI with None currently Hemispherectomy,
encephalitis hemiparesis, cognitive profile unihemispheric unihemispheric focal reported in children AEDs
decline slowing with or cortical atrophy
without epileptiform
activity
Antibody-negative Seizure, movement Lymphocytic Can be similar to NMDA Can be similar to NMDA None currently Unknown Good outcome
encephalitis disorders, behavioral pleocytosis or normal or normal reported in children
change, psychosis

Abbreviations:
AEDs ¼ Antiepilepsy drugs
CaspR2 ¼ Contactin-associated protein like 2
CSF ¼ Cerebrospinal fluid
GABA-A ¼ Gamma-aminobutyric acid type A
GABA-B ¼ Gamma-aminobutyric acid type B
GAD ¼ Glutamate deoxycarboxylase
GFAP ¼ Glial fibrillary acidic protein astrocytopathy
GlyR ¼ Glycine receptor
Hu ¼ antineuronal nuclear antibody type 1
LGI-1 ¼ Leucine-rich glioma inactivated 1
mGluR5 ¼ Metabotropic glutamate receptor 5
MOG ¼ Myelin oligodendrocyte glycoprotein
MRI ¼ Magnetic resonance imaging
NMDA ¼ N-methyl-D-aspartate
PERM ¼ Progressive encephalomyelitis with rigidity and myoclonus
SPS ¼ Stiff person syndrome
TPO ¼ Thyroid peroxidase
59

Pediatric Neurology 132 (2022) 56e66

D. Hardy Pediatric Neurology 132 (2022) 56e66

Gamma-aminobutyric acid type A receptor encephalitis AE.45 In general, MOG disorders affect children more frequently
Gamma-aminobutyric acid type A receptor encephalitis has than adults, and MOG encephalitis is more common in younger
been rarely reported in children. The primary manifestations of children. The most common clinical manifestations of MOG en-
gamma-aminobutyric acid type A receptor encephalitis are seizure, cephalitis are altered mental status, seizure, abnormal behaviors
refractory status epilepticus, and altered mental status. Neuro- and abnormal movements. The cerebral cortex and deep gray
imaging often demonstrates multifocal cortical and subcortical structures including the basal ganglia and thalamus are most
involvement.35 EEG is often abnormal with diffuse abnormalities or commonly affected on brain MRI.42,46 CSF profile typically shows
seizure. Treatment with immunotherapy appears to be effective in pleocytosis with lymphocytic predominance. Unique CSF oligoclo-
most; however, treatment approaches are ill-defined.35 nal bands are rare.42 Roughly 20% of these patients had relapse with
the most common relapsing phenotype being optic neuritis.45
Gamma-aminobutyric acid type B (GABA-B) receptor encephalitis Overlap syndromes, with concurrent NMDA-R antibodies and
Gamma-aminobutyric acid type B (GABA-B) receptor encepha- MOG antibodies, have been reported. In one study, about 4% of
litis is also exceedingly rare in children and typically occurs in patients with NMDA-R antibodies had concurrent glial antibodies
adults with a median age of 62 years.36 The clinical presentations with half of these patients having MOG antibodies.47 In another
are commonly seizure, memory loss, confusion, and altered mental study, MOG antibodies were identified in nine of 23 (~40%) patients
status. Neuroimaging of the brain is often abnormal with the most with NMDA-R encephalitis with these patients all demonstrating
common finding being T2 hyperintense lesions within the temporal evidence of CNS demyelination.11 The majority of patients with
lobes. CSF can demonstrate lymphocytic pleocytosis. About 50% of MOG encephalitis are treated with steroids, IVIG, or PLEX.42,45
adult cases are associated with tumor, the most common being Generally, long-term immunotherapy is only initiated in children
small cell lung carcinoma.36,37 Patients treated with immuno- with relapsing MOG disease as most MOG-positive children will
therapy and/or tumor removal have good recovery.37,38 In one study have a monophasic disease course.44 For relapsing disease, monthly
of 20 children and adults with GABA-B antibodies, 15 of 19 patients IVIG and/or rituximab have been shown to be most effective at
with outcome data showed complete or partial neurological re- reducing relapse rate with monthly IVIG also showing improve-
covery after IVMP, IVIG, or PLEX and tumor removal when ment in expanded disability status score.42,45,48 Larger studies are
indicated.37 needed to confirm these findings. Up to 85% of children respond to
immunotherapy with favorable outcomes.44,45
Ophelia syndrome
Ophelia syndrome was first described by Ian Carr in his Autoimmune glial fibrillary acidic protein astrocytopathy
daughter at age 15 years when she developed symptoms of limbic Glial fibrillary acidic protein is an intermediate filament protein
encephalitis. A Hodgkin lymphoma was detected, and she was in astrocytes that is often used as a biomarker for astrocytes. An-
treated resulting in significant neurological improvement. Dr. Carr tibodies against this protein have been identified in both children
suspected a humoral-mediated process causing this disorder, and adults presenting with features of encephalitis, meningoen-
which he named “Ophelia syndrome.” Since this time, there have cephalomyelitis, meningitis, and myelitis.49,50 The median age of
been additional patients with similar presentations (symptoms of onset is around 44 years with men and women being affected
limbic encephalitis in the setting of Hodgkin lymphoma), and some equally.49 The most common presenting features include menin-
have been found to have antibodies against the metabotropic geal symptoms (headache, photophobia, neck stiffness), encepha-
glutamate receptor 5. In a case series written in 2011 by Lancaster lopathy, seizure, symptoms of myelopathy (paresthesias or
et al., two patients were described who presented with limbic weakness), symptoms of papillitis, cognitive impairment, and
encephalopathy and were found to have antibodies against the psychiatric disturbance.49-51 MRI of the brain is frequently
metabotropic glutamate receptor 5. Neuroimaging in both of these abnormal with the characteristic linear perivascular enhancement
patients was abnormal, one with mesial temporal lobe involvement extending radially from the ventricles. CSF is also commonly
and the second with bilateral posterior parietal-occipital cortex abnormal with profound lymphocytic pleocytosis, elevated protein,
involvement. CSF demonstrated pleocytosis in both patients. Both and often positive oligoclonal bands.49-51 Coexisting autoimmunity
patients had good outcomes with tumor treatment.39 The role of is common with concurrent NMDA-R antibodies being the most
immunotherapy in these patients is unknown. commonly identified.49,50 Children with autoimmune glial fibrillary
acidic protein astrocytopathy are generally steroid-responsive and
Myelin oligodendrocyte glycoprotein (MOG) ultimately have favorable outcomes.49,51
Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein
exclusively expressed in the CNS that is believed to play roles in Hashimoto encephalopathy
myelin protein integrity, oligodendrocyte maturation, and cell- The first case of Hashimoto encephalopathy (HE) was described
mediated and humoral immune responses.40 Antibodies to MOG by Lord Brain and colleagues in 1966. The patient described in this
have been identified in up to one-third of children with an acquired report presented with tremor, hallucinations, altered mental status,
demyelinating syndrome with the common presenting phenotypes and agitation in the setting of elevated thyroid antibodies.52 More
being ADEM, optic neuritis, and transverse myelitis.41,42 Children than 200 cases have now been reported in adults and children, and
with MOG antibodies commonly follow a monophasic disease HE has a prevalence of about 2.1 per 100,000. In children, the dis-
course with approximately 20% to 34% of children having relapsing order is even more rare, with only a little over 60 cases being re-
disease.43,44 Encephalitis, distinct from ADEM, is another pheno- ported.53,54 Similar to the first described case of HE, the most
type that has recently expanded the spectrum of MOG disorders. A common presenting symptoms in children include psychosis,
large prospective observational study performed between 2013 and confusion, abnormal movements, cognitive deterioration, and
2018 investigated and described MOG encephalitis other than seizure.54 Diagnostic criteria for HE in adults proposed by Graus
ADEM in children. This study identified MOG antibodies in 34% of et al. was based on clinical presentation; the presence of elevated
children with an encephalitis phenotype and demonstrated that anti-thyroid antibodies, namely, thyroid peroxidase antibodies and/
MOG antibodies were more commonly identified than all other or thyroglobulin antibodies; MRI findings; absence of well-
neuronal antibodies combined; this confirms the importance of characterized neuronal antibodies in the serum or CSF; and pres-
MOG antibody testing in all children presenting with features of ence of subclinical or mild overt thyroid disease.55 However, more
60
D. Hardy Pediatric Neurology 132 (2022) 56e66

recently, a study with 17 pediatric patients with HE revealed that midbrain.6,29,64,67 Like anti-Hu encephalitis, most patients have
adult diagnostic criteria lacked sensitivity when applied to chil- poor response to immunotherapy and poor outcomes.6,29,64,67
dren, given that the majority of children in this study did not have
thyroid disease.56 Moreover, in the largest meta-analysis of HE, only Anti-glutamate decarboxylase encephalitis
32% of patients had evidence of thyroid disease at the time of Glutamate decarboxylase (GAD) antibodies are most commonly
diagnosis.57 In children, thyroid peroxidase antibodies are elevated identified in patients with SPS, limbic encephalitis, autoimmune
in about 80% to 100% of patients and thyroglobulin antibodies are epilepsy, and cerebellar ataxia.68 In children, these antibodies are
elevated in 60% to 70%.54 However, elevated thyroid peroxidase uncommon, but when present these children manifest with
antibodies have been found in up to 10% to 13% of asymptomatic seizure, memory loss, confusion, and psychiatric symptoms.69-71
children.4,58 Brain MRI is often normal in patients with HE; how- GAD antibodies are also identified in non-neurological conditions
ever, nonspecific white matter changes or meningeal enhancement such as type I diabetes, as well as in up to 1% of healthy individuals
can be seen.4,53 CSF protein is often elevated in HE, but the CSF at low titers,55,72 and thus it is important to take caution when
profile can also be normal.53 Initially, HE was thought to be interpreting positive GAD antibodies. Most studies suggest that
particularly responsive to steroids, and thus it was referred to as high serum titers of GAD antibodies (often 100 to 1000 times higher
“steroid-responsive encephalopathy associated with autoimmune than found in patients with diabetes) and/or confirmation of
thyroiditis.” However, only 30% to 55% of patients have a complete intrathecal production of GAD antibodies in the appropriate clinical
response to steroids.4,58 In children, a review performed in 2008 setting (e.g., patients with SPS, cerebellar ataxia, or refractory epi-
showed that of 25 pediatric patients with HE, about 55% had lepsy) are required to support the association of these antibodies
complete response to steroids.59 Patients refractory to steroids or with neurological syndromes.55,68,72 Neuroimaging most
patients unable to receive steroids are often treated with IVIG or commonly shows abnormalities within the hippocampus, and EEG
PLEX with good effect.60-62 Rituximab therapy is also used in pa- is often abnormal.69-71 Treatment with IVMP, IVIG, and PLEX has
tients with relapsing HE.63 Most patients have favorable outcomes shown mixed results,68-71 but there is growing evidence that rit-
with a relapse rate ranging from 12.5% to 50%.53,58,63 uximab might be effective.69,70

Antibodies to intracellular proteins Other autoimmune encephalitides

Anti-Hu encephalitis Rasmussen encephalitis

Antineuronal nuclear antibody type 1 antibodies, also known as Rasmussen encephalitis was first described in the 1950s by Dr.
anti-Hu antibodies, have been associated with paraneoplastic Theodore Rasmussen and colleagues.73 This disorder is character-
limbic encephalitis (PLE) mostly affecting adults; however, there ized by progressive refractory focal seizures, focal neurological
have been few reports of children with these antibodies. PLE is disability (usually hemiparesis), and cognitive decline in the setting
characterized by alteration in mental status, seizure, and psychi- of gradual atrophy of one hemisphere of the brain.4,74 The disorder
atric symptoms. In the largest series of PLE, which included chil- predominantly affects children between the ages six and eight
dren and adults, 60% of patients had antineuronal antibodies, with years. The estimated incidence of Rasmussen encephalitis is 2.4 per
anti-Hu antibodies being most common.64 In this series, the ma- 10 million people aged 18 years or younger.74 The pathogenesis of
jority of patients had associated small cell lung carcinoma and poor Rasmussen encephalitis is unclear, although it is postulated to be
neurological outcomes.64 In children, the most common presenta- secondary to a T-cell-mediated process based on pathologic studies.
tion is also with progressive memory loss, confusion, and seizure. In 1994, Dr. Roger and colleagues identified antibodies to the
Unlike adults, children less likely have associated cancer. When a metabotropic glutamate receptor 3 suggesting an antibody-
tumor is identified in these children, it is most commonly neuro- mediated process; however, these findings have not been repro-
blastoma.65,66 In a large series of eight children with anti-Hu an- duced.75 MRI findings include unilateral ventricular enlargement
tibodies, only 25% had associated tumor (neuroblastoma), whereas and unilateral cortical and/or subcortical T2-hyperintense
the remaining 75% presented with limbic encephalitis without signal.74,76 CSF profiles are variable with about 50% of cases hav-
neoplasm. Two-thirds of the children who presented with limbic ing normal CSF profiles.76 In 2005, a European consensus panel
encephalitis in this series had abnormal brain MRIs that most proposed formal diagnostic criteria that requires all three of the
commonly revealed T2 hyperintensities in the medial temporal following: (1) clinical focal seizures, (2) EEG demonstrating uni-
lobes. CSF cell counts and protein were normal in all of the chil- hemispheric slowing with or without epileptiform activity, and (3)
dren.66 The majority of the children had refractory seizures, poor MRI with unihemispheric focal cortical atrophy or two of the
response to immunotherapy, and poor outcomes consistent with following: (1) epilepsia partialis continua or progressive unilateral
other reports of pediatric and adult anti-Hu encephalitis.29,64,66 cortical deficits, (2) MRI with unihemispheric focal cortical atrophy,
or (3) histopathology demonstrating T-cell-dominated encephali-
Anti-Ma2 encephalitis tis.74,76 Treatment for Rasmussen encephalitis includes steroids and
Anti-Ma2 encephalitis is a rare PLE that is associated with IVIG with benefit in some cases, but definitive treatment remains
testicular tumors in adult men. Anti-Ma2 encephalitis has also been surgical hemispherectomy.76 There have been cases of Rasmussen
associated with nonesmall cell lung carcinoma, breast cancer, and encephalitis treated with rituximab and tacrolimus with some ef-
lymphoma. Anti-Ma2 encephalitis is believed to be mediated by a fect, but this is limited to case report data.76,77
T-cell cytotoxic process rather than being antibody-meditated as
seen with other forms of AE that are associated with extracellular Antibody-negative autoimmune encephalitis
proteins and receptors.64,67 Only a few cases of anti-Ma2 enceph-
alitis have been described in children, and in these reports, the One of the more difficult types of AE to diagnose is antibody-
clinical manifestations include seizures, behavioral change, speech negative AE given that there is no identified antibody or known
disturbance, and dystonia.29,67 Tumor is rarely seen in these chil- AE syndrome to explain the presentation. Nonetheless, a significant
dren, but there is one report of an adolescent with anti-Ma2 anti- number of children presenting with features of AE have no iden-
bodies with a mediastinal seminoma.6 MRI typically demonstrates tified serum or CSF autoantibody. In one study of 48 patients with
abnormalities in the temporal lobes, hypothalamus, and probable AE, only 44% of these children had an identified
61
D. Hardy Pediatric Neurology 132 (2022) 56e66

autoantibody.78 In this study, clinical features were similar between evaluation can be pursued. Consultation with psychiatric, rheu-
both antibody-negative and antibody-positive patients.78 Children matology, and infectious disease colleagues can be particularly
categorized as antibody-negative AE include patients who present helpful in these cases. If there is evidence of neuroinflammation or
with clinical features of AE but do not meet criteria for a defined AE neurological dysfunction based on initial testing and alternate di-
syndrome, such as ADEM or Rasmussen encephalitis, and who also agnoses have been excluded, further testing with CSF analysis
have negative AE antibody testing.55 Diagnostic criteria to help should be pursued and empirical treatment can be considered (Fig).
guide our approach to diagnosing these patients was proposed by For children with low clinical suspicion of AE, noninvasive evalua-
Graus et al. requiring the following 4 criteria be met: (1) rapid tion (EEG, MRI, serology); consultation with rheumatology, infec-
progression (over less than three months) of alteration in mental tious disease, and psychiatry to rule out alternate diagnoses; and
status, psychiatric symptoms, or memory loss; (2) exclusion of further observation for the development of features consistent with
well-defined AE syndromes (ex-Bickerstaff encephalitis, ADEM); AE is recommended. If these patients develop features of AE or if
(3) absence of well-known autoantibodies in the serum and CSF; antibodies return positive during observation, treatment should be
and at least two of the following: (a) MRI findings suggestive of AE, initiated (Fig). This approach allows for discretion as to who gets
(b) CSF with pleocytosis or oligoclonal bands, (c) brain biopsy more invasive testing and empirical treatment and therefore can
showing CNS inflammation; and (4) exclusion of alternate prevent invasive testing (i.e. lumbar puncture) and potentially
diagnoses.55 harmful therapy when clinical suspicion for AE is moderate or low.
Treatment of these children relies on the same immunother-
apies that are utilized in antibody-positive AE. Response to Serum laboratory evaluation and cerebrospinal fluid (CSF) analysis
immunotherapy in antibody-negative children is similar to that in Systemic infection, neuroinflammatory and neuro-
antibody-positive patients in most reports.78 However, one cohort rheumatologic conditions, metabolic and mitochondrial conditions,
study that evaluated cognitive outcomes of antibody-negative AE and drug ingestion/toxic exposures can all mimic AE and should be
showed that children with antibody-negative AE had poorer ruled out with appropriate laboratory testing (Table 2). In partic-
cognitive outcomes at 1-year follow-up compared with children ular, serum MOG and AQP-4 antibody testing should be performed
with NMDA-R encephalitis.79 This study also demonstrated that as these antibodies can coexist with NMDA-R antibodies. Table 2
postencephalitic epilepsy was more common in antibody-negative outlines studies to consider during evaluation; however, evalua-
AE.79 Larger studies will be required to better understand treat- tion should be tailored specifically to the patient. For definitive
ment response and optimal treatment approaches. diagnosis, both serum and CSF AE antibody panels should be sent.
CSF testing is more sensitive than serum testing, except in the case
Diagnostic approach of MOG and LGI-1 antibodies where serum is more sensitive. Up to
14% of patients with AE have evidence of antibodies in the CSF but
General approach to diagnosis and acute management not in the serum.18 With CSF testing, pleocytosis and elevated CSF
The diagnosis of AE in children can be challenging due to the protein can be seen, commonly with a lymphocytic predominance;
variety of presenting features and extensive differential diagnosis.4 however, normal CSF does not exclude a diagnosis of AE.78 CSF
A multidisciplinary approach is essential including discussions oligoclonal bands can be positive and are commonly identified in
between neurologists, rheumatologists, psychiatrists, and infec- certain subtypes of AE (NMDA, GABA-B, and GAD encephalitis).82
tious disease physicians. In children, the differential diagnosis in-
cludes infection, vascular etiologies, demyelinating disorders, Neuroimaging and EEG
metabolic and/or mitochondrial disorders, malignancies, drug in- Neuroimaging is often normal in AE, but if abnormalities are
toxications, neurorheumatologic disorders, genetic leukoencepha- identified, they are generally nonspecific. More than 50% of chil-
lopathies, and psychiatric disorders. Infection should be specifically dren with AE will have normal neuroimaging.81 GABA-B encepha-
ruled out promptly as immunotherapies used in AE could worsen litis and MOG encephalitis are more likely to have abnormal MRI
an infectious process. findings than other forms of AE.5,45 Neuroimaging is often helpful
An additional challenge with the diagnosis of AE is that auto- to rule out AE mimics such as vasculitis, demyelinating syndromes,
antibody testing can take days to weeks to result. Definitive anti- stroke, or malignancy. EEG findings in pediatric AE are often
body testing should not prevent the initiation of immunotherapy in abnormal, although nonspecific. In children, EEG findings are more
children where there is a high index of suspicion for AE as early likely to be generalized rather than focal compared with adults.81 In
treatment leads to better outcomes and a reduction in relapse children with AE, extreme delta brush, characterized by rhythmic
rate.1,17,20 A proposed diagnostic approach to children presenting delta activity with overriding fast beta frequencies, can be seen in
with features of AE is outlined in Figure. Concepts proposed in this up to half of children with NMDA-R encephalitis.83
figure are derived from previously proposed diagnostic criteria,
observed clinical features, and described treatment Tumor evaluation
approaches.3,4,12,55,80,81 For children with high clinical suspicion of Although tumors are rarely identified in children with AE, tumor
AE (children presenting with all three of the major clinical features evaluation should be performed in all children with a diagnosis of
of AE), full workup including serologic, CSF, neuroimaging, and EEG AE given that approximately one-third of female children 18 years
(if indicated) evaluation is recommended. EEG may be considered or younger are found to have an ovarian teratoma.12 Evaluation
clinically indicated in patients with profound encephalopathy, with MRI of the chest, abdomen, and pelvis or ultrasound of the
abnormal movements, or paroxysmal events or behaviors sugges- ovaries or testes is generally recommended at the time of diagnosis,
tive of seizure activity. As long as alternate diagnoses are ruled out, and biannual focused surveillance imaging (i.e., ultrasound of the
empirical treatment with IVMP, IVIG, or PLEX should be started ovaries or testes) is recommended for at least two years post
(Fig). Children presenting with severe neurological deficits or diagnosis.3,12
profound encephalopathy should receive PLEX and IVMP, whereas
children with mild symptoms can receive IVMP ± IVIG. Children Symptomatic therapies for children with autoimmune encephalitis
who may not present with all of the typical features of AE, but
present with moderate clinical suspicion, noninvasive testing Children with AE often develop symptoms that require specific
including neuroimaging ± EEG (if indicated), and serologic treatments in addition to immunotherapy. The most common
62
D. Hardy Pediatric Neurology 132 (2022) 56e66

MINOR PRESENTING FEATURES[1,3,4,9,10,79,80] POTENTIAL SIGNS OF NEUROINFLAMMATION [1,3,4,10,79,80]

MAJOR PRESENTING FEATURES[1,3,4,9,10,79,80]
1.) Dysautonomia 1. MRI with cor cal T2 hyperintense lesions
1. Seizures
2.) Speech changes or focal neurologic sugges ve of encephali s
2. Movement disorder
deficit 2. Abnormal EEG
3. Behavioral change/psychosis
3.) Memory disturbance 3. CSF pleocytosis
4.) Decreased level of consciousness

Pa ent presents with: Pa ent presents with: Pa ent presents with:

• 1 of 3 major features • 2 of 3 major features • ALL 3 major features
• 2 minor features • 1 major and 2 minor features • 1 major and 3+ minor features
• ALL 4 minor features
LOW CLINICAL SUSPICION MODERATE CLINICAL SUSPICION
HIGH CLINICAL SUSPICION

Perform the following: Perform the following: Perform the following:

• Consider psychiatry, rheumatology, • Consider psychiatry, rheumatology, • Consider psychiatry, rheumatology,

and/or infectious disease consultation and/or infectious disease consultation • and/or infectious disease consultation
• Serum workup* and urine drug screen • Serum workup* and urine drug screen • Serum workup* and urine drug screen
(UDS) (UDS) (UDS)
• Evaluate for Neuroinflammation: • Evaluate for Neuroinflammation: • Evaluate for Neuroinflammation:
1.Consider MRI of the brain 1.MRI of the brain 1.MRI of the brain
2.Consider EEG as clinically indicated 2.Consider EEG as clinically indicated 2.Consider EEG as clinically
3.CSF analysis** indicated
3.CSF analysis

Normal AND alternate diagnoses ruled out

Ini ate empiric immunotherapy:

Clinical observa on:
• Consider steroids and/or IVIG for
• Monitor for the development of new Evidence suppor ng mild to moderate presentations
clinical symptoms consistent with AE neuroinflamma on • Consider plasma exchange and
NO YES
• Wait for serum autoantibodies to result AND alternate steroids for severe presentations
• Consider CSF testing based on clinical • Rituximab or cyclophosphamide
changes diagnosis ruled out?
for refractory or relapsing cases
• Rule out alternative diagnoses

Development of new symptoms consistent with AE

OR An body + in serum or CSF
AND
Alternate diagnoses ruled out

FIGURE. Proposed diagnostic approach and acute management. This algorithm describes a general approach to a child presenting with signs and symptoms of autoimmune
encephalitis (AE). This algorithm is based on previously proposed criteria, observational data, and described treatment approaches.1,3,4,11,12,80,81 Treatment should be initiated before
the return of autoantibodies in cases with moderate to high clinical suspicion. First-line therapies include intravenous steroids, intravenous immunoglobulin (IVIG), and/or plasma
exchange based on severity of symptoms. Immunotherapy should be escalated to second-line therapies such as rituximab or cyclophosphamide in refractory cases.17 Cases with low
clinical suspicion require further observation, thorough investigation for alternate causes, and the development of further evidence to support an AE diagnosis (i.e., positive au-
toantibodies). *Serum workup could include infectious studies (erythrocyte sedimentation rate, C-reactive protein, complete blood cell count, herpes simplex virus testing, human
immunodeficiency virus testing, varicella zoster testing, and viral encephalitis panel), neuroinflammatory studies (autoimmune encephalopathy panel, myelin oligodendrocyte
glycoprotein antibodies, aquaporin-4 antibodies, oligoclonal bands), neurorheumatologic studies (angiotensin converting enzyme, anti-nuclear antibody testing, anti-neutrophil
cytoplasmic antibody testing, double-stranded DNA testing), metabolic and mitochondrial testing (lactate/pyruvate ratio, comprehensive metabolic panel, plasma amino acids,
ammonia level, copper, ceruloplasmin, vitamin B12, vitamin B1), thyroid studies (thyroid stimulating hormone, thyroxine, thyroglobulin antibodies, thyroid peroxidase antibodies),
and serum drug screens. **Cerebrospinal fluid (CSF) analysis should be pursued based on results of initial serologic and neuroimaging results. The color version of this figure is
available in the online edition.

symptoms associated with pediatric AE include seizures, move- The most common antiseizure medications utilized in pediatric AE
ment disorders, psychosis and behavioral abnormalities, dysauto- include levetiracetam, valproic acid, oxcarbazepine, carbamaze-
nomia, sleep dysfunction, and physical and cognitive impairment. pine, and lacosamide.84,85 Valproic acid has also shown to be useful

63
D. Hardy Pediatric Neurology 132 (2022) 56e66

TABLE 2.
Serum Laboratory Evaluation and Cerebrospinal Fluid Analysis

Diagnostic Study Categories Serum Studies Cerebrospinal Fluid Studies Urine Studies

Infectious studies  CBC  Routine studies (WBC, protein, glucose)  Urinalysis

 ESR  HSV  Urine culture
 CRP
 HSV
 HIV
 VZV
 Viral encephalitis panel/meningitis panel
Neuroinflammatory studies  MOG antibodies  Oligoclonal bands  None
 AQP-4 antibodies
 Autoimmune encephalopathy panel
 Paraneoplastic panel
 Oligoclonal bands
Neurorheumatologic studies  ACE  ACE  None
 ESR
 ANCA
 ANA antibody panel
 dsDNA
Mitochondrial, metabolic, & malignancy studies  Comprehensive metabolic panel  Cytology  Urine organic acids
 Lactate/pyruvate ratio  Flow cytometry
 Plasma amino acids
 Acylcarnitine profile
 Ammonia
 Copper
 Ceruloplasmin
 Vitamin B12
 Vitamin B1
Thyroid studies  TSH  None  None
 T4
 Thyroglobulin antibodies
 Thyroid peroxidase antibodies
Toxicology screens  Serum drug screen  None  Urine drug screen

Abbreviations:
ACE ¼ Angiotensin-converting enzyme
ANA ¼ Anti-nuclear antibody panel
ANCA ¼ Antineutrophil cytoplasmic antibodies
AQP-4 ¼ Aquaporin-4
CBC ¼ Complete blood cell count
CRP ¼ C-reactive protein
dsDNA ¼ Double-stranded DNA
ESR ¼ Erythrocyte sedimentation rate
HIV ¼ Human immunodeficiency virus
HSV ¼ Herpes simplex virus
MOG ¼ Myelin oligodendrocyte glycoprotein
T4 ¼ Thyroxine
TSH ¼ Thyroid-stimulating hormone
VZV ¼ Varicella zoster virus
WBC ¼ White blood cell

for mood stabilization. Beta-blockers and alpha agonists are occur in children. In particular, MOG-positive AE is increasingly
commonly used for dysautonomia management,84,86 whereas more recognized in children. Associated tumors are uncommon in
benzodiazepines are the mainstays of treatment for movement pediatric AE, but it is recommended that all children undergo tu-
disorders and sleep dysfunction.84,86,87 Intensive rehabilitation mor evaluation as tumor removal can lead to complete recovery. All
leads to significant functional improvements and even complete children presenting with symptoms of AE should undergo evalua-
recovery, although ongoing cognitive impairment and memory tion for not only the most common autoantibodies associated with
deficits are common.88-90 Neuropsychologic evaluation and reha- AE but also alternate etiologies that can mimic AE. Empirical
bilitation is strongly encouraged. It is important to reiterate that treatment should be initiated in children with high clinical suspi-
these therapies are “adjunctive therapies” as immunotherapy is the cion of AE to achieve the best possible outcomes. Symptomatic
primary treatment for AE. therapies and intensive rehabilitation should be tailored to the
individual patient to allow for the most optimal recovery.
Summary Future research, ideally in the form of randomized clinical tri-
als, will be essential to determine the most effective treatment
Pediatric AE diagnosis and treatment approaches have evolved approaches for AE in children. This will require multicenter col-
tremendously since the initial discovery of antibodies to the laborations given the rarity of these disorders. Physical and
NMDA-R. With advances in reliable antibody detection methods, cognitive rehabilitation, crucial components to management of AE,
the field can more confidently identify autoantibodies in patients will need to be studied to enhance overall recovery. Further
with corresponding symptoms of AE. Here we reviewed the most research will be required to identify novel disease-causing auto-
common autoantibodies found in children presenting with features antibodies, which will ultimately help elucidate the underlying
of AE. NMDA-R encephalitis is the most common form of known pathogenesis of the disease and broaden the scope of our under-
antibody-mediated AE; however, many other AE syndromes can standing of pediatric AE.
64
D. Hardy Pediatric Neurology 132 (2022) 56e66

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