ARTICLE OPEN ACCESS ...is frequently elevated in anti-NMDAR encephalitis and other encephalitides, but normal in PANS.33 There is evidence that AE (particularly anti-NMDAR encephalitis)

ARTICLE OPEN ACCESS

Clinical approach to the diagnosis of autoimmuneencephalitis in the pediatric patientTania Cellucci MD MScCH Heather Van Mater MD MSc Francesc Graus MD PhD Eyal Muscal MD MS

William Gallentine DO Marisa S Klein-Gitelman MD MPH Susanne M Benseler MD PhD

Jennifer Frankovich MD MS Mark P Gorman MD Keith Van Haren MD Josep Dalmau MD PhD and

Russell C Dale MBChB MSc PhD

Neurol Neuroimmunol Neuroinflamm 20207e663 doi101212NXI0000000000000663

Correspondence

Dr Dale

Russelldalehealthnswgovau

AbstractObjectiveAutoimmune encephalitis (AE) is an important and treatable cause of acute encephalitisDiagnosis of AE in a developing child is challenging because of overlap in clinical presentationswith other diseases and complexity of normal behavior changes Existing diagnostic criteria foradult AE require modification to be applied to children who differ from adults in their clinicalpresentations paraclinical findings autoantibody profiles treatment response and long-termoutcomes

MethodsA subcommittee of the Autoimmune Encephalitis International Working Group collaboratedthrough conference calls and email correspondence to consider the pediatric-specific approachto AE The subcommittee reviewed the literature of relevant AE studies and sought additionalinput from other expert clinicians and researchers

ResultsExisting consensus criteria for adult AE were refined for use in children Provisional pediatricAE classification criteria and an algorithm to facilitate early diagnosis are proposed There is alsodiscussion about how to distinguish pediatric AE from conditions within the differentialdiagnosis

ConclusionsDiagnosing AE is based on the combination of a clinical history consistent with pediatric AEand supportive diagnostic testing which includes but is not dependent on antibody testing Theproposed criteria and algorithm require validation in prospective pediatric cohorts

From the Department of Pediatrics (TC) McMaster Childrenrsquos Hospital McMaster University Hamilton Ontario Canada Department of Pediatrics (HVM) Duke UniversityDurham NC Neuroimmunology Program (FG JD) Institut drsquoInvestigacions Biomediques August Pi I Sunyer Barcelona Spain Department of Pediatrics (EM) Baylor College ofMedicine Houston TX Department of Neurology (WG KVH) Lucile Packard Childrenrsquos Hospital Stanford University Palo Alto CA Division of Rheumatology (MSK-G) Ann ampRobert H Lurie Childrenrsquos Hospital of Chicago Northwestern University Feinberg School of Medicine IL Department of Pediatrics (SMB) Alberta Childrenrsquos Hospital University ofCalgary Canada Division of Pediatric Allergy Immunology and Rheumatology (JF) Lucile Packard Childrenrsquos Hospital Stanford University Palo Alto CA Department of Neurology(MPG) Boston Childrenrsquos Hospital Harvard University MA Department of Neurology (JD) University of Pennsylvania Philadelphia Catalan Institution for Research and AdvancedStudies (ICREA) (JD) Neuroimmunology Group (RCD) Childrenrsquos Hospital at Westmead Faculty of Medicine and Health University of Sydney New South Wales Australia

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by Neurology Neuroimmunology amp Neuroinflammation

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Autoimmune encephalitis (AE) refers to an increasingly rec-ognized group of inflammatory brain diseases Children withAE present with acute or subacute onset of neuropsychiatricsymptoms due to an underlying abnormal immune responseto the CNS12 Many AE associate with antibodies directedtoward extracellular antigens such as synaptic receptors andion channels23 Autoantibodies that bind to extracellularantigens are generally pathogenic whereas antibodies thatbind intracellular antigens are not considered pathogenicinstead general markers of autoimmunity

A number of different antibodies have been described inchildren with AE4ndash21 Currently the most common auto-antibodies in children target the N-methyl-D-aspartate re-ceptor (NMDAR) myelin oligodendrocyte glycoprotein(MOG) and glutamic acid decarboxylase 65 (GAD65)5ndash12 Itis also recognized that not all children with a clinical pheno-type of AE have a known autoantibody14

Diagnosing AE is challenging because of overlap in clinical pre-sentations between the types of AE other inflammatory braindiseases infections metabolic diseases and psychiatric disorders1

It is especially difficult in children because of the complexity of

normal behavioral changes during childhood and the limited ca-pacity of younger children to describe their symptoms1 Comparedto adults with AE children may manifest important differences insymptoms paraclinicalfindings comorbidities treatment responseand prognosis4ndash722ndash24 There is an urgent need to recognize pe-diatric AE because treatment delays worsen prognosis and increasethe risk of permanent neurocognitive deficits62526

In this article we build on existing consensus criteria for adult AEby refining them for use in children27 We propose provisionalpediatric AE classification criteria and an algorithm to facilitate earlydiagnosis Diagnosing AE is based on the combination of a clinicalhistory consistent with the disease and supportive diagnostic test-ing which includes but is not dependent on antibody testing Wealso discuss the differential diagnosis in childrenwith suspectedAE

MethodologyAt the 2014 Autoimmune Encephalitis Alliance (AEallianceorg)conference in North Carolina the Autoimmune EncephalitisInternational Working Group was formed and initiated dis-cussions around developing diagnostic criteria for AE A sub-committee of pediatric neurologists and rheumatologists

GlossaryAE = autoimmune encephalitis Caspr2 = contactin-associated protein-like 2 FIRES = febrile infection-related epilepsysyndrome GABAAR = gamma-aminobutyric acid A receptor GAD65 = glutamic acid decarboxylase 65 HE = Hashimotoencephalopathy LGI1 = leucine-rich glioma-inactivated protein 1MOG = myelin oligodendrocyte glycoprotein NMDAR =N-methyl-D-aspartate receptor PANDAS = pediatric autoimmune neuropsychiatric disorders associated with streptococcalinfections PANS = pediatric acute-onset neuropsychiatric syndrome VGKCC = voltage-gated potassium channel complex

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 2 | March 2020 NeurologyorgNN

identified that adult-focused criteria may not apply well to chil-dren As a result this subcommittee collaborated through con-ference calls and email correspondence to consider the pediatric-specific approach to AE The subcommittee reviewed the litera-ture on relevant AE studies and sought additional input fromother experts The first author (TC) developed a draft based onthe preceding discussions that was subsequently reviewed andmodified by all authors

Existing diagnostic criteria for AEThe International Encephalitis Consortium 2013 diagnosticcriteria for encephalitis of presumed infectious or autoimmuneetiology require patients to have altered mental status lastingmore than 24 hours with no alternative cause identified28

Confirmation of this diagnosis requires at least 3 minor criteriaincluding fever within 72 hours of presentation new onset focalneurologic findings CSF leukocytosis acute new neuro-imaging abnormality suggestive of encephalitis or EEG ab-normalities consistent with encephalitis28 These criteria do notdifferentiate autoimmune from infectious encephalitis

More recently an international group developed diagnosticcriteria for early diagnosis of AE in adults which require (1)subacute onset over less than 3 months of working memorydeficits altered mental status or psychiatric symptoms (2) atleast one of the following new focal CNS findings seizures notexplained by a preexisting disorder CSF pleocytosis andorMRI features suggestive of encephalitis and (3) reasonableexclusion of alternative causes27 Specific neurologic syndromeswere given criteria including limbic encephalitis anti-NMDARencephalitis and autoantibody-negative AE27

These AE criteria requiredmodification to be applied to childrenFor example deficits in working memory are challenging toidentify in younger children Also children are less likely topresent with a well-defined neurologic syndrome and even inanti-NMDAR encephalitis the sequence of symptom de-velopment may differ from adults5ndash7 Furthermore the differen-tial diagnosis for a child presenting with temporal lobe seizuresand cognitive slowing is broad whereas this presentation in adultssuggests limbic encephalitis or acquired temporal pathology

Clinical features distinguishing adultsand children with AETypically children with AE are previously healthy and presentwith rapid onset of neuropsychiatric symptoms Prodromalsymptoms including fever occur in over 50 of patients24ndash6

Between disease onset and initiation of therapy symptoms typ-ically persist over time This distinguishes AE from pediatricacute-onset neuropsychiatric syndrome (PANS) where patientsoften experience a relapsing-remitting course with rapid pro-gression to maximum symptom severity and rapid return toprevious function over hours or days sometimeswithout therapy

Neurologic manifestations of AE include altered level of con-sciousness confusion disturbed sleep movement disorders andseizures Seizures are the most common feature in AE and maybe the predominant manifestation4ndash710ndash21 Seizures may befocal or generalized and are often multifocal4ndash710ndash21 Over onethird of patients with AE have abnormal movements such asataxia chorea dystonia myoclonus or tremor4ndash71315 Bothseizures and movement disorders can be highly refractory tostandard treatments in children with AE10141624 Some degreeof cognitive impairment is seen in the overwhelmingmajority ofAE patients and is considered a cardinal symptom451314161921

As such a diagnosis of AE would be highly questionable inpatients with documented normal cognition again differenti-ating AE from PANS where cognition is often preservedAssessing memory deficits in young children may be challeng-ing however developmental regression language loss or speechimpairments may be presenting features of pediatric AE5ndash729

Behavioral changes such as repetitive or stereotypical behav-iors irritability hyperactivity hypersexuality insomnia andanger outbursts are common in pediatric AE4ndash7 Psychiatricsymptoms may range from mood swings and mild personalitychanges to fulminant psychosis and occur in over 50 of AEpatients4ndash7 New-onset psychosis in children younger than 13years is uncommon and considered a red flag for an underlyingmedical rather than primary psychiatric condition It is criticalto assess for cognitive changes seizures movement abnor-malities or other neurologic symptoms in children with acutepsychiatric symptoms as these symptoms are suggestive of AE

Children with AE likely differ from adults in their clinicalpresentations due to evolution of neuronal circuits neuro-receptor densities and myelination during normal de-velopment Children with AE are more likely to present withmultifocal neuropsychiatric symptoms rather than isolatedclinical syndromes For example children with GAD65 anti-bodies may not present with the classic stiff-person syndromeor cerebellar degeneration seen in adults111222 Children withantindashNMDAR-associated encephalitis are more likely to pres-ent withmovement abnormalities agitation insomnia seizuresspeech deficits ataxia andor hemiparesis whereas memorydeficits psychiatric manifestations and central hypoventilationare more common in adults with the same antibody5ndash7 Pedi-atric AE is less associated with tumors compared with adults4ndash7

Diagnostic evaluation of children andteenagers with suspected AEAlthough no single investigation is diagnostic of pediatric AEthe presence of a suggestive clinical phenotype and supportiveparaclinical testing is essential to diagnose an underlying in-flammatory process and to exclude alternative diagnoses Initialinvestigations to be considered for any child with suspected AEare listed in table 1 although diagnostic workup should betailored to the individual

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 2 | March 2020 3

Blood tests are helpful to assess for systemic inflammatorychanges autoantibodies associated with systemic autoim-mune diseases vitamin B12 deficiency markers of infectionelevated lactate due to metabolic conditions and recreationaldrug use Erythrocyte sedimentation rate C-reactive proteinleukocyte counts and platelet counts may be normal in chil-dren with AE14ndash21

CSF pleocytosis andor elevated protein levels may be seen atdiagnosis or during disease course but are not uniformlypresent14ndash21 Recommended tests to assess for infectious en-cephalitis were based on population-based studies in Californiaand England (table 1)3031 However workup for infectious

etiologies varies depending on the season and region where thepatient lives or has traveled A recent report suggests that anti-NMDAR encephalitis may bemore common in children than anyspecific infectious encephalitis further highlighting the importanceof considering AE when evaluating for infectious encephalitis32

CSF neopterin is a useful but not rapidly accessible biomarker thatis frequently elevated in anti-NMDAR encephalitis and otherencephalitides but normal in PANS33 There is evidence that AE(particularly anti-NMDAR encephalitis) may be triggered byherpes simplex virus encephalitis and Japanese encephalitis34

All patients should have a brain MRI with and withoutgadolinium Over half of patients with AE will have a normal

Table 1 Recommended investigations for children with suspected AE

A Initial investigations for patients withpossible AE

Diagnostic imaging Brain MRI with gadolinium (including T1 T2 FLAIR and diffusion-weighted sequences)

Consider adding spine MRI if neurologic abnormalities potentially mediated by spinal cord involvement

Blood tests Complete blood cell count and differential

Erythrocyte sedimentation rate C-reactive protein and ferritin

Vitamin B12 level and vitamin D level

Serum lactate

Thyroid-stimulating hormone free thyroxine and thyroid autoantibodies (eg antithyroid peroxidaseantithyroglobulin and antindashthyroid-stimulating hormone receptor)

Serologic testing for infectious causes (dependent on regional epidemiology)

Consider antinuclear antibodies and specific antinuclear antibodies (eg antindashdouble-stranded DNA andanti-Smith) if indicated by clinical presentation

Consider serum complement and immunoglobulin levels if personal or family history of autoimmunity orimmune deficiency

Urine tests Testing for recreational drugs (eg marijuana cocaine and opioids)

Lumbar puncture Opening pressure

CSF cell counts protein lactate oligoclonal bands and neopterin (if available)

Infectious testing dependent on regional epidemiology but often includes PCR for enterovirus herpessimplex virus and varicella zoster viruses

Save 5ndash10 mL of CSF for future testing

Respiratory tests Nasopharyngeal swab for respiratory viruses and mycoplasma PCR

EEG Assess for focal or generalized seizures epileptiform discharges and changes in background activity

B More specific investigations forpatients with possible AE

Blood tests Serum testing for antibodies associated with AEa

Lumbar puncture CSF testing for antibodies associated with AEa

Neurocognitive tests Assess for cognitive deficits affecting memory attention problem solving language and cognitiveprocessing

Consider using symbol digit modalities test to screen for cognitive dysfunction

Other tests Consider if available andor if required based on initial investigations PET and SPECT

Abbreviations AE = autoimmune encephalitis FLAIR = fluid-attenuated inversion recoverya See tables 2 and 3 for details regarding neural antibodies identified in children


brain and spine MRI at diagnosis4ndash7162122 Inflammatorylesions (high signal on T2 and fluid-attenuated inversionrecovery sequences) may develop over time and cerebralatrophy may occur months later46715 MRI lesions are mostlikely to be present in those with antibodies to MOG or thegamma-aminobutyric acid-A receptor (GABAAR)

91415

Neuroimaging findings are not limited to the temporal lobeor cortex15ndash21 A normal MRI lessens suspicion for CNSvasculitis demyelinating diseases infections and malig-nancies1 In contrast restriction on diffusion-weighted im-aging reduces the likelihood of pediatric AE and shouldprompt consideration of other etiologies such as infection-associated encephalopathies and vasculitis1 Small retro-spective adult AE studies have proposed that functional PETand SPECT studies may demonstrate brain dysfunction butexperience is limited in pediatric AE3536

A normal EEG is unusual in children with AE during ac-tive disease although prolonged EEG may be needed for

improved sensitivity Therefore focal or generalized seiz-ures epileptiform discharges and encephalopathic changessuch as diffuse or focal slowing may help to distinguish AEfrom primary psychiatric disorders or PANS Adults withAE are more likely to have EEG changes predominantlyinvolving the temporal lobes whereas EEG findings inchildren may be more generalized4ndash714ndash21 Specific EEGfeatures such as the ldquodelta brushrdquo pattern and extremespindles have been linked to anti-NMDAR encephalitis butsensitivity is low62223

Neurocognitive testing may identify deficits in memory at-tention problem solving language and processing speedparticularly in younger children A change in neurocognitivefunction supports a diagnosis of pediatric AE and may dif-ferentiate these patients from those with primary psychiatricdisorders However interpretation of neurocognitive testing atdiagnosis should be undertaken with caution as there is oftenno premorbid testing for comparison

Table 2 Antibodies that are commonly identified in pediatric AE

Antibody target(localization) Typical clinical features in children

GAD6510212

(intracellular)Frequency Common in AE but only pathologic if high titers in serum and present in CSF

Clinical Encephalitis with memory loss cognitive impairment cerebellar ataxia and temporal lobe seizures

MRI May be normal initially often progresses to lesions in the limbic system cerebellum and cortices with possibleatrophy

EEG Epileptiform discharges may be multifocal

Other CSF leukocytosis may be mild with oligoclonal bandsAssociated personal or family history of autoimmunityOften resistant to immunotherapy

MOG894245ndash47

(extracellular)Frequency Common in AE

Clinical Acute disseminated encephalomyelitis including encephalopathy optic neuritis or transverse myelitis (but nottypical MS) cortical encephalitis with seizures brainstem encephalitis and meningoencephalitis withoutdemyelination

MRI Focal or multifocal white matter lesions longitudinally extensive myelitis and optic neuritis

EEG Nonspecific slowing

Other Serum antibody testing preferable to CSFHigher titers of antibodies in younger childrenPersistent antibodies in relapsing disease

NMDAR5ndash7

(extracellular)Frequency Most common antibody target in pediatric AE

Clinical Encephalitis with movement disorder seizures psychiatric symptoms reduced verbal outputmutismdevelopmental regression (in younger children) sleep dysfunction (mainly insomnia) and autonomic instability

MRI Normal in at least 65 of patients T2FLAIR lesions may be identified in the cortex white matter cerebellum orbasal ganglia reversible cerebral atrophy is a late finding

EEG Abnormal in over 90 of patientsmdashmost have generalized slowing but may see focal epileptic activity focalslowing or ldquoprolonged spindlesdelta brush patternrdquo

Other CSF antibody testing preferable to serumIncreased association with tumors in females and in patients older than 12 y

Abbreviations AE = autoimmune encephalitis FLAIR = fluid-attenuated inversion recovery GAD65 = glutamic acid decarboxylase 65 MOG = myelin oligo-dendrocyte glycoprotein NMDAR = NMDA receptor


Other diagnostic tests may be considered Most childrenwith AE do not require brain biopsy However a targetedbrain biopsy of MRI abnormalities may be needed when thediagnosis remains uncertain after initial workup The di-agnostic yield of brain biopsy is higher in pediatric patientsthan in adults37

Antibody testing and interpretation inchildren and teenagers withsuspected AEAntibodies associated with pediatric AE are listed in tables2 and 3 Each antibody is associated with characteristic

Table 3 Antibodies that are identified less frequently in pediatric autoimmune encephalitis


Dopamine-2 receptor13

(extracellular)Frequency Very uncommon

Clinical Encephalitis with predominant movement disorders psychiatric symptoms sleep disturbance mutism anddecreased consciousness

MRI Abnormal in 50 of patients usually symmetric selective involvement of basal ganglia

EEG No consistent pattern reported

Other Variable CSF findings sometimes lymphocytic pleocytosis or oligoclonal bands

GABAA receptor1415

(extracellular)Frequency Uncommon

Clinical Encephalitis with refractory seizures status epilepticus or epilepsia partialis continua

MRI Multifocal T2FLAIR lesions in corticalsubcortical areas

EEG Epileptiform activity and generalized slowing

Other Most patients have CSF leukocytosisOften associated with GAD or thyroid autoantibodies

GABA-B receptor1617


Clinical Encephalitis with focal or generalized seizures and mixed movement disorder

MRI Abnormal in over 50with increased T2FLAIR signal in themedial temporal lobe (may bemultifocal andmaybe associated with changes on diffusion-weighted imaging)

EEG Diffuse slowing and epileptiform discharges

Other CSF abnormal in up to 90 with lymphocytic pleocytosisPediatric cases not linked to infection or tumor

Glycine receptor1819


Clinical Progressive encephalomyelitis with rigidity and myoclonus encephalitis and other brainstem syndromes

MRI Frequently normal (70 reported cases)

EEG Abnormal in approximately 70 usually slowing

Other Variable CSF findings of lymphocytosis elevated protein and oligoclonal bandsMay be associated with antibodies to other targets (eg GAD)

m-GluR52021


Clinical Encephalitis with psychiatric symptoms

MRI Variable MRI findings often T2FLAIR

EEG Variable EEG findings typically absent epileptiform discharges

Other CSF lymphocytic pleocytosis

Abbreviations FLAIR = fluid-attenuated inversion recovery GABA = gamma-aminobutyric acid GAD = glutamic acid decarboxylase m-GluR5 =metabotropicglutamate receptor 5


symptoms seizure types and other clinical findingsHowever there is significant overlap between the differentdisorders and so testing a panel of neural autoantibodies isrecommended for any child with suspected AE The mostcommon autoantibodies identified in children targetNMDAR MOG GAD65 and GABA

AR Given the rarity of

other autoantibodies further testing should be consideredonly if antibodies to these targets are negative and suspi-cion of AE persists (table 3)

Antibody testing should be performed in both CSF and serum toavoid false-negative and false-positive results For example testingfor NMDAR antibodies typically has higher sensitivity in CSFcompared with serum with up to 15 of patients having negativeserum results5ndash7 In contrast MOG autoantibodies have highersensitivity in serum9

Interpretation of antibody test results should carefully considerthe childrsquos clinical presentation especially when more than 1antibody is identified For example GAD65 antibodies tend to beassociated with personal or familial autoimmunity and low titerssuch as those seen in type 1 diabetes mellitus are not neurolog-ically relevant22 The presence of more than 1 antibody in somepatients with AE has been recognized andmay be associated withoverlapping syndromes Antibody specificity is also importantwhen interpreting antibody test results For instance only IgGisotype antibodies to theGluN1 subunit of theNMDARon a cell-based assay are specifically associated with AE538

In adults with AE most antibodies to the voltage-gated potas-sium channel complex (VGKCC) do not bind to the channelbut to proteins in the complex particularly leucine-richglioma-inactivated protein 1 (LGI1) and contactin-

Table 4 Proposed classification criteria for possible definite antibody-positive andprobable antibody-negative pediatric AE

Categorical features of AE Specific diagnostic features

Diagnostic categories

PossibleAE

Probableantibody-negative AE Definite antibody-positive AE

1 Evidence of acute orsubacute symptom onset

Onset of neurologic andor psychiatric symptoms overle3 mo in a previously healthy child

Yes Yes Yes

2 Clinical evidence ofneurologic dysfunction

Features include ge2featurespresent

ge2 featurespresent

ge2 features present

Altered mental statuslevel of consciousness or EEGwith slowing or epileptiform activity (focal orgeneralized)

Focal neurologic deficits

Cognitive difficultiesa

Acute developmental regression

Movement disorder (except tics)

Psychiatric symptoms

Seizures not explainedby apreviously known seizuredisorder or other condition

3 Paraclinical evidence ofneuroinflammation

Features include Notavailable

ge1 featurespresent

ge1b features present

CSF inflammatory changes (leukocytosis gt5 cellsmm3

andor oligoclonal banding)

MRI features of encephalitis

Brain biopsy showing inflammatory infiltrates andexcluding other disorders

4 AE serology Presence in serum andor CSF of well-characterizedautoantibodies associated with AE

Notavailable

No Yes

5 Exclusion of otheretiologies

Reasonable exclusion of alternative causes includingother causes of CNS inflammation

Yes Yes Yes

Abbreviation AE = autoimmune encephalitisa Severe cognitive dysfunction that is not attributable to a primary psychiatric syndrome as documented by a qualified clinician (eg neurologist psychiatristand neuropsychologist) or a significant drop in IQ (gt20 points)b When antibodies against NMDA receptor gamma-aminobutyric acid A receptor or glutamic acid decarboxylase 65 are present in CSF further paraclinicalmarkers ofneuroinflammation are not required to diagnose definite AE When only serum antibodies are present one or more paraclinical marker(s) of neuroinflammation isrequired


associated protein-like 2 (Caspr2)39 In children VGKCCantibodies rarely target LGI1 or Caspr24041 It has beenargued that VGKCC antibodies without specific binding toLGl1 or Caspr2 have limited clinical significance40

Proposed classification criteria andalgorithm for diagnosis of pediatric AEWemodified the criteria for adult AE and propose provisionalclassification criteria for possible pediatric AE probableantibody-negative pediatric AE and definite antibody-positivepediatric AE in table 427 A diagnostic algorithm is also pro-vided in figure The provisional criteria and algorithm shouldbe assessed prospectively in future cohorts

A diagnosis of pediatric AE should be considered in previouslyhealthy children who present with acute or subacute (less than3 months) onset of new focal or diffuse neurologic deficitscognitive difficulties developmental regression movementabnormalities psychiatric symptoms andor seizures Al-though children with preexisting developmental delay orchronic behaviorpsychiatric abnormalities may develop AEalternative diagnoses such as genetic metabolic or neurode-generative etiologies should be considered in these patients

Children with a clinical presentation suggestive of AE shouldhave serum and CSF examined for neuronal antibodies un-dergo paraclinical testing for neuroinflammation and havedisease mimics excluded (tables 1 and 4) EEG is not included

Figure Algorithm for diagnostic workup of children with suspected AE using provisional criteria

AE = autoimmune encephalitis


as paraclinical evidence of neuroinflammation because EEGcannot differentiate AE from other encephalopathies How-ever EEG encephalopathic features are allowable as an alter-native for clinical features of encephalopathy If a patient fulfillscriteria for possible pediatric AE (table 4) and is functionallyimpaired therapy may be started while awaiting the results of

antibody and other testing given the importance of earlytreatment to improve outcomes42526 If a patient with possibleAE subsequently does not have positive antibodies or para-clinical testing for neuroinflammation a diagnosis of AE is notsupported For these children careful further consideration ofthe differential diagnosis is warranted and additional immune

Table 5 Differential diagnosis of AE in children and adolescents

Primary CNS inflammatory AE including HE

Primary or secondary CNS vasculitis

Demyelinating diseases acute disseminated encephalomyelitis MS and neuromyelitis optica

Rasmussen encephalitis

Systemic inflammatory Autoimmune diseases antiphospholipid syndrome celiac disease Behccedilet disease sarcoidosis systemiclupus erythematosus and Sjogren syndrome

Autoinflammatory diseases interferonopathies and hemophagocytic lymphohistiocytosis

Infectious Bacteria Borrelia burgdorferi Listeria monocytogenes Mycoplasma pneumoniae Mycobacterium tuberculosisand Treponema pallidum

Viruses adenovirus enterovirus Epstein-Barr virus HSV HIV influenza JC virus measles rabies varicellazoster virus and West Nile virus

Parasites malaria

Postinfectious or infection-associatedencephalopathy

Postmycoplasma basal ganglia encephalitis

Post-HSV encephalitis movement disorder

Poststreptococcal neuropsychiatric disorders (including Sydenham chorea)

Encephalitis lethargica

Diseases with immune mechanismsunder review

FIRES

ANE

AESD

PANDAS

PANS

Metabolic Geneticinherited diseases leukodystrophies mitochondrial diseases mucopolysaccharidoses organicacidurias and Wilson disease

Hepatic encephalopathy

Neoplastic Primary CNS tumors (eg lymphoma glioma and astrocytoma)

Metastatic disease (eg neuroblastoma and leukemia)

Nutritional Vitamin B12 deficiency

Psychiatric New onset schizophrenia bipolar disorder conversion disorder childhood disintegrative disorder andpsychogenic seizures

Toxic Recreational drugs (eg alcohol marijuana synthetic cannabinoids cocaine opioids andmethamphetamines)

Ingestions (eg ethylene glycol methanol and inhalants)

Medications such as metronidazole and cyclosporine

Other Child abuse and neglect

Abbreviations AE = autoimmune encephalitis AESD = acute encephalopathy with biphasic seizures and diffusion restriction ANE = acute necrotizingencephalopathy FIRES = febrile infection-related epilepsy syndrome HE = Hashimoto encephalopathy HSV = herpes simplex virus PANDAS = pediatricautoimmune neuropsychiatric disorders associated with streptococcal infections PANS = pediatric acute-onset neuropsychiatric syndrome


therapy should only be undertaken with caution (table 5figure)

Children may have AE caused by antibodies that have not yetbeen identified and may meet criteria for probable antibody-negative pediatric AE (table 4) These patients will have 1 ormore positive paraclinical tests for neuroinflammation butnegative antibody testing Children who meet the criteria fordefinite antibody-positive pediatric AE will have positive anti-body testing If CSF antibodies are present (eg NMDAR andGAD65) no other paraclinical evidence of neuroinflammationis required for a diagnosis of definite AE (table 4) If only serumantibodies are present 1 or more paraclinical tests of neuro-inflammation must be abnormal There should be caution indiagnosing AE when only serum antibodies (particularlyNMDAR GABAAR and glycine receptor) are found in theabsence of paraclinical evidence of neuroinflammation

The proposed pediatric AE criteria differ from the adult criteria inseveral ways (table 4 table e-5 linkslwwcomnxiA184)27 Firstthe pediatric criteria include both acute and subacute time framesfor symptomonset reflecting the range in disease course observedin children Adult AE criteria were developed for several well-defined syndromes (ie limbic encephalitis acute dis-seminated encephalomyelitis [ADEM] and anti-NMDARencephalitis) and the associated algorithm focuses onwhether patients meet criteria for these syndromes27 Incontrast many pediatric patients with AE do not presentwith a well-defined syndrome and so the pediatric criteriawere devised to capture the breadth of clinical and para-clinical findings reported in children Similarly the pedi-atric AE algorithm (figure) does not focus on syndromeidentification but is intended to guide a clinician inassessing clinical features and in paraclinical and antibodytesting so as to determine whether an AE diagnosis isappropriate The adult AE criteria group clinical and par-aclinical markers together whereas the pediatric criteriadistinguish clinical evidence of neurologic dysfunctionfrom paraclinical evidence of neuroinflammation

Patients with definite AE may benefit from continued or ad-vanced immunosuppressive therapy although specific protocolsare not yet validated Identification of an antibody associatedwithAEmay facilitate counseling regarding expected course andoutcomes Timing of clinical responses to immunotherapy inchildren with AE may vary from immediate to months afterstarting5ndash72442 Therefore using response to therapy as con-firmatory support for a diagnosis of AE may be misleading

Approach to clinicallyrecognizable syndromesAnti-NMDAR encephalitisAnti-NMDAR encephalitis is the most common pediatric AEThe current adult diagnostic criteria for antindashNMDAR-associated encephalitis have been tested and apply well in

children43 However children are more likely to present withneurologic symptoms instead of psychiatric symptoms andmay not present with the classic sequence of symptoms de-scribed in adultsmdashfor example movement disorders and au-tonomic dysfunction occur earlier in children5ndash7

AE associated with antibodies to MOGincluding acute disseminatedencephalomyelitisThe most common autoantibody associated with autoimmunedemyelination targets MOG8942 Patients who have ADEM as-sociated withMOG autoantibodies aremore likely to exhibit largeglobular lesions and long segment myelitis compared with thosewithout these antibodies44 Children with MOG antibodies arealso less likely to have oligoclonal bands than those with MS4244

However the spectrum of brain disease associated with MOGantibodies in adults and children has broadened to includeADEM meningoencephalitis cortical encephalitis with seizuresbrainstem encephalitis and mimics of vasculitis45ndash47 Some ofthese patients will evolve into more typical demyelinating phe-notypes such as ADEM therefore MOG antibodies should beconsidered in pediatric AE presentations beyond ADEM45ndash47

MOG autoantibodies are typically transient in monophasicADEM but remain positive in relapsing phenotypes8942

Limbic encephalitisThe clinical EEG and radiologic features of limbic encephalitisare uncommon in children48 Autoantibodies associated withadult limbic encephalitis include those that target LGI1 GAD65alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid re-ceptor gamma-aminobutyric acid-B receptor Caspr2 Hu andMa23With the exception ofGAD65 these specific antibodies arerare in children48

Hashimoto encephalopathyHashimoto encephalopathy (HE) presents with nonspecificneuropsychiatric symptoms accompanied by antithyroid anti-bodies which are considered markers of autoimmunity ratherthan pathogenic Patients may develop seizures altered mentalstatus cognitive decline psychosis paranoia focal neurologicdefects and movement disorders4950 Over 70 of childrenwith HE have a normal brain MRI CSF rarely shows pleocy-tosis and EEG often shows generalized or focal slowingwithout seizures4950 Most children have normal thyroidfunction despite having antithyroid antibodies4950 Thoughtfulinterpretation is required because serum thyroid autoanti-bodies have been identified in healthy children4950

Approach to probable antibody-negative pediatric AEChildren with a clinical phenotype of AE and paraclinicalfindings of neuroinflammation but negative testing for neuralantibodies may meet criteria for probable antibody-negativepediatric AE (table 4) It is well recognized that not all neuralautoantibodies have been identified Having CSF and serum


testing in a research laboratory may identify patients who haveantibodies against neural cell surface antigens of yet unknownidentity and who may respond to immunotherapy

Probable antibody-negative AE is one of the most challengingclinical scenarios It is appropriate that a child presenting withnew onset encephalopathy neuropsychiatric features andchanges in function be investigated for possible AE Howeverthe differential diagnosis in children is arguably broader than inadults and so it is important to ensure that other diagnoseshave been excluded before giving an AE diagnosis Pathologicentities that often cause diagnostic difficulty are cortical dys-plasias and genetic epilepsies presenting with fever-provokedsymptomatic focal seizures infection-provoked encephalopa-thy and PANS In these syndromes CSF pleocytosis or oli-goclonal bands are usually absent and MRI is either normal ordemonstrates alternative pathology Therefore critical exami-nation of paraclinical tests for evidence of CNS inflammation ismandatory to avoid unnecessary immune suppression A di-agnosis of probable antibody-negative pediatric AE should alsobe reassessed in children with atypical features

Differential diagnosis of AEThe spectrum of inflammatory brain diseases in children hasrapidly expanded as new diseases and new etiologies for existingconditions have been described The underlying pathogenicmechanisms that lead to CNS inflammation may involve vesselwall inflammation demyelination or an immune response di-rected against neurons and supporting structures13 In-flammation may also occur secondary to infection malignancyor a systemic inflammatory disease Diagnosing pediatric AE isespecially challenging because of the clinical overlap betweenconditions in the differential diagnosis (table 5) and the clinicalheterogeneity within patients having the same disease

Specific conditions within the differentialdiagnosis of AEComprehensive evaluation is required to distinguish childrenwith AE from those who have other inflammatory brain diseasesFor example children with large-vessel CNS vasculitis typicallydemonstrate a stroke phenotype including paresis and speechdeficits and may be distinguished by the presence of ischemicchanges on MRI and angiographic abnormalities such as aneu-rysm and beading51 In contrast children with small-vessel CNSvasculitis present with cognitive dysfunction seizures vision ab-normalities and bilateral nonischemic lesions on MRI and haveinflammatory vessel wall changes identified on brain biopsy51

Infection-associated encephalopathy disorders include febrileinfection-related epilepsy syndrome (FIRES) acute necrotizingencephalopathy mild encephalopathy with reversible spleniumlesion and acute encephalopathy with biphasic seizures anddiffusion restriction52 These syndromes have typical clinical andradiologic features often with diffusion restriction on imagingwhich may infer cytotoxicity and distinguish these patients fromthose with AE For example children with FIRES develop

a nonspecific febrile illness followed by sustained refractorystatus and then progress to chronic drug-resistant epilepsy withneuropsychological impairment52 Neuroimaging and brain bi-opsy in FIRES are usually normal52 The pathogenesis of thesediseases is unresolved but may include genetic vulnerabilityleading to an infection-triggered ldquocytokine stormrdquo52

Other diagnoses within the differential are PANS and pediatricautoimmune neuropsychiatric disorders associated with strep-tococcal infections (PANDAS) These conditions describe anidiopathic or postinfectious onset of obsessive-compulsive dis-order eating restriction other emotional syndromes tics loss ofskills or personality change53 Both clinical phenotypes lackrobust biomarkers and pathogenesis remains disputed how-ever there is some evidence of immune mediation and immu-notherapy responsiveness5354 Although patients may appear tohave an acquired brain syndrome most children with PANDASor PANS would not fulfill the proposed pediatric AE criteria

Also monogenic autoinflammatory syndromes may involve thebrain such as the genetic interferonopathies vasculopathies andhemophagocytic lymphohistiocytosis55 These disorders typi-cally present in early childhood result in chronic progressivedisease often involving increasing spasticity intracranial calcifi-cations andmicrocephaly and are associatedwith persistentCSFimmune activation55 These syndromes are distinguished fromAE by the presence of non-neurologic features such as skinlesions cytopenias hepatosplenomegaly and lung disease55

Finally neuropsychiatric symptoms are common in pediatricAE and are also the hallmark of primary psychiatric disordersDelusions hallucinations reduced speech sleep disturbanceand cognitive difficulties may be seen in both disease groupsFeatures that distinguish patients with AE from those withpsychiatric disease include autonomic instability hyperkinesiadyskinesia rapid progression of psychosis despite therapyseizures slowing or epileptic activity on EEG CSF pleocytosisCSF oligoclonal bands and MRI abnormalities56

DiscussionProposed pediatric AE criteria are intended to address differ-ences in clinical presentations paraclinical findings and auto-antibody profiles between children and adults Theaccompanying algorithm aims to guide diagnostic workup andfacilitate earlier initiation of therapy

Study fundingThere was no external funding for this manuscript

DisclosureThe authors have no conflicts of interest relevant to this articleto disclose with the exception of Dr Dalmau being the editorof Neurology Neuroimmunology amp Neuroinflammation Go toNeurologyorgNN for full disclosures


Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationJuly 31 2019 Accepted in final form November 25 2019

References1 Van Mater H Pediatric inflammatory brain disease a diagnostic approach Curr Opin

Rheumatol 201426553ndash5612 Dalmau J Graus F Antibody-mediated encephalitis N Engl J Med 2018378

840ndash8513 Dalmau J Geis C Graus F Autoantibodies to synaptic receptors and neuronal cell-

surface proteins in autoimmune diseases of the central nervous system Physiol Rev201797839ndash887

4 Hacohen Y Wright S Waters P et al Paediatric autoimmune encephalopathiesclinical features laboratory investigations and outcomes in patients with or withoutantibodies to known central nervous system autoantigens J Neurol Neurosurg Psy-chiatry 201384748ndash755

5 Titulaer MJ McCracken L Gabilondo I et al Treatment and prognostic factors forlong-term outcome in patients with anti-NMDA receptor encephalitis an observa-tional cohort study Lancet Neurol 201312157ndash165

6 Armangue T Titulaer MJ Malaga I et al Pediatric anti-N-methyl-D-aspartate re-ceptor encephalitis ndash clinical analysis and novel findings in a series of 20 patientsJ Pediatr 201312157ndash165

7 Florance NR Davis RL LamC et al Anti-N-methyl-D-aspartate receptor (NMDAR)encephalitis in children and adolescents Ann Neurol 20096611ndash18

8 Probstel AK Dornmair K Bittner R et al Antibodies to MOG are transient inchildhood acute disseminated encephalomyelitis Neurology 201177580ndash588

9 Brilot F Dale RC Selter RC et al Antibodies to native myelin oligodendrocyteglycoprotein in children with inflammatory demyelinating central nervous systemdisease Ann Neurol 200966833ndash842

10 Malter MP Helmstaedter C Urbach H Vincent A Bien CG Antibodies to glutamicacid decarboxylase define a form of limbic encephalitis Ann Neurol 201067470ndash478

11 Mishra N Rodan LH Nita DA et al Anti-glutamic acid decarboxylase antibodyassociated limbic encephalitis in a child expanding the spectrum of pediatric in-flammatory brain diseases J Child Neurol 201429677ndash683

12 Gresa-Arribas N Arinos H Martinez-Hernandez E et al Antibodies to inhibitorysynaptic proteins in neurological syndromes associated with glutamic acid decar-boxylase autoimmunity PLoS One 201510e0121364

13 Dale RC Merheb V Pillai S et al Antibodies to surface dopamine-2 receptor inautoimmune movement and psychiatric disorders Brain 20121353453ndash3468

14 Petit-Pedrol M Armangue T Peng X et al Encephalitis with refractory seizuresstatus epilepticus and antibodies to the GABAA receptor a case series character-ization of the antigen and analysis of the effects of antibodies Lancet Neurol 201413276ndash286

15 Spatola M Petit-Pedrol M Simabakuro MM et al Investigations in GABAA receptorantibody-associated encephalitis Neurology 2017881012ndash1020

16 Lancaster E Lai M Peng X et al Antibodies to the GABAB receptor in limbicencephalitis with seizures case series and characterization of the antigen LancetNeurol 2010967ndash76

17 Hoftberger R Titulaer MJ Sabater L et al Encephalitis and GABAB receptor anti-bodies novel findings in a new case series of 20 patients Neurology 2013811500ndash1506

18 Damasio J Leite MI Coutinho E et al Progressive encephalomyelitis with rigidityand myoclonus the first pediatric case with glycine receptor antibodies JAMANeurol201370498ndash501

19 Carvajal-Gonzalez A Leite MI Waters P et al Glycine receptor antibodies in PERMand related syndromes characteristics clinical features and outcomes Brain 20141372178ndash2192

20 Lancaster E Martinez-Hernandez E Titulaer MJ et al Antibodies to metabotropicglutamate receptor 5 in the Ophelia syndrome Neurology 2011771698ndash1701

21 Spatola M Sabater L Planaguma J et al Encephalitis with mGluR5 antibodiessymptoms and antibody effects Neurology 201890e1964ndashe1972

22 Suleiman J Dale RC The recognition and treatment of autoimmune epilepsy inchildren Dev Med Child Neurol 201557431ndash440

23 Armangue T Petit-Pedrol M Dalmau J Autoimmune encephalitis in children J ChildNeurol 2012271460ndash1469

24 Nosadini M Mohammad SS Ramanathan S Brilot F Dale RC Immune therapy inautoimmune encephalitis a systematic review Expert Rev Neurother 2015151391ndash1419

25 Breese EH Dalmau J Lennon VA Apiwattanakul M Sokol DK Anti-N-methyl-D-aspartate receptor encephalitis early treatment is beneficial Pediatr Neurol 201042213ndash214

Appendix Authors

Name Location Role Contribution

TaniaCellucciMD MScCH

McMasterUniversityHamilton ONCanada

Author Conceptualized anddesigned the studydrafted theinitial manuscriptand reviewedand revisedthe manuscript

HeatherVan MaterMD MSc

Duke UniversityDurham NC

Author Conceptualizedand designed thestudy and reviewedand revisedthe manuscript

FrancescGraus MDPhD

InstitutdrsquoInvestigacionsBiomediquesAugust Pi I SunyerBarcelona Spain

Author Conceptualized anddesigned the studyand reviewed andrevised themanuscript

Eyal MuscalMD MS

Baylor College ofMedicine HoustonTX

Author Conceptualizedand designed thestudy and reviewedand revised themanuscript

WilliamGallentineDO

StanfordUniversity PaloAlto CA

Author Conceptualizedand designed thestudy andreviewed andrevised themanuscript

Marisa SKlein-GitelmanMD MPH

NorthwesternUniversity FeinbergSchool of MedicineChicago IL


Susanne MBenselerMD PhD

University ofCalgary AlbertaCanada


JenniferFrankovichMD MS



Mark PGormanMD

Harvard UniversityBoston MA


Keith VanHaren MD



JosepDalmauMD PhD


Author Conceptualizedand designedthe study andreviewed andrevised themanuscript

Appendix (continued)


Russell CDaleMBChBMSc PhD

University ofSydney New SouthWales Australia



26 Byrne S Walsh C Hacohen Y et al Earlier treatment of NMDAR antibody en-cephalitis in children results in a better outcome Neurol Neuroimmunol Neuro-inflamm 20152e130 doi 101212NXI0000000000000130

27 Graus F Titulaer MJ Balu R et al A clinical approach to diagnosis of autoimmuneencephalitis Lancet Neurol 201615391ndash404

28 Venkatesan A Tunkel AR Bloch KC et al Case definitions diagnostic algorithmsand priorities in encephalitis consensus statement of the International EncephalitisConsortium Clin Infect Dis 2013571114ndash1128

29 Goldberg EM Titulaer M de Blank PM Sievert A Ryan N Anti-N-methyl-D-aspartate receptor-mediated encephalitis in infants and toddlers case report andreview of the literature Pediatr Neurol 201450181ndash184

30 Glaser CA Gilliam S Schnurr D et al In search of encephalitis etiologies diagnosticchallenges in the California Encephalitis Project 1998-2000 Clin Infect Dis 200336731ndash742

31 Granerod J Ambrose HE Davies NW et al Causes of encephalitis and differences intheir clinical presentations in England a multicentre population-based prospectivestudy Lancet Infect Dis 201010835ndash844

32 Gable MS Sheriff H Dalmau J et al The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in youngindividuals enrolled in the California Encephalitis Project Clin Infect Dis 2012 54899ndash904

33 Kothur K Wienholt L Mohammad SS et al Utility of CSF cytokinechemokines asmarkers of active intrathecal inflammation comparison of demyelinating anti-NMDAR and enterviral encephalitis PLoS One 2016 11e0161656

34 Armangue T Spatola M Vlagea A et al Frequency symptoms risk factors andoutcomes of autoimmune encephalitis after herpes simplex encephalitis a prospectiveobservational study and retrospective analysis Lancet Neurol 201817760ndash772

35 Probasco JC Solnes L Nalluri A et al Abnormal brain metabolism on FDG-PETCTis a common early finding in autoimmune encephalitis Neurol NeuroimmunolNeuroinflamm 20174e352 doi 101212NXI0000000000000352

36 Solnes LB Jones KM Rowe SP et al Diagnostic value of 18F-FDG PETCT versusMRI in the setting of antibody-specific autoimmune encephalitis J Nucl Med 2017581307ndash1313

37 Venkateswaran S Hawkins C Wassmer E Diagnostic yield of brain biopsies inchildren presenting to neurology J Child Neurol 200823253ndash258

38 Hara M Martinez-Hernandez E Arintildeo H et al Clinical and pathogenic significance ofIgG IgA and IgMantibodies against theNMDA receptor Neurology 201890e1386ndash94

39 Irani SR Alexander SWaters P et al Antibodies toKv1 potassium channel-complex proteinsleucine-rich glioma inactivated 1 protein and contactin-associated protein-2 in limbic en-cephalitis Morvanrsquos syndrome and acquired myotonia Brain 20101332734ndash2748

40 Hacohen Y Singh R Rossi M et al Clinical relevance of voltage-gated potassiumchannelndashcomplex antibodies in children Neurology 20155967ndash975

41 Lopez-Chiriboga AS Klein C Zekeridou A et al LGl1 and CASPR2 neurologicalautoimmunity in children Ann Neurol 201884473ndash480

42 Hacohen Y Wong YY Lechner C et al Disease course and treatment responses inchildren with relapsing myelin oligodendrocyte glycoprotein antibody-associateddiseases JAMA Neurol 201875478ndash487

43 Ho ACC Mohammad SS Pillai SC et al High sensitivity and specificity in proposedclinical diagnostic criteria for anti-N-methyl-D-aspartate receptor encephalitis DevMed Child Neurol 2017591256ndash1260

44 Baumann M Sahin K Lechner C et al Clinical and neuroradiological differences ofpaediatric acute disseminating encephalomyelitis with and without antibodies to themyelin oligodendrocyte glycoprotein J Neurol Neurosurg Psychiatry 201586265ndash272

45 Matesanz S Kotch C Perrone C et al Expanding the MOG phenotype brainstemencephalitis with punctate and curvilinear enhancement Neurol NeuroimmunolNeuroinflamm 20196e619 doi 101212NXI0000000000000619

46 Budhram A Mirian A Le C et al Unilateral cortical FLAIR-hyperintense lesions inanti-MOG-associated encephalitis with seizures (FLAMES) characterization ofa distinct clinico-radiographic syndrome J Neurol 20192662481ndash2487

47 Patterson K Iglesias E Nasrallah M et al Anti-MOG encephalitis mimicking smallvessel CNS vasculitis Neurol Neuroimmunol Neuroinflamm 20196e538 doi 101212NXI0000000000000538

48 Haberlandt E Bast T Ebner A et al Limbic encephalitis in children and adolescentsArch Dis Child 201196186ndash191

49 Mamoudjy N Korff C Maurey H et al Hashimotorsquos encephalopathy identificationand long-term outcome in children Eur J Paediatr Neurol 201317280ndash287

50 Laurent C Capron J Quillerou B et al Steroid-responsive encephalopathy associatedwith autoimmune thyroiditis (SREAT) characteristics treatment and outcome in 251cases from the literature Autoimmun Rev 2016151129ndash1133

51 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756

52 Saitoh M Kobayashi K Ohmori I et al Cytokine-related and sodium channelpolymorphism as candidate predisposing factors for childhood encephalopathyFIRESAERRPS J Neurol Sci 2016368272ndash276

53 Chang K Frankovich J Cooperstock M et al Clinical evaluation of youth withpediatric acute-onset neuropsychiatric syndrome (PANS) recommendations fromthe 2013 PANS Consensus Conference J Child Adolesc Psychopharmacol 2015253ndash13

54 Swedo SE Frankovich J Murphy TK Overview of treatment of pediatric acute-onsetneuropsychiatric syndrome J Child Adolesc Psychopharmacol 201727562ndash565

55 Crow YJ Chase DS Lowenstein Schmidt J et al Characterization of human diseasephenotypes associated with mutations in TREX1 RNASEH2A RNASEH2BRNASEH2C SAMHD1 ADAR and IFIH1 Am J Med Genet A 2015167A296ndash312

56 Herken J Pruss H Red flags clinical signs for identifying autoimmune encephalitis inpsychiatric patients Front Psychiatry 2017825


DOI 101212NXI000000000000066320207 Neurol Neuroimmunol Neuroinflamm

Tania Cellucci Heather Van Mater Francesc Graus et al Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

This information is current as of January 17 2020

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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

Autoimmune encephalitis (AE) refers to an increasingly rec-ognized group of inflammatory brain diseases Children withAE present with acute or subacute onset of neuropsychiatricsymptoms due to an underlying abnormal immune responseto the CNS12 Many AE associate with antibodies directedtoward extracellular antigens such as synaptic receptors andion channels23 Autoantibodies that bind to extracellularantigens are generally pathogenic whereas antibodies thatbind intracellular antigens are not considered pathogenicinstead general markers of autoimmunity

A number of different antibodies have been described inchildren with AE4ndash21 Currently the most common auto-antibodies in children target the N-methyl-D-aspartate re-ceptor (NMDAR) myelin oligodendrocyte glycoprotein(MOG) and glutamic acid decarboxylase 65 (GAD65)5ndash12 Itis also recognized that not all children with a clinical pheno-type of AE have a known autoantibody14

Diagnosing AE is challenging because of overlap in clinical pre-sentations between the types of AE other inflammatory braindiseases infections metabolic diseases and psychiatric disorders1

It is especially difficult in children because of the complexity of

normal behavioral changes during childhood and the limited ca-pacity of younger children to describe their symptoms1 Comparedto adults with AE children may manifest important differences insymptoms paraclinicalfindings comorbidities treatment responseand prognosis4ndash722ndash24 There is an urgent need to recognize pe-diatric AE because treatment delays worsen prognosis and increasethe risk of permanent neurocognitive deficits62526

In this article we build on existing consensus criteria for adult AEby refining them for use in children27 We propose provisionalpediatric AE classification criteria and an algorithm to facilitate earlydiagnosis Diagnosing AE is based on the combination of a clinicalhistory consistent with the disease and supportive diagnostic test-ing which includes but is not dependent on antibody testing Wealso discuss the differential diagnosis in childrenwith suspectedAE

MethodologyAt the 2014 Autoimmune Encephalitis Alliance (AEallianceorg)conference in North Carolina the Autoimmune EncephalitisInternational Working Group was formed and initiated dis-cussions around developing diagnostic criteria for AE A sub-committee of pediatric neurologists and rheumatologists

GlossaryAE = autoimmune encephalitis Caspr2 = contactin-associated protein-like 2 FIRES = febrile infection-related epilepsysyndrome GABAAR = gamma-aminobutyric acid A receptor GAD65 = glutamic acid decarboxylase 65 HE = Hashimotoencephalopathy LGI1 = leucine-rich glioma-inactivated protein 1MOG = myelin oligodendrocyte glycoprotein NMDAR =N-methyl-D-aspartate receptor PANDAS = pediatric autoimmune neuropsychiatric disorders associated with streptococcalinfections PANS = pediatric acute-onset neuropsychiatric syndrome VGKCC = voltage-gated potassium channel complex



























Serum lactate





















91415







GAD6510212






MOG894245ndash47






NMDAR5ndash7


















GABAA receptor1415






GABA-B receptor1617












m-GluR52021

















PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints





























Serum lactate





















91415







GAD6510212






MOG894245ndash47






NMDAR5ndash7


















GABAA receptor1415






GABA-B receptor1617












m-GluR52021

















PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints
















Serum lactate





















91415







GAD6510212






MOG894245ndash47






NMDAR5ndash7


















GABAA receptor1415






GABA-B receptor1617












m-GluR52021

















PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints





91415







GAD6510212






MOG894245ndash47






NMDAR5ndash7


















GABAA receptor1415






GABA-B receptor1617












m-GluR52021

















PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints














GABAA receptor1415






GABA-B receptor1617












m-GluR52021

















PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints













PossibleAE




Yes Yes Yes



ge2 featurespresent











ge1 featurespresent







Notavailable

No Yes



Yes Yes Yes





















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints






















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints















Parasites malaria







FIRES

ANE

AESD

PANDAS

PANS


































































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints

























































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints












































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints































Appendix Authors








FrancescGraus MDPhD



Eyal MuscalMD MS



WilliamGallentineDO












Mark PGormanMD



Keith VanHaren MD



JosepDalmauMD PhD






















































Reprints

















































Reprints

















Reprints




Documents

ARTICLE OPEN ACCESS ...is frequently elevated in anti-NMDAR encephalitis and other encephalitides, but normal in PANS.33 There is evidence that AE (particularly anti-NMDAR encephalitis)