ARTICLE OPEN ACCESS

International Consensus Recommendations forthe Treatment of Pediatric NMDAR AntibodyEncephalitisMargherita Nosadini MD PhD Terrence Thomas MD Michael Eyre MD Banu Anlar MD

Thais ArmangueMD PhD SusanneM Benseler MD Tania Cellucci MD FRCPCMScCH KumaranDeiva MD

William Gallentine DO Grace Gombolay MD Mark P Gorman MD Yael Hacohen MD Yuwu Jiang MD

Byung Chan Lim MD Eyal Muscal MD MS Alvin Ndondo MD Rinze Neuteboom MD PhD

Kevin Rostasy MD Hiroshi Sakuma MD Suvasini Sharma MD Silvia Noemi Tenembaum MD

Heather Ann Van Mater MD Elizabeth Wells MD Ronny Wickstrom MD PhD Anusha K Yeshokumar MD

Sarosh R Irani MD PhD Josep Dalmau MD PhD Ming Lim MD PhD and Russell C Dale MD PhD

Neurol Neuroimmunol Neuroinflamm 08e1052 doi101212NXI0000000000001052

Correspondence

Dr Dale

russelldalehealthnswgovau

AbstractObjectiveTo create an international consensus treatment recommendation for pediatric NMDA receptorantibody encephalitis (NMDARE)

MethodsAfter selection of a panel of 27 experts with representation from all continents a 2-step Delphimethod was adopted to develop consensus on relevant treatment regimens and statements alongwith key definitions in pediatric NMDARE (disease severity failure to improve and relapse)Finally an online face-to-face meeting was held to reach consensus (defined as ge75 agreement)

ResultsCorticosteroids are recommended in all children with NMDARE (pulsed IV preferred) withadditional IV immunoglobulin or plasma exchange in severe patients Prolonged first-lineimmunotherapy can be offered for up to 3ndash12 months (oral corticosteroids or monthly IVcorticosteroidsimmunoglobulin) dependent on disease severity Second-line treatmentsare recommended for cases refractory to first-line therapies (rituximab preferred over

From the Paediatric Neurology and Neurophysiology Unit (MN) Department of Womenrsquos and Childrenrsquos Health University Hospital of Padova Neuroimmunology Group (MN)Paediatric Research Institute ldquoCitta della Speranzardquo Padova Italy Department of Paediatrics (TT) Neurology Service KK Womenrsquos and Childrenrsquos Hospital Singapore School ofBiomedical Engineering amp Imaging Sciences (ME) Kingrsquos College London Childrenrsquos Neurosciences (ME) Evelina London Childrenrsquos Hospital at Guyrsquos and St ThomasrsquoNHS FoundationTrust United Kingdom Department of Pediatric Neurology (BA) Hacettepe University Ankara Turkey Neuroimmunology Program (TA) Institut drsquoInvestigacions BiomediquesAugust Pi i Sunyer (IDIBAPS) Hospital Clınic Universitat de Barcelona Pediatric Neuroimmunology Unit (TA) Neurology Department Sant Joan de Deu (SJD) Childrenrsquos HospitalUniversity of Barcelona Spain Alberta Childrenrsquos Hospital Research Institute (SMB) Department of Pediatrics Cumming School of Medicine University of Calgary Division ofRheumatology (TC) Department of Pediatrics McMaster University Hamilton Ontario Canada Assistance Publique-Hopitaux de Paris (KD) Pediatric Neurology DepartmentUniversity Hospitals Paris Saclay Bicetre Hospital France French Reference Network of Rare Inflammatory Brain and Spinal Diseases (KD) Le Kremlin Bicetre France and EuropeanReference Network-RITA Departments of Neurology and Pediatrics (WG) Stanford University and Lucile Packard Childrenrsquos Hospital Palo Alto CA Division of Pediatric Neurology(GG) Department of Pediatrics Emory University School ofMedicine and Childrenrsquos Healthcare of Atlanta GA Department of Neurology (MPG) Boston Childrenrsquos Hospital HarvardMedical School Boston MA Department of Neuroinflammation (YH) Queen Square MS Centre UCL Institute of Neurology University College London Department of PaediatricNeurology (YH) Great Ormond Street Hospital for Children London United Kingdom Department of Pediatrics (YJ) Peking University First Hospital Beijing China Department ofPediatrics (BCL) Pediatric Clinical Neuroscience Center Seoul National University Childrenrsquos Hospital Seoul National University College of Medicine South Korea Department ofPediatrics (EM) Section Rheumatology Co-appointment in the Section of Neurology and Developmental Neuroscience Texas Childrenrsquos Hospital Baylor College of MedicineHouston Division of Paediatric Neurology (AN) Department of Paediatrics and Child Health Red Cross War Memorial Childrenrsquos Hospital University of Cape Town Faculty of HealthSciences (AN) University of Cape Town Neuroscience Institute South Africa Department of Neurology (RN) Erasmus Medical Center Rotterdam the Netherlands Department ofPediatric Neurology (KR) Childrenrsquos Hospital Datteln University WittenHerdecke Germany Department of Brain and Neural Science (HS) Tokyo Metropolitan Institute of MedicalScience Japan Department of Pediatrics (NeurologyDivision) (SS) LadyHardingeMedical College and Associated Kalawati Saran Childrenrsquos Hospital NewDelhi India Department ofNeurology (SNT) National Pediatric Hospital Dr J Garrahan Buenos Aires Argentina Department of Pediatrics (HAVM) Duke University Durham NC Department of Neurology(EW) Childrenrsquos National Medical Center Washington DC Neuropaediatric Unit (RW) Karolinska University Hospital Stockholm Sweden Department of Neurology (AKY) IcahnSchool of Medicine at Mount Sinai New York Oxford Autoimmune Neurology Group (SRI) Nuffield Department of Clinical Neurosciences University of Oxford John RadcliffeHospital Department of Neurology (SRI) Oxford University Hospitals NHS Foundation Trust United Kingdom Neuroimmunology Program (JD) Institut drsquoInvestigacions Bio-mediques August Pi i Sunyer (IDIBAPS) Hospital Clınic University of Barcelona Spain Department of Neurology (JD) University of Pennsylvania Philadelphia Institucio Catalana deRecerca i Estudis Avanccedilats (ICREA) (JD) Barcelona Spain Childrenrsquos Neurosciences (ML) Evelina London Childrenrsquos Hospital at Guyrsquos and St Thomasrsquo NHS Foundation Trust KingrsquosHealth Partners Academic Health Science Centre (ML) Faculty of Life Sciences and Medicine (ML) Kingrsquos College Hospital United Kingdom and Kids Neuroscience Centre (RCD)The Childrenrsquos Hospital at Westmead Faculty of Medicine and Health University of Sydney NSW Australia

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

The Article Processing Charge was funded by Wellcome Trust

This is an open access article distributed under the terms of the Creative Commons Attribution License 40 (CC BY) which permits unrestricted use distribution and reproduction in anymedium provided the original work is properly cited

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

cyclophosphamide) and should be considered about 2 weeks after first-line initiation Further immunotherapies for refractorydisease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and esca-lation to tocilizumab Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolatemofetil) is generally not required except for patients with a more severe course or prolonged impairments and hospitalizationFor patients with relapsing disease second-line and prolonged maintenance therapy should be considered The treatment ofNMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE Broad guidance is provided for thetotal treatment duration (first line second line and maintenance) which is dictated by the severity and clinical course(ie median 3 9 and 18 months in the best average and worst responders respectively) Recommendations on the timing ofoncologic searches are provided

ConclusionThese international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatmentand provide practical guidance for clinicians rather than absolute rules A similar recommendation could be applicable to adultpatients

NMDA receptor antibody encephalitis (NMDARE) is one ofthe most common autoimmune encephalitides characterizedby a recognizable constellation of neurologic and psychiatricfeatures alongside positive NMDAR antibodies12 NMDAREmostly affects children and young adults particularly femalesIt may be very severe in the acute phase with a mortality ofabout 5 relapses occur in about 15 of patients and thefinal physician-assessed functional outcome is generally fa-vorable although neuropsychological and psychiatric se-quelae are relatively common23

The use of immunotherapies has been shown to improveoutcomes24-6 especially with early administration2467 In ad-dition immunotherapies reduce the risk of relapses289 How-ever several aspects of treatment remain incompletely clarifiedand treatment strategies are still heterogeneous especially withregard to second-line and long-term immunotherapies1011 In-deed although a number of reviews have been published12-18 norandomized controlled trials or consensus guidelines for thetreatment of NMDARE are available

With support from the Autoimmune Encephalitis Alliance weaimed to create a consensus recommendation for the treatmentof pediatric NMDARE which was pragmatic and relevant to aglobal community and could serve as a practical decision supporttool for the clinician confronted with this rare and challengingcondition Notably the present document is intended as a rec-ommendation guideline rather than absolute rules given thelimited evidence supporting most treatment statements Al-though this document is focused on immunotherapy and to someextent symptomatic management there are multiple outstandingissues in the management of pediatric NMDARE such as edu-cation around the diagnosis and rehabilitation of patients after theacute phase which are beyond the scope of this current article

MethodsEstablishment of a Consensus Expert PanelA steering committee (RCD ML TT MN and ME)carefully selected a panel of 27 experts with representation fromall continents (later referred to as ldquothe Panelrdquo) and based on theindividual (1) being a specialist (usually pediatric neurologist orrheumatologist) with clinical andor research expertise in pe-diatric NMDARE these experts were identified as lead clinicalresearchers in the field based on the systematic review con-ducted before the consensus recommendations project (paperin preparation) or were nominated by national child neurologysocieties (2) having a publication track record in the field ofpediatric autoimmune encephalitisCNS disease (3) beingcommitted to completing 2 Delphi studies (approximately 45minutes each)1920 and participating in a 2-hour face-to-faceonline meeting to reach consensus The 27 experts were pedi-atric neurologists (n = 23) or pediatric rheumatologists (n = 4)from North America (n = 9) South America (n = 1) Europe(n = 9) Asia (n = 6) Oceania (n = 1) and Africa (n = 1) Inaddition patient representatives (parents n = 2) a member ofthe Autoimmune Encephalitis Alliance (n = 1) and adultneurology experts in NMDARE (n = 2 JD and SRI) wereinvited to provide input in the later stages of the process

Delphi MethodA 2-step Delphi method was adopted to develop the con-sensus of relevant statements similar to the method used bythe European League Against Rheumatism21 A documentwith key definitions in pediatric NMDARE (disease severityfailure to improve and relapse) used in the Delphi statementswas shared online with the Panel (January 2020) before thefirst Delphi questionnaire A revised version of the modifiedRankin Scale22 was used to be more applicable in children

GlossaryHSE = herpes simplex virus encephalitis IQR = interquartile range IgG = immunoglobulin G IVIg = IV immunoglobulinNMDARE = NMDA receptor antibody encephalitis TPE = therapeutic plasma exchange

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Table 1 Definitions Used in the Consensus Recommendations for the Treatment of Pediatric NMDAR AntibodyEncephalitis (NMDARE) (Tables 2 and 3)

Key definitions in pediatric NMDARE Agree (numbervoting)a

11 Disease severity

Severe is defined by issues affecting SAFETY and FUNCTION Any (ge1) of the severity markers present below (items a-i) scoring ldquosevererdquorather than ldquostandardrdquo would classify as severe disease

Severity and function markers 96 (24)

Markers Score severe Score standard

a Safety Intensive care None of

Airway support

Dysautonomia threatening safety

b Mobility Bed bound Not bed bound

Movement disorder resulting in potential for injury

c Nursing care 247 support for safety 247 care not required(developmental equivalence)

1 on 1 nurse or parent required for safety

d Psychiatry Suicidal thoughts Psychiatric symptoms are notimmediate compromise to safety

Dangerous impulse control issues (risk of injury)

Self-injurious behavior

e Self-care Unable to self-care requiring complete assistance(toileting dressing and feeding)

Able to self-care (with someassistance or not)

f Communication Unable to communicate to make themselvesunderstood (including confusion and mutismaphasia)

Able to communicate and makeneeds understood

g Alertness Unresponsive to the immediate environment blankstaringsevere catatonia

Generally able to attend to events inthe immediate environment

h Epilepsy Frequent requirement for rescue medication toterminate seizures

Seizures not requiring interventionwith rescue medication

i Adapted mRS score Adapted mRS score 4ndash5 Adapted mRS score 0ndash3

Adapted modified Rankin Scale (mRS) score 100 (23)

Score Description Comments

0 No symptoms mdash

1 Nondisabling symptoms that do not interfere withthe daily activity and playinglearning habits of thechild

Playinglearning habits includesattending school or kindergarten

2 Minor symptoms that lead to some restriction indaily activity and playinglearning habits of the childbut do not interfere with the age-appropriate basicfunctions

Basic functions drinking eatingdressing undressing combingwashing and bathing

Symptoms may include minorphysical cognitive andorrelational symptoms

3 Moderate symptoms that significantly interfere withthe daily activity and playinglearning habits orprevent total independence in age-appropriate basicfunctions

Basic functions and symptoms asabove

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 3

The first Delphi questionnaire (Delphi 1 eAppendix 1linkslwwcomNXIA530) included key statements onthe treatment of pediatric NMDARE which were createdbased on the steering committeersquos clinical practice and theavailable literature and was sent out to the Panel in Feb-ruary 2020 using a web-based survey tool (SurveyMonkeycom) The Panel members were asked to vote on eachstatement of the first Delphi questionnaire according to a5-point Likert scale (strongly agreeagreeneither agreenor disagreedisagreestrongly disagree) and provide opentext comments as appropriate Consensus was definedas an agreement by at least 75 of the participants(ie ge75 agreestrongly agree or ge75 disagreestronglydisagree)

Twenty-six of 27 experts completed Delphi 1 then thestatements were revised according to the Panelrsquos responsesand comments and statements that reached consensus werecollated into a second Delphi document (Delphi 2) In thissecond Delphi survey time durations were added (ie totalduration of immunotherapy in NMDARE or timing oftreatment escalation) and median interquartile range(IQR) and range were calculated The Delphi 2 statementswere shared with 2 adult experts (JD and SRI) with theAutoimmune Encephalitis Alliance representative and familyrepresentatives for further input Delphi 2 was completedby 26 of the 27 experts by online survey in May 2020(eAppendix 1 linkslwwcomNXIA530) and final draftedrecommendations were created

Face-to-Face MeetingThe drafted recommendations were then voted on during a2-hour online consensus meeting via the platform Zoom(zoomus) on November 3 2020 and included 26 partici-pants from the expert Panel with representatives from allcontinents Each recommendation was voted on via theplatform slido with the outcomes agree do not agree orabstain The definitions used in the recommendations and thedrug regimens were also voted on for consensus As beforeconsensus was defined as an agreement by at least 75 of theparticipants

The number of voters varied (22-26 panelists) for the state-ments due to connectivity issues during the meeting Thestatements that reached consensus were collated and arepresented

Data AvailabilityThe Delphi questionnaires used to create the consensus-based recommendations for the treatment of pediatricNMDARE are provided in eAppendix 1 (linkslwwcomNXIA530)

ResultseAppendix 1 (linkslwwcomNXIA530) provides the Del-phi 1 and Delphi 2 questionnaires and answers Only finalrecommendations that reached consensus at the final face-to-

Table 1 Definitions Used in the Consensus Recommendations for the Treatment of Pediatric NMDAR AntibodyEncephalitis (NMDARE) (Tables 2 and 3) (continued)

4 Moderately severe symptoms that clearly preventindependence in basic functions as would beappropriate for age although the patient does notneed a constant attention

Basic functions and symptoms asabove

5 Severely disabled totally dependent and requiresconstant attention

Bed bound may have impairedconsciousness agitationdysautonomia and severemovement disorder

6 Dead mdash

12 Failure to improve 92 (24)

During the clinical course a ldquofailure to improverdquo(required to determine need for escalation oftherapy) is defined as failure to achievesignificant gains in function

13 Relapse 96 (25)

Returnof previous resolved symptoms and signsor appearance of new symptoms or signsassociated with change in function lastingmorethan 1wk (or shorter if associatedwith change insafety) that cannot be explained by adversereactions to current medications or intercurrentillness after a period of stability or improvementof at least 1 mo

a The agreement percentage shown in the last column refers to the final face-to-face agreement the Delphi 1 and 2 agreement percentages are shown ineAppendix 1 (linkslwwcomNXIA530)

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Table 2 Consensus-Based Recommendations on the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis(NMDARE) General Principles (21) First-Line Immunotherapy (22) Second-Line Immunotherapy (23)Maintenance Immune Suppression (24) and Overall Duration of Immunotherapy (25)

Statements reaching consensusAgree (numbervoting)a

21 General principles in pediatric NMDARE

211 The management of children with NMDARE should ideally be guided by a pediatric neurology team in a center withmultidisciplinary expertise in NMDARE

100 (26)

212 Priorities are to make an accurate and early diagnosis (exclude alternative diagnoses) initiate appropriate andtimely treatment manage symptoms and complications support recovery identify and treat ongoing sequelae andpreventtreat relapses

100 (24)

213 All treatment recommendations are subject to absence of contraindications local experience and availability anddiscussion and approval by family

100 (25)

214 Appropriate management of pediatric NMDARE includes accurate communication and updates with the familyespecially regarding suspected diagnosis uncertainty in treatment responses need for symptomatic treatment aswell asimmunotherapy and challenges in the clinical course

100 (24)

22 First-line immunotherapy at first event of pediatric NMDARE

221 First-line immunotherapy should be offered to all childrenwithNMDARE unless they are already back to baseline atthe time of diagnosis (ie late diagnosis or rapid improvement and remission)

100 (25)

222 If NMDARE is suspected immunotherapy should be started promptly even before antibody results are available ifalternative diagnoses have been reasonably excluded (ie infectious encephalitis)

100 (25)

223 IV corticosteroids should be the first immunotherapy used (ie IV methylprednisolone IVMP) If IV corticosteroidsare not available or are contraindicated oral corticosteroids (prednisone OP or dexamethasone DEX) should be used

96 (25)

224 Oral prednisone oral DEX pulses or IVMP pulses can be given as an extended taper following an initial course ofIVMP depending on severity treatment response and adverse reactions

96 (25)

225 Therapeutic plasma exchange (TPE) should be strongly considered in patients with severe disease TPE shouldprecede IV immunoglobulin (IVIg) if both are used

84 (25)

226 IVIg should be part of the first-line immunotherapy options for all children especially in severe disease and can begiven with corticosteroids at diagnostic suspicion

88 (25)

227 In a child who has only received one first-line immunotherapy and who has severe disease or is failing to improveafter 1wk postinitiation of corticosteroids another first-line immunotherapy (ie corticosteroids + TPE or corticosteroids+ IVIg) should be considered

96 (25)

228 In patients who are failing to improve approximately 2 wk after initiation of 2 or more first-line therapies second-line therapy is favored over further first-line therapies

92 (25)

229 Prolonged first-line immunotherapy can be offered for up to 3ndash12mo depending on severity and improvement (ieespecially in countries without access to second-line therapies)Prolonged first-line immunotherapy corticosteroids (OP monthly IVMP and oral DEX pulses) andor 3ndash4 weekly IVIg (regardless ofinitiation of second line)

92 (24)

23 Second-line immunotherapy at first event of pediatric NMDARE

231 Second-line immunotherapy should be offered to patients with severe disease 96 (25)

232 Rituximab (RTX) is generally the second-line therapy of choice Cyclophosphamide (CYC) may be considered if RTX iscontraindicated or not available

100 (25)

233 Another second-line therapy (ie CYC if RTX was used first or vice versa) can be used in any patient with severedisease who fails to improve adequately 1ndash3 mo following initiation of the first second-line immunotherapy

96 (25)

234 Escalation to IV tocilizumab should be considered only in the most refractory patients who fail to improveadequately after about 1ndash3 mo of treatment with RTX andor CYC

80 (25)

24 Maintenance (gt6 mo) immune suppression with mycophenolate mofetil (MMF) or RTX redosing after first event of pediatric NMDARE

241 In general maintenance immune suppression beyond 6 mo is not typically required 88 (24)

242Maintenance (gt6mo) immune suppression can be considered in any patientwho fails to improve adequately despiteconventional second-line or escalation therapy

96 (25)

243 RTX redosing (when repopulation of CD19 occurs) and MMF are appropriate treatments if maintenance (gt6 mo)immune suppression is required

96 (25)

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 5

face meeting are presented in Tables 1ndash4 and the FigureTable 1 shows the key definitions in pediatric NMDARE(disease severity failure to improve and relapse) whichreached consensus support In addition to aid clinicians withless experience in the management of NMDARE definitionsfor best average and poorest responders are described (Table5) Tables 2 and 3 show the recommendations for the treat-ment of pediatric NMDARE and are subdivided into generalmanagement principles (Table 2 21) treatment of first en-cephalitis event including first-line second-line and mainte-nance immunotherapy (Table 2 22ndash24) overall duration ofimmunotherapy at first event (Table 2 25) treatment atrelapse (Table 3 31) treatment of NMDARE triggered bypreceding herpes simplex virus encephalitis (HSE) (Table 332) symptomatic treatments (Table 3 33) and oncologicsearches (Table 3 34) Table 4 shows the recommendationsfor immunotherapy doses and regimens23-25 The Figureprovides a therapeutic pathway for guidance

DiscussionEvidence on treatment of NMDARE is restricted to retro-spective and some prospective descriptive studies Noconsensus-based treatment guidelines have previously beenproposed Hence our purpose was to create internationalconsensus-based recommendations for the treatment of pedi-atric NMDARE with expertise from an international group ofclinical and academic pediatric neurologists and rheumatolo-gists Our vision was to have a global approach with applicabilityacross all health care settings therefore the expert Panel in-cluded representatives from all continents We also wanted thisdocument to be useful for clinicians less experienced in thetreatment of autoimmune encephalitis hence a practical anddetailed approach was adopted wherever possible including

definitions of failure to respond and timing of treatment esca-lation Indeed although the management of pediatricNMDARE should ideally be guided by a pediatric neurologyteam in a center with multidisciplinary expertise in NMDAREthis may not always be possible particularly in the acute phaseof the disease

Our recommendations begin with general management princi-ples highlighting the importance of early diagnosis and carefulcommunication with the family (Table 2 21) The importance ofraising awareness of this disorder which may present to psychi-atrists and emergency physicians as well as neurologists cannot beoveremphasized and the diagnostic criteria26 andmodification forchildren27 along with the distinctive clinical characteristics122829

may aid an expeditious diagnosis Similarly families need to beinformed of the expected or potential disease evolution thetreatment possibilities and the often long and demanding courseof the illness Understanding the timeline of the disease and thespeed of recovery is one of the greatest challenges of this diseaseand it is essential for clinicians and family members to appreciatethat the typical course is of little change (or worsening) in thefirst weeks and slow improvements in the followingmonths andimprovements may continue into the second year

As regards first-line immunotherapy (Table 2 22) there wasconsensus that corticosteroids are the first agent to be used inpediatric NMDARE with IV use (ie IV methylprednisolone)preferred over oral use (ie oral prednisone) although high-doseoral administration of corticosteroids is a good alternative par-ticularly if IV access is a problem In high-income countriestherapeutic plasma exchange (TPE) andor IV immunoglobulin(IVIg) are often used in conjunction with corticosteroids30 Al-though some physicians use TPE or IVIg at the same time ascorticosteroids other administer them sequentially with more

Table 2 Consensus-Based Recommendations on the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis(NMDARE) General Principles (21) First-Line Immunotherapy (22) Second-Line Immunotherapy (23)Maintenance Immune Suppression (24) and Overall Duration of Immunotherapy (25) (continued)

Statements reaching consensusAgree (numbervoting)a

244 Prolonged first-line therapy (with IVMP DEX and IVIG) can be used as an alternative form of maintenance (gt6 mo)immunotherapy if RTX and mycophenolate are not available (ie in countries without access to other maintenanceimmunotherapies)

96 (25)

25 Overall duration of immunotherapy during first event of pediatric NMDARE

251 In the absence of clinical relapse the overall duration of total immunotherapy (including all first line second lineand maintenance ie IVMP to completion of MMF or to B-cell repopulation after RTX) depends on the severity of theclinical picture the response to first- and second-line or escalation immunotherapy and treatment adverse reactionsAs a guidelinebcbull Median 3 mo (IQR 3ndash6 mo range 1ndash18 mo) in the best responders (without relapse or adverse reactions)bull Median 9 mo (IQR 6ndash12 mo range 1ndash24 mo) in the average responders (without relapse or adverse reactions)bull Median 18 mo (IQR 12ndash24 mo range 1ndash25 mo) in the poorest responders (without relapse or adverse reactions)

96 (24)

Abbreviations IQR = interquartile range OP = oral prednisonea The agreement percentage shown in the last column refers to the final face-to-face agreement the Delphi 1 and 2 agreement percentages are shown ineAppendix 1 (linkslwwcomNXIA530)b A general guide toward understanding clinical response in children with NMDARE (in the absence of clinical relapse) and its role in determining the overallduration of total immunotherapy can be found in Table 5c The timelines were voted on during the Delphi process (eAppendix 1)

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 NeurologyorgNN

severe patients often prompting a more aggressive combinedtreatment or rapid escalation TPE was recommended for pa-tients with severe disease although it is recognized that TPE canbe associated with more severe complications (eg central line

Table 3 Consensus-Based Recommendations on theTreatment of Pediatric NMDAR AntibodyEncephalitis (NMDARE) NMDARE Relapse (31)Herpes Simplex Virus Encephalitis Followed byNMDARE (32) Symptomatic Therapies (33) andOncologic Searches (34)

Statements reaching consensusAgree (numbervoting)a

31 Pediatric NMDARE relapse first-line second-line immunotherapyand maintenance (gt6 mo) immune suppression

311 First-line immunotherapy should be offeredto all children with NMDARE relapse even if theyare improving at the time of diagnosis (ie latediagnosis or rapid improvement and remission)First-line immunotherapy and combinations canbe used as per Table 2 22

96 (25)

312 In patients who relapse second-lineimmunotherapy andor maintenance (gt6 mo)immunotherapy (mycophenolate mofetil orrituximab [RTX] redosing) should be consideredstartedwithinmedian 2wkafter initiationof first-line treatment (range 1ndash3 wk)c

100 (25)

313 Although generally only one second-linetreatment is used another second-line treatment(ie cyclophosphamide [CYC] if RTX was usedfirst or vice versa) can be used in patientswho failto improve after relapse

100 (25)

314 In patientswithNMDARE relapse escalationto IV tocilizumab should be considered only in themost refractory patients who fail to improveadequately after about 1ndash3 mo of treatment withRTX andor CYC

84 (25)

315 Duration of maintenanceimmunosuppression in patients with relapseshould be 12ndash24 mo depending on the severity ofthe clinical picture the response to first- andsecond-line immunotherapy the number ofrelapses and treatment adverse reactions

88 (25)

316 If NMDARE relapse occurs while onmaintenance immunosuppression (RTXredosing mycophenolate or prolonged first-line treatment) given for first event prompt first-line immunotherapy should be administered (ieIV methylprednisolone andor therapeuticplasma exchangeIV immunoglobulin)followed by second-line treatment andalternative maintenance immunosuppression

84 (25)

32 Herpes simplex virus encephalitis (HSE) followed by NMDARE inchildren

321 Patients with relapse of neurologicsymptoms after HSE should be given acyclovirpromptly (until HSE can be excluded based onclinical picture and negative CSF herpessimplex virus PCR)whilemaintaining ahigh indexof suspicion for an underlying autoimmuneetiology

84 (25)

322 Patients with NMDARE following HSE shouldbe treated with immunotherapy in a similar wayto those with naive NMDARE

96 (25)

33 Symptomatic therapies for pediatric NMDARE

331 Assessment of improvement followingimmunotherapy (ie failure to improve) iscontingent on optimization of treatments forsleep agitation moodbehavior dyskinesia andseizures

100 (25)

Table 3 Consensus-Based Recommendations on theTreatment of Pediatric NMDAR AntibodyEncephalitis (NMDARE) NMDARE Relapse (31)Herpes Simplex Virus Encephalitis Followed byNMDARE (32) Symptomatic Therapies (33) andOncologic Searches (34) (continued)

Statements reaching consensusAgree (numbervoting)a

332 Use of antipsychotics and management ofpsychiatric symptoms should be undertaken incollaboration with a child psychiatrist It shouldbe remembered that the use of antipsychotics inchildren with NMDARE may be associated with aworsening of dyskinesia or result in neurolepticmalignant syndrome

96 (25)

333 In descending order of recommendationthe following agents can be useful in thesymptomatic management of agitationbenzodiazepines sleep induction agents (chloralhydrate or melatonin) alpha adrenergic agents(clonidine and dexmedetomidine) and atypicalantipsychotics (risperidone olanzapine andquetiapine)d

92 (25)

334 In descending order of recommendationthe following agents can be useful in thesymptomatic management of dyskinesia andstereotypy alpha adrenergic agents (clonidineand dexmedetomidine) benzodiazepinesantiepileptics (valproate carbamazepine andgabapentin) anticholinergic agents and sleepinduction (chloral hydrate or melatonin)d

88 (24)

34 Oncologic searches

341 Tumor searches for ovarian teratoma andother tumors are mandatory in all children withNMDARE should be started early and becompleted in the first days to weeks afteradmission If tumor is found removal is requiredas this can result in rapid improvements

100 (25)

342 Generally recommended tumor searchesinclude the followingOvariantesticular ultrasound andor MRI abdomenand pelvis (in all patients)Urinary catecholamines andor CT or MRI of the chest(in very young patients aged lt5 y)b

It is important to consult oncologists and radiologistsfor best imaging modality to search occult tumors

88 (25)

343 Recommended duration for tumor searches(if no tumor found on initial searches) isbull In patients with good recoveryo Prepubertal females and all males only at diagnosiso Postpubertal females annually up to 2 ybull In all patients who fail to improve adequately orrelapse annually up to 5 y (or at the time of relapse)

92 (26)

a The agreement percentage shown in the last column refers to the finalface-to-face agreement the Delphi 1 and 2 agreement percentages areshown in eAppendix 1 (linkslwwcomNXIA530)b Due to the possible presence of neural crest tumorc The timelines were voted on during the Delphi process (eAppendix 1)d These agents were voted on during the Delphi process (eAppendix 1) Allthe listed agents were supported by different members of the Panel butonly benzodiazepines and sleep induction agents reached 75 consensussupport (eAppendix 1)

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 7

infection) compared with IVIg3132 TPEwas recommended overimmunoadsorption where there is less evidence3334 In generalongoing corticosteroids are continued in the first months ofdisease preferably as pulses or alternatively oral tapers Longer orrepeated IVIg courses may be continued monthly for 3ndash6months depending on severity and availability whereas monthlypulsed oral dexamethasone or IV methylprednisolone or evenACTH for 3-6 months may be used in resource-limited settings

In patients who are failing to improve (definition in Table 1)approximately 2 weeks after initiation of 2 or more first-linetherapies second-line treatment is recommended over furtherfirst-line therapies Second-line treatments are recommendedespecially in patients with severe disease with rituximab nowgenerally preferred over cyclophosphamide (Table 2 23)Rituximab dosing protocols were all equally accepted (Table4) as there are no data to support one protocol over anotherThere is evidence suggesting that use of second-line

immunotherapy improves outcome in patients failing to im-prove after first-line therapy2 and that second-line therapyreduces the risk of relapses8913 Moreover earlier initiation ofrituximab also seems more favorable compared with latetreatment7

The use of second-line immunotherapy is still variable glob-ally and considerably less frequent in some countries Forinstance rituximab use is 0ndash55 in Chinese cohorts35-37

and more variable in India (0ndash61)38-40 although withgenerally favorable outcomes which suggests the outcomesdescribed in the published literature may be affected by re-ferral bias publication bias or ethnic vulnerability to worseoutcomes41 The specific approaches toward the use ofsecond-line immunotherapy varied within the Panel withsome clinicians supporting the use of rituximab in all patientswith NMDARE and others reserving it to cases with severedisease or failure to improve (Table 1) The consensus

Table 4 Treatment Regimens and Doses for Pediatric NMDAR Antibody Encephalitis (NMDARE) (95 Agreement 22VotingmdashFinal Face-to-Face Agreement)

Treatment regimens and doses

Immunotherapies Type of use Dosemode of administration

IVmethylprednisolone

First-line immunotherapy 20ndash30 mgkgd (max 1 gd) for 3ndash5 d

Prolonged first-lineimmunotherapy

20ndash30 mgkgd (max 1 gd) for 1ndash3 d monthly

Oral prednisone First-line immunotherapyalternative to IV corticosteroidsFirst-line immunotherapy taperafter IV corticosteroidsProlonged first-lineimmunotherapy

2 mgkgd (max 60 mgd) for 1 wk then gradually tapered (see main guideline)

Oraldexamethasone

First-line immunotherapyalternative to IV corticosteroids

20 mgm2d (divided into 2 or 3 doses max 12 mg tid) for 3 d

First-line immunotherapy taperafter IV corticosteroidsProlonged first-lineimmunotherapy

20 mgm2d (divided into 2 or 3 doses max 12 mg tid) for 3 d every 3ndash4 wk

Therapeutic plasmaexchange

First-line immunotherapy One course is typically 5ndash7 single or double plasma volume exchanges over 7ndash10 d

IV immunoglobulin First-line immunotherapy 2 gkg over 2ndash5 d

Prolonged first-lineimmunotherapy

1ndash2 gkg over 1ndash2 d monthly

IV rituximab Second-line immunotherapy The following doses are acceptablebull 500ndash1000 mg (500 mg for lt40 kg 1000 mg for gt40 kg) given twice separated by 2 wk orbull 375ndash750 mgm2 (max 1 g) given twice separated by 2 wk orbull 375 mgm2 (max 1 g) weekly for 4 wk

Maintenance (gt6 mo) immunesuppression

Rituximab redosing (same doses as above or reduced dose as per local recommendations)when repopulation of CD19 occurs (or about 6 mo after the first course)

IVcyclophosphamide

Second-line immunotherapy 500ndash1000 mgm2 (max 1500 mg)23ndash25 monthly pulses for up to 6 mo

Oralmycophenolatemofetil

Maintenance (gt6 mo) immunesuppression

600 mgm2dose (max 1 gdose) twice a day

IV tocilizumab Escalation second-lineimmunotherapy

12mgkgdose (lt30 kg) 8 mgkgdose (ge30 kg) (max 800mg) givenmonthly over 6 mo or more(duration of required immunosuppression)

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 NeurologyorgNN

opinion was that second-line therapy is not needed in allpatients but only in patients with severe disease and thosewho fail to improve

One of the greatest challenges is deciding the timing of es-calation after 1 second-line therapy There was consensus thatin the patient failing to improve 1-3 months (generally gt6

Figure International Consensus Recommendations for the Treatment of First Event of Pediatric NMDAR Antibody En-cephalitis (NMDARE)

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 9

weeks) following initiation of the first second-line immuno-therapy another second-line therapy such as cyclophospha-mide if rituximab was used first can be considered

In the patient who fails rituximab cyclophosphamide is gen-erally recommended as an escalation agent although somemembers of the Panel have increasing interest in tocilizumabas an alternative escalation therapy due to a more favorableperceived safety profile42-44 Other escalation treatments havebeen reported in the literature such as IVintrathecal meth-otrexate with intrathecal corticosteroids and subcutaneousIVbortezomib these have more limited evidence but can beused according to the local treating centerrsquos expertise4143-57

The patient who has severe disease and is failing to improveremains a major challenge The clinician needs to balance therisk of severe disease (such as being on the intensive care unit)with the risk of treatment side effects in the knowledge thatNMDARE symptoms may take many weeks or months toimprove27 Indeed unlike in acute disseminated encephalo-myelitis when treatment often results in rapid improvementswithin days in NMDARE the improvements are slow andcontinue for ge24 months after the acute phase2 Thereforeallowing treatments to have their effect including theircombined actions is important to avoid hasty therapeuticdecisions In general second-line agents such as rituximab orcyclophosphamide should be given 1-3 months before makingjudgment on effect with 6 weeks being a broadly acceptedguideline The timing of escalation is very challenging andinfluenced by severity age risk-benefit ratio treating centerrsquosexperience and access to treatments Overall for patients inthe intensive care unit where there may bemultiple additionalrisk factors7 earlier escalation seems reasonable Anecdotalreports from our expert group of benefit of treatment withrituximab or tocilizumab years after onset suggest that in thepatient who continues to have major impairments furtherimmunotherapies are warranted within reason although thereare likely to be diminishing returns when treatment is usedlater in the disease course

In the patient who has failed to improve a year or more aftertreatment it is sometimes difficult to determine residual

sequelae from ongoing inflammation In this situation CSF re-examination for ongoing neuroinflammation (ie persistentpleocytosis intrathecal oligoclonal bands elevated immuno-globulin G [IgG] index or CSF neopterin)58 may help withdecision making and the risk vs benefit consideration of anempiric retrial or immunotherapy (pulsed corticosteroid for 3months IVIg monthly rituximab reinduction or tocilizumab)CSF NMDAR antibody titers seem to correlate better withdisease course compared with serum antibodies5960 but there isnot a strong correlation between titer and clinical course in theindividual patient and antibodies can persist long after recov-ery60e1e2 Although all stages of management of NMDAREmay be challenging even for experienced physicians this is es-pecially true when dealing with a severe patient failing to im-prove and a second opinionmay be useful and help the clinicianmake further therapeutic decisions Organizations such as theAutoimmune Encephalitis Alliance (aeallianceorg) the En-cephalitis Society (encephalitisinfo) and the Anti NMDAReceptor Encephalitis Foundation Inc (antinmdafoundationorg) may help connect with experts

There was overall agreement that maintenance immune sup-pression beyond 6 months from onset is generally not needed(Table 2 24) apart from patients with more severe course orprolonged impairments and hospitalization Indeed literaturedata show that early and adequate treatment including use ofsecond-line therapies when appropriate is the priority2 ratherthan prolonged maintenance immune suppression Moreoverthe relatively low relapse rate of NMDARE is in significantcontrast with that of other disorders such as neuromyelitisoptica where chronic immune suppression is recommendedfrom the first event When giving immune suppression formore than 6 months rituximab redosing was generally pre-ferred although mycophenolate mofetil is also used936e3-e5

and there is little evidence to suggest superiority of either Withregard to rituximab redosing most experts recommendredosing when CD19 cells repopulate in view of the variabilityin the time to B-cell repopulation between individualse6 Analternative approach is to redose rituximab at regular 6-monthintervals similar to practice in adult patients with neuromyelitisopticae7e8 There was no consensus in the dosage and fre-quency of redosing with some experts using the same dose

Table 5 Definition of Responder to Immunotherapy

Definition of response to immunotherapy

Best responder These patients regardless of severity improve rapidly after immunotherapy (withinweeks) and are clearlymaking functional gains in the first2 mo after treatment and by 3 mo are returning to normal function (returning home considering return to school and life activities)

Average responder These patients regardless of severity may not make any clear functional improvements in the first month after treatmentcommencement but in the second and thirdmonth start tomake clear functional gains By 6mo the patient is home andmay still have deficits but continuesto make slow improvements

Poorest responder These patients fail to make substantial and functionally useful improvements in the first 3 mo after treatment commencement remainimpaired and have significant care needs These patients require prolonged rehabilitation and inpatient care often for gt3 mo

The following definitions of responder to immunotherapy are generated as a general guidance for a global audience and to support clinicians less familiarwith the treatment of pediatric NMDAR antibody encephalitis especially with regard to the duration of total immunotherapy (Table 2 25)

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 NeurologyorgNN

regimen used at induction and others using lower doses (Table4) As regards mycophenolate mofetil given its slow onset ofefficacy there should initially be overlap with other immuno-therapies (ie oral corticosteroids) for 3-6 months after com-mencemente3 Other maintenance agents such as oralazathioprine and methotrexate are sometimes used for main-tenance immune suppression although the paucity of experi-ence precluded consensus recommendations from our expertgroup In resource-poor countries the Panel also agreed thatprolonged first-line therapy (with IV pulsed methylpredniso-lone dexamethasone or IVIg) can be used as an alternativeform of maintenance (gt6 months) immunotherapy if ritux-imab and mycophenolate mofetil are not available

There was agreement in the need for a more aggressive andprolonged treatment approach in patients with relapsingdisease (Table 3 31) with a lower threshold for second-lineand maintenance treatments (rituximab or mycophenolate)and more prolonged overall immunotherapy duration In-deed the median overall duration of immunotherapy at firstevent of pediatric NMDAREwas recommended to be about 3months (IQR 3ndash6 months) in the best responders 9 months(IQR 6ndash12 months) in the average responders 18 months(IQR 12ndash24 months) in the poorest responders (Table 225) and 12ndash24months after a relapse acknowledging patientseverity and management variables (Table 3 31) We ac-knowledge that the definition of ldquobestrdquo ldquoaveragerdquo andldquopoorestrdquo is dependent on experience of the clinician there-fore some guidance is provided in Table 5

Although not the focus of this work the Panel acknowledgesthat infectious risk mitigation strategies are key to ensure thepatientsrsquo safety while receiving immunotherapy especiallyclose monitoring for infections and adherence to hospitalinfection control protocols to prevent hospital acquired in-fection In selected patients on prolonged high-dose cortico-steroids multiple second-line or escalation immunotherapiesprophylactic trimethoprim-sulfamethoxazole for Pneumocystiscarinii pneumonia may be required In patients with low IgGlevels and recurrent infections despite prophylactic antibi-otics immunoglobulin supplementation may be required

As regards patients with relapse of neurologic symptoms afterHSE (Table 3 32) acyclovir should be administered promptlyuntil HSE recurrence is excluded while maintaining a highindex of suspicion for an underlying autoimmune etiology ThePanel agreed that if autoimmune encephalitis is confirmed afterHSE immunotherapy should be used in a similar way toidiopathicnaive NMDAREe9e10

The Panel acknowledged that although immunotherapy is thetherapeutic priority to treat the underlying disease symptom-atic management (such as antiseizure medications) is equallyimportant (Table 3 33) However symptom managementmay be challenging and requires multidisciplinary expertisee11

As stated in the recommendations there was consensus on apreferred list of medications found to be useful in the treatment

of behavior agitation and dyskinesia (full list of medicationsconsidered is detailed in eAppendix 1 linkslwwcomNXIA530) Caution was also drawn to the observation that the useof antipsychotics in pediatric NMDARE may worsen dyski-nesia or induce a neuroleptic malignant syndrome

Although paraneoplastic etiology is rare in prepubertal childrenand in boys29e12 oncologic searches for ovarian teratoma (andneural crest tumors in children aged lt5 years) are mandatory inall children with NMDARE should be performed early and becompleted in the first days-weeks after admission (Table 3 34)Ultrasound or MRI of the abdomen and pelvis and CT or MRIof the chest are the recommended imaging modalities andcollaboration with local oncologists and radiologists will helpguide the need for additional studies (eg PET scan) to optimizediagnostic yield in patients with severe disease or a failure toimprove The timely identification of a tumor and its subsequentremoval may improve the outcome considerably although theprognosis also depends on the type of tumor2e12 The Panelreached agreement on oncologic searches that should be per-formed in all patients both at baseline and in patients who fail toimprove or relapse with particular focus on postpubertal femalesin whom ovarian teratoma screening and longitudinal surveil-lance for ovarian teratoma should be strongly pursued

Although not the main aim of this consensus document thePanel acknowledged that adequate rehabilitation after theacute phase of NMDARE is essential and may improve out-comes We strongly support the need for rehabilitation to beprovided in a center familiar with rehabilitating young peoplewith acquired brain injury such as encephalitis or traumaticbrain injury acknowledging that improvements may continuefor up to 24 months Rehabilitation often includes focus oncognitive and behavioral problems (including executive dys-function and fatigue) post-NMDARE

In view of the relative rarity of this condition any recom-mendation or guideline for the treatment of pediatricNMDARE is inevitably based on limited evidence thereforethis document should be intended as a recommendationmeant to provide guidance rather than absolute rules and itshould not be used to prevent access to therapies if these arerecommended by a patientrsquos physician Moreover by puttingtogether international experts from very different settings thepresent work highlighted heterogeneity in the management ofthis condition The differences stimulated discussion and re-flection and there was still consensus around most aspects ofpediatric NMDARE treatment Although the experts includedpeople with broad international expertise the opinions re-main vulnerable to anecdote and potential bias related toreferral of complicated or atypical patients

Despite these limitations we strove to create an internationalconsensus-based recommendation aimed at supporting theclinician in the treatment of pediatric NMDARE with adedicated global approach for all health care settingsWe hopethat with the aid of recently released diagnostic criteria2627

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 11

the present treatment recommendation may contribute to amore systematic approach resulting in more comparable datainternationally which may generate better quality evidenceNonetheless there are still major unresolved issues whichshould represent the focus of future research

AcknowledgmentThe authors thank Kimberley de Haseth from AEA and theDe Vivero family for support and advice

Study FundingThere was funding commitment for the face to face meeting bythe Autoimmune Encephalitis Alliance (AEA) which due toCOVID-19 was not needed as the face-to-face meeting wasvirtual AEA has supported costs of open access for journalpublication M Eyre is supported by Action Medical Researchand the British Paediatric Neurology Association T Armangue issupported by research grants Instituto Carlos IIIFEDER Spain(PI1800486) and Generalitat de Catalunya PERIS (SLT0061700362) SR Irani is supported by the Wellcome Trust(104079Z14Z) the UCB-Oxford University Alliance BMAResearch Grants Vera Down grant (2013) andMargaret Temple(2017) Epilepsy Research UK (P1201) the Fulbright UK-UScommission (MS-Society research award) and by the NIHROxford Biomedical Research Centre The views expressed arethose of the author(s) and not necessarily those of the NHS theNIHR or the Department of Health) RCD is supported byNHMRC Investigator grant (Australia) and Petre Foundation

DisclosureM Nosadini T Thomas M Eyre B Anlar T ArmangueSM Benseler T Cellucci K Deiva andW Gallentine reportno disclosures relevant to the manuscript G Gombolay re-ceives part-time salary support from the Centers for DiseaseControl and Prevention to review acute flaccid myelitis casesfor surveillance MP Gorman has received research fundingfrom Pfizer and Roche for research unrelated to the currenttopic Y Hacohen Y Jiang BC Lim E Muscal and ANdondo report no disclosures relevant to the manuscript RNeuteboom participates in treatment studies in pediatric MSby Novartis and Sanofi-Genzyme and received consultationfees fromNovartis Zogenix and Sanofi-Genzyme K RostasyH Sakuma and S Sharma report no disclosures relevant tothe manuscript SN Tenembaum participates as member ofthe NMO Scientific Advisory Committee (Genentech-RocheInc) and chair of the NMORelapse Adjudication Committee(Alexion Pharmaceuticals Inc) she has received speakerhonoraria from Biogen Idec Argentina Merck SeronoLATAM Genzyme Novartis Argentina andNovartis PharmaInc HA Van Mater and E Wells report no disclosures rel-evant to the manuscript R Wickstrom has received consul-tation fees from Roche Novartis and Octapharma AKYeshokumar reports no disclosures relevant to the manu-script SR Irani is a coapplicant and receives royalties onpatent application WO210046716 (UK patent no PCTGB2009051441) entitled ldquoNeurological Autoimmune Dis-ordersrdquo (the patent has been licensed for the development of

assays for LGI1 and other VGKC-complex antibodies) and onan unlicensed patent to improve detection of autoantibodiesJ Dalmau reports no disclosures relevant to the manuscriptM Lim has received consultation fees from CSL BehringNovartis and Octapharma travel grants from Merck Seronoand was awarded educational grants to organize meetings byNovartis Biogen Idec Merck Serono and Bayer RC Dalereports no disclosures relevant to the manuscript Go toNeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationFebruary 14 2021 Accepted in final form May 21 2021

Appendix Authors

Name Location Contribution

MargheritaNosadiniMD PhD

Paediatric Neurology andNeurophysiology UnitDepartment of Womenrsquosand Childrenrsquos HealthUniversity Hospital ofPadova Italy

Literature reviewparticipation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statementspreparation of therecommendation draftediting and approval of thefinal draft andaccess toall thedata and responsibility forthe data accuracy of the dataanalysis and the conduct ofthe research

TerrenceThomas MD

Department of PaediatricsNeurology Service KKWomenrsquos and ChildrenrsquosHospital Singapore

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statementstechnical support dataanalysis preparation of therecommendation draft andediting and approval of thefinal draft

Michael EyreMD

Department of PaediatricNeurology Great OrmondStreet Hospital for ChildrenLondon United Kingdom

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statementspreparation of therecommendation draft andediting and approval of thefinal draft

Banu AnlarMD

Department of PediatricNeurology HacettepeUniversity Ankara Turkey

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

ThaisArmangueMD PhD

Neuroimmunology ProgramInstitut drsquoInvestigacionsBiomediques August Pi iSunyer (IDIBAPS) HospitalClınic Universitat deBarcelona Spain PediatricNeuroimmunology UnitNeurology Department SantJoan de Deu (SJD) ChildrenrsquosHospital University ofBarcelona Spain

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 NeurologyorgNN

Appendix (continued)

Name Location Contribution

Susanne MBenseler MD

Alberta Childrenrsquos HospitalResearch InstituteDepartment of PediatricsCumming School ofMedicine University ofCalgary Canada

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

TaniaCellucci MDFRCPCMScCH

Division of RheumatologyDepartment of PediatricsMcMaster UniversityHamilton Ontario Canada

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

KumaranDeiva MD

Assistance Publique-Hopitauxde Paris Pediatric NeurologyDepartment UniversityHospitals Paris Saclay BicetreHospital France FrenchReference Network of RareInflammatory Brain and SpinalDiseases Le Kremlin BicetreFrance and EuropeanReference Network-RITAFrance

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

WilliamGallentineDO

Departments of Neurologyand Pediatrics StanfordUniversity and LucilePackard Childrenrsquos HospitalPalo Alto CA

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

GraceGombolayMD

Division of PediatricNeurology Department ofPediatrics Emory UniversitySchool of Medicine andChildrenrsquos Healthcare ofAtlanta GA

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Mark PGorman MD

Department of NeurologyBoston Childrenrsquos HospitalHarvard Medical SchoolBoston MA

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

YaelHacohen MD

Department ofNeuroinflammation QueenSquare MS Centre UCLInstitute of NeurologyUniversity College LondonDepartment of PaediatricNeurology Great OrmondStreet Hospital for ChildrenLondon United Kingdom

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Yuwu JiangMD

Department of PediatricsPeking University FirstHospital Beijing China

Participation to the Delphiprocess for creation of theconsensus treatmentstatements and revision ofthe manuscript forintellectual content

Byung ChanLim MD

Department of PediatricsPediatric ClinicalNeuroscience Center SeoulNational UniversityChildrenrsquos Hospital SeoulNational University Collegeof Medicine South Korea

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Appendix (continued)

Name Location Contribution

Eyal MuscalMD MS

Department of PediatricsSection Rheumatology co-appointment in the section ofNeurology andDevelopmental NeuroscienceTexas Childrenrsquos HospitalBaylor College of MedicineHouston TX

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

AlvinNdondo MD

Division of PaediatricNeurology Department ofPaediatrics and ChildHealth Red Cross WarMemorial ChildrenrsquosHospital University of CapeTown Faculty of HealthSciences University of CapeTown NeuroscienceInstitute South Africa

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

RinzeNeuteboomMD PhD

Department of NeurologyErasmus Medical CenterRotterdam the Netherlands

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

KevinRostasy MD

Department of PediatricNeurology ChildrenrsquosHospital Datteln UniversityWittenHerdecke Germany

Participation to the Delphiprocess and the finalonline face-to-facemeeting for creation of theconsensus treatmentstatements and revision ofthe manuscript forintellectual content

HiroshiSakuma MD

Department of Brain andNeural Science TokyoMetropolitan Institute ofMedical Science Japan

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

SuvasiniSharma MD

Department of Pediatrics(Neurology Division) LadyHardinge Medical Collegeand Associated KalawatiSaran Childrenrsquos HospitalNew Delhi India

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Silvia NoemiTenembaumMD

Department of NeurologyNational Pediatric HospitalDr J Garrahan BuenosAires Argentina

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Heather AnnVan MaterMD

Department of PediatricsDuke University DurhamNC

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

ElizabethWells MD

Department of NeurologyChildrenrsquos National MedicalCenter Washington DC

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 13

References1 Dalmau J Gleichman AJ Hughes EG et al Anti-NMDA-receptor encephalitis case

series and analysis of the effects of antibodies Lancet Neurol 20087(12)1091-10982 Titulaer MJ McCracken L Gabilondo I et al Treatment and prognostic factors for

long-term outcome in patients with anti-NMDA receptor encephalitis an observa-tional cohort study Lancet Neurol 201312(2)157-165

3 de Bruijn MAAM Aarsen FK van Oosterhout MP et al Long-term neuro-psychological outcome following pediatric anti-NMDAR encephalitis Neurology201890(22)e1997-e2005

4 Irani SR Bera K Waters P et al N-methyl-D-aspartate antibody encephalitis tem-poral progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes Brain 2010133(pt 6)1655-1667

5 Hacohen Y Absoud M Hemingway C et al NMDA receptor antibodies associatedwith distinct white matter syndromes Neurol Neuroimmunol Neuroinflamm 20141(1)e2

6 Byrne S Walsh C Hacohen Y et al Earlier treatment of NMDAR antibody en-cephalitis in children results in a better outcomeNeurol Neuroimmunol Neuroinflamm20152(4)e130

7 Dale RC Brilot F Duffy LV et al Utility and safety of Rituximab in pediatricautoimmune and inflammatory CNS disease Neurology 201483(2)142-150

8 Gabilondo I Saiz A Galan L et al Analysis of relapses in anti-NMDAR encephalitisNeurology 201177(10)996-999

9 Nosadini M Granata T Matricardi S et al Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis Dev Med Child Neurol 201961(9)1101-1107

10 Bartolini L Muscal E Differences in treatment of anti-NMDA receptor encephalitisresults of a worldwide survey J Neurol 2017264(4)647-653

11 Kahn I Helman G Vanderver A Wells E Anti-N-methyl-d-aspartate (NMDA) re-ceptor encephalitis J Child Neurol 201732(2)243-245

12 Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon RClinical experience and laboratory investigations in patients with anti-NMDAR en-cephalitis Lancet Neurol 201110(1)63-74

13 Nosadini M Mohammad SS Ramanathan S Brilot F Dale RC Immune therapy inautoimmune encephalitis a systematic review Expert Rev Neurother 201515(12)1391-1419

14 Lancaster E The diagnosis and treatment of autoimmune encephalitis J Clin Neurol201612(1)1-13

15 Dale RC Gorman MP Lim M Autoimmune encephalitis in children clinical phe-nomenology therapeutics and emerging challenges Curr Opin Neurol 201730(3)334-344

16 Shin YW Lee ST Park KI et al Treatment strategies for autoimmune encephalitisTher Adv Neurol Disord 2017111756285617722347

17 Zuliani L Nosadini M Gastaldi M et al Management of antibody-mediated auto-immune encephalitis in adults and children literature review and consensus-basedpractical recommendations Neurol Sci 201940(10)2017-2030

18 Dalmau J Armangue T Planaguma J et al An update on anti-NMDA receptorencephalitis for neurologists and psychiatrists mechanisms and models LancetNeurol 201918(11)1045-1057

19 Linstone HA TuroffM edsThe Delphi Method Techniques and Applications Addison-Wesley 1975

20 Hasson F Keeney S McKenna H Research guidelines for the Delphi survey tech-nique J Adv Nurs 200032(4)1008-1015

21 ter Haar NM Oswald M Jeyaratnam J et al Recommendations for the managementof autoinflammatory diseases Ann Rheum Dis 201574(9)1636-1644

22 van Swieten JC Koudstaal PJ Visser MC Schouten HJ van Gijn J Interobserveragreement for the assessment of handicap in stroke patients Stroke 198819(5)604-607

23 Bertsias GK Tektonidou M Amoura Z et al Joint European League AgainstRheumatism and European Renal Association-European Dialysis and TransplantAssociation (EULARERA-EDTA) recommendations for the management of adultand paediatric lupus nephritis Ann Rheum Dis 201271(11)1771-1782

24 Mina R von Scheven E Ardoin SP et al Consensus treatment plans for inductiontherapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupuserythematosus Arthritis Care Res (Hoboken) 201264(3)375-383

25 Stingl C Cardinale K Van Mater H An update on the treatment of pediatric auto-immune encephalitis Curr Treatm Opt Rheumatol 20184(1)14-28

26 Graus F Titulaer MJ Balu R et al A clinical approach to diagnosis of autoimmuneencephalitis Lancet Neurol 201615(4)391-404

27 Cellucci T Van Mater H Graus F et al Clinical approach to the diagnosis ofautoimmune encephalitis in the pediatric patient Neurol Neuroimmunol Neuro-inflamm 20207(2)e663

28 Al-Diwani A Handel A Townsend L et al The psychopathology of NMDAR-antibody encephalitis in adults a systematic review and phenotypic analysis of in-dividual patient data Lancet Psychiatry 20196(3)235-246

29 Varley JA Webb AJS Balint B et al The Movement disorder associated withNMDAR antibody-encephalitis is complex and characteristic an expert video-ratingstudy J Neurol Neurosurg Psychiatry 201990(6)724-726

30 Suppiej A Nosadini M Zuliani L et al Plasma exchange in pediatric anti-NMDARencephalitis a systematic review Brain Dev 201638(7)613-622

31 Eyre M Hacohen Y Barton C Hemingway C Lim M Therapeutic plasma exchangein paediatric neurology a critical review and proposed treatment algorithm Dev MedChild Neurol 201860(8)765-779

32 Eyre M Hacohen Y Lamb K et al Utility and safety of plasma exchange in paediatricneuroimmune disorders Dev Med Child Neurol 201961(5)540-546

33 Dogan Onugoren M Golombeck KS Bien C et al Immunoadsorption therapy inautoimmune encephalitides Neurol Neuroimmunol Neuroinflamm 20163(2)e207

34 Heine J Ly LT Lieker I et al Immunoadsorption or plasma exchange in the treat-ment of autoimmune encephalitis a pilot study J Neurol 2016263(12)2395-2402

35 Zhang M Li W Zhou S et al Clinical features treatment and outcomes amongChinese children with anti-methyl-D-aspartate receptor (anti-NMDAR) encephalitisFront Neurol 201910596

36 Xu X Lu Q Huang Y et al Anti-NMDAR encephalitis a single-center longitudinalstudy in China Neurol Neuroimmunol Neuroinflamm 20197(1)e633

Appendix (continued)

Name Location Contribution

RonnyWickstromMD PhD

Neuropaediatric UnitKarolinska UniversityHospital StockholmSweden

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Anusha KYeshokumarMD

Department of NeurologyIcahn School of Medicine atMount Sinai New York

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statements andrevision of the manuscriptfor intellectual content

Sarosh RIrani MDPhD

Oxford AutoimmuneNeurology Group NuffieldDepartment of ClinicalNeurosciences University ofOxford John RadcliffeHospital Department ofNeurology OxfordUniversity Hospitals NHSFoundation Trust UnitedKingdom

Expert guidance andrevision of the manuscriptfor intellectual content

JosepDalmau MDPhD

NeuroimmunologyProgram InstitutdrsquoInvestigacionsBiomediques August Pi iSunyer (IDIBAPS) HospitalClınic University ofBarcelona SpainDepartment of NeurologyUniversity of PennsylvaniaPhiladelphia

Expert guidance andrevision of the manuscriptfor intellectual content

Ming LimMD PhD

Childrenrsquos NeurosciencesEvelina London ChildrenrsquosHospital at Guyrsquos and StThomasrsquo NHS FoundationTrust Kingrsquos HealthPartners Academic HealthScience Centre LondonFaculty of Life Sciences andMedicine Kingrsquos CollegeHospital London UnitedKingdom

Participation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statementspreparation of therecommendation draft andediting and approval of thefinal draft

Russell CDale MDPhD

Kids Neuroscience CentreThe Childrenrsquos Hospital atWestmead Faculty ofMedicine and HealthUniversity of Sydney NSWAustralia

Project conception anddesign literature reviewparticipation to the Delphiprocess and the final onlineface-to-face meeting forcreation of the consensustreatment statementspreparation of therecommendation draftediting and approval of thefinal draft and access to allthe data and responsibilityfor the data accuracy of thedata analysis and theconduct of the research

14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 5 | 0 0 NeurologyorgNN

37 Mo Y Wang L Zhu L et al Analysis of risk factors for a poor prognosis in patientswith anti-N-methyl-D-aspartate receptor encephalitis and construction of a prog-nostic composite score J Clin Neurol 202016(3)438-447

38 Raha S Gadgil P Sankhla C Udani V Nonparaneoplastic anti-N-methyl-D-aspartatereceptor encephalitis a case series of four children Pediatr Neurol 201246(4)246-249

39 Nagappa M Bindu PS Mahadevan A Sinha S Mathuranath PS Taly AB Clinicalfeatures therapeutic response and follow-up in pediatric anti-N-methyl-D-aspartatereceptor encephalitis experience from a tertiary care university hospital in IndiaNeuropediatrics 201647(1)24-32

40 Nair A V Menon J Kuzhikkathukandiyil P Clinical profile and neuropsychiatric out-come in children with anti-NMDAR encephalitis Indian Pediatr 201956(3)247-249

41 Jones HF Mohammad SS Reed PW et al Anti-N-methyl-d-aspartate receptor en-cephalitis in Maori and Pacific Island children in New Zealand Dev Med Child Neurol201759(7)719-724

42 Lee WJ Lee ST Shin YW et al Teratoma removal steroid IVIG rituximab andtocilizumab (T-SIRT) in anti-NMDAR encephalitis Neurotherapeutics 202118(1)474-487 doi 101007s13311-020-00921-7

43 Sveinsson O Granqvist M Forslin Y Blennow K Zetterberg H Piehl F Successfulcombined targeting of B- and plasma cells in treatment refractory anti-NMDARencephalitis J Neuroimmunol 201731215-18

44 Jun JS Seo HG Lee ST Chu K Lee SK Botulinum toxin treatment for hypersali-vation in anti-NMDA receptor encephalitis Ann Clin Transl Neurol 20174(11)830-834

45 Thomas A Rauschkolb P Gresa-Arribas N Schned A Dalmau JO Fadul CE Anti-N-methyl-D-aspartate receptor encephalitis a patient with refractory illness after 25months of intensive immunotherapy JAMA Neurol 201370(12)1566-1568

46 DeSena AD Greenberg BM Graves D Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children prevalence of symptoms andprognosis Pediatr Neurol 201451(4)542-549

47 DeSena AD Noland DKMatevosyan K et al Intravenous methylprednisolone versustherapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptorantibody encephalitis a retrospective review J Clin Apher 201530(4)212-216

48 Tatencloux S Chretien P Rogemond V Honnorat J Tardieu M Deiva K Intrathecaltreatment of anti-N-Methyl-D-aspartate receptor encephalitis in children Dev MedChild Neurol 201557(1)95-99

49 Liba Z Kayserova J Elisak M et al Anti-N-methyl-D-aspartate receptor encephalitisthe clinical course in light of the chemokine and cytokine levels in cerebrospinal fluidJ Neuroinflammation 201613(1)55

50 Behrendt V Krogias C Reinacher-Schick A Gold R Kleiter I Bortezomib treatment forpatients with anti-N-methyl-d-aspartate receptor encephalitis JAMA Neurol 201673(10)1251-1253

51 Mehr SR Neeley RC Wiley M Kumar AB Profound autonomic instability compli-cated by multiple episodes of cardiac asystole and refractory bradycardia in a patientwith anti-NMDA encephalitis Case Rep Neurol Med 201620167967526

52 Scheibe F Pruss H Mengel AM et al Bortezomib for treatment of therapy-refractoryanti-NMDA receptor encephalitis Neurology 201788(4)366-370

53 Schroeder C Back C Koc U et al Breakthrough treatment with bortezomib for apatient with anti-NMDAR encephalitis Clin Neurol Neurosurg 201817224-26

54 Shin YW Lee ST Kim TJ Jun JS Chu K Bortezomib treatment for severerefractory anti-NMDA receptor encephalitis Ann Clin Transl Neurol 20185(5)598-605

55 Keddie S Crisp SJ Blackaby J et al Plasma cell depletion with bortezomib in thetreatment of refractory NMDAR-antibody encephalitis Rational developments inneuroimmunological treatment Eur J Neurol 201825(11)1384-1388

56 Janmohamed M Knezevic W Needham M Salman S Primary lateral sclerosis-likepicture in a patient with a remote history of anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis BMJ Case Rep 20182018bcr2017224060

57 Yang XZ Zhu HD Ren HT et al Utility and safety of intrathecal methotrexatetreatment in severe anti-N-methyl-D-aspartate receptor encephalitis a pilot studyChin Med J (Engl) 2018131(2)156-160

58 Dale RC Brilot F Fagan E Earl J Cerebrospinal fluid neopterin in paediatric neu-rology a marker of active central nervous system inflammationDevMed Child Neurol200951(4)317-323

59 Frechette ES Zhou L Galetta SL Chen L Dalmau J Prolonged follow-up and CSFantibody titers in a patient with anti-NMDA receptor encephalitis Neurology 201176(7 suppl)S64-S66

60 Gresa-Arribas N Titulaer MJ Torrents A et al Antibody titres at diagnosis and duringfollow-up of anti-NMDA receptor encephalitis a retrospective study Lancet Neurol201413(2)167-177Additional references e1-e12 are available at eAppendix 2 (linkslwwcomNXIA531)

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International Consensus Recommendations for the Treatment of Pediatric NMDAR

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