ARTICLE OPEN ACCESS

International Consensus Recommendations for

the Treatment of Pediatric NMDAR Antibody
Encephalitis
Margherita Nosadini, MD, PhD, Terrence Thomas, MD, Michael Eyre, MD, Banu Anlar, MD, Correspondence
Dr. Dale
Thais Armangue, MD, PhD, Susanne M. Benseler, MD, Tania Cellucci, MD, FRCPC, MScCH, Kumaran Deiva, MD,
[email protected]
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 Rostásy, 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 0;8:e1052. doi:10.1212/NXI.0000000000001052

Abstract
Objective
To create an international consensus treatment recommendation for pediatric NMDA receptor
antibody encephalitis (NMDARE).

Methods
After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi
method was adopted to develop consensus on relevant treatment regimens and statements, along
with 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 ≥75% agreement).

Results
Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with
additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line
immunotherapy can be offered for up to 3–12 months (oral corticosteroids or monthly IV
corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments
are recommended for cases refractory to first-line therapies (rituximab preferred over

From the Paediatric Neurology and Neurophysiology Unit (M.N.), Department of Women’s and Children’s Health, University Hospital of Padova; Neuroimmunology Group (M.N.),
Paediatric Research Institute “Città della Speranza,” Padova, Italy; Department of Paediatrics (T.T.), Neurology Service, KK Women’s and Children’s Hospital, Singapore; School of
Biomedical Engineering & Imaging Sciences (M.E.), King’s College London; Children’s Neurosciences (M.E.), Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS Foundation
Trust, United Kingdom; Department of Pediatric Neurology (B.A.), Hacettepe University, Ankara, Turkey; Neuroimmunology Program (T.A.), Institut d’Investigacions Biomèdiques
August Pi i Sunyer (IDIBAPS), Hospital Clı́nic, Universitat de Barcelona; Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu (SJD) Children’s Hospital,
University of Barcelona, Spain; Alberta Children’s Hospital Research Institute (S.M.B.), Department of Pediatrics, Cumming School of Medicine, University of Calgary; Division of
Rheumatology (T.C.), Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Assistance Publique-Hôpitaux de Paris (K.D.), Pediatric Neurology Department,
University Hospitals Paris Saclay, Bicêtre Hospital, France; French Reference Network of Rare Inflammatory Brain and Spinal Diseases (K.D.), Le Kremlin Bicêtre, France and European
Reference Network-RITA; Departments of Neurology and Pediatrics (W.G.), Stanford University and Lucile Packard Children’s Hospital, Palo Alto, CA; Division of Pediatric Neurology
(G.G.), Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, GA; Department of Neurology (M.P.G.), Boston Children’s Hospital, Harvard
Medical School, Boston, MA; Department of Neuroinflammation (Y.H.), Queen Square MS Centre, UCL Institute of Neurology, University College London; Department of Paediatric
Neurology (Y.H.), Great Ormond Street Hospital for Children, London, United Kingdom; Department of Pediatrics (Y.J.), Peking University First Hospital, Beijing, China; Department of
Pediatrics (B.C.L.), Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University College of Medicine, South Korea; Department of
Pediatrics (E.M.), Section Rheumatology, Co-appointment in the Section of Neurology and Developmental Neuroscience, Texas Children’s Hospital, Baylor College of Medicine,
Houston; Division of Paediatric Neurology (A.N.), Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town; Faculty of Health
Sciences (A.N.), University of Cape Town Neuroscience Institute, South Africa; Department of Neurology (R.N.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of
Pediatric Neurology (K.R.), Children’s Hospital Datteln, University Witten/Herdecke, Germany; Department of Brain and Neural Science (H.S.), Tokyo Metropolitan Institute of Medical
Science, Japan; Department of Pediatrics (Neurology Division) (S.S.), Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India; Department of
Neurology (S.N.T.), National Pediatric Hospital Dr. J. Garrahan, Buenos Aires, Argentina; Department of Pediatrics (H.A.V.M.), Duke University, Durham, NC; Department of Neurology
(E.W.), Children’s National Medical Center, Washington, DC; Neuropaediatric Unit (R.W.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (A.K.Y.), Icahn
School of Medicine at Mount Sinai, New York; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe
Hospital; Department of Neurology (S.R.I.), Oxford University Hospitals NHS Foundation Trust, United Kingdom; Neuroimmunology Program (J.D.), Institut d’Investigacions Bio-
mèdiques August Pi i Sunyer (IDIBAPS), Hospital Clı́nic, University of Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de
Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; Children’s Neurosciences (M.L.), Evelina London Children’s Hospital at Guy’s and St Thomas’ NHS Foundation Trust; King’s
Health Partners Academic Health Science Centre (M.L.); Faculty of Life Sciences and Medicine (M.L.), King’s College Hospital, United Kingdom; and Kids Neuroscience Centre (R.C.D.),
The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Go to Neurology.org/NN 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 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1
 Glossary
HSE = herpes simplex virus encephalitis; IQR = interquartile range; IgG = immunoglobulin G; IVIg = IV immunoglobulin;
NMDARE = NMDA receptor antibody encephalitis; TPE = therapeutic plasma exchange.

cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory
disease 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 mycophenolate
mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization.
For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of
NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the
total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course
(i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of
oncologic searches are provided.

Conclusion
These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment
and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult
patients.

NMDA receptor antibody encephalitis (NMDARE) is one of Methods

the most common autoimmune encephalitides, characterized
by a recognizable constellation of neurologic and psychiatric Establishment of a Consensus Expert Panel
features alongside positive NMDAR antibodies.1,2 NMDARE A steering committee (R.C.D., M.L., T.T., M.N., and M.E.)
mostly affects children and young adults, particularly females. carefully selected a panel of 27 experts with representation from
It may be very severe in the acute phase with a mortality of all continents (later referred to as “the Panel”), and based on the
about 5%, relapses occur in about 15% of patients, and the individual: (1) being a specialist (usually pediatric neurologist or
final physician-assessed functional outcome is generally fa- rheumatologist) with clinical and/or research expertise in pe-
vorable, although neuropsychological and psychiatric se- diatric NMDARE; these experts were identified as lead clinical
quelae are relatively common.2,3 researchers in the field based on the systematic review con-
ducted before the consensus recommendations project (paper
The use of immunotherapies has been shown to improve in preparation), or were nominated by national child neurology
outcomes,2,4-6 especially with early administration.2,4,6,7 In ad- societies; (2) having a publication track record in the field of
dition, immunotherapies reduce the risk of relapses.2,8,9 How- pediatric autoimmune encephalitis/CNS disease; (3) being
ever, several aspects of treatment remain incompletely clarified, committed to completing 2 Delphi studies (approximately 45
and treatment strategies are still heterogeneous, especially with minutes each),19,20 and participating in a 2-hour face-to-face/
regard to second-line and long-term immunotherapies.10,11 In- online meeting to reach consensus. The 27 experts were pedi-
deed, although a number of reviews have been published,12-18 no atric neurologists (n = 23) or pediatric rheumatologists (n = 4),
randomized controlled trials or consensus guidelines for the from North America (n = 9), South America (n = 1), Europe
treatment of NMDARE are available. (n = 9), Asia (n = 6), Oceania (n = 1), and Africa (n = 1). In
addition, patient representatives (parents, n = 2), a member of
With support from the Autoimmune Encephalitis Alliance, we the Autoimmune Encephalitis Alliance (n = 1), and adult
aimed to create a consensus recommendation for the treatment neurology experts in NMDARE (n = 2, J.D. and S.R.I.) were
of pediatric NMDARE, which was pragmatic and relevant to a invited to provide input in the later stages of the process.
global community and could serve as a practical decision support
tool for the clinician confronted with this rare and challenging Delphi Method
condition. Notably, the present document is intended as a rec- A 2-step Delphi method was adopted to develop the con-
ommendation guideline rather than absolute rules, given the sensus of relevant statements, similar to the method used by
limited evidence supporting most treatment statements. Al- the European League Against Rheumatism.21 A document
though this document is focused on immunotherapy and to some with key definitions in pediatric NMDARE (disease severity,
extent symptomatic management, there are multiple outstanding failure to improve, and relapse) used in the Delphi statements
issues in the management of pediatric NMDARE, such as edu- was shared online with the Panel (January 2020) before the
cation around the diagnosis and rehabilitation of patients after the first Delphi questionnaire. A revised version of the modified
acute phase, which are beyond the scope of this current article. Rankin Scale22 was used, to be more applicable in children.

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Table 1 Definitions Used in the Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody
Encephalitis (NMDARE) (Tables 2 and 3)
Key definitions in pediatric NMDARE Agree %
(number
voting)a

1.1. Disease severity

Severe is defined by issues affecting SAFETY and FUNCTION. Any (≥1) of the severity markers present below (items a-i) scoring “severe”
rather than “standard” 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 24/7 support for safety 24/7 care not required
(developmental equivalence)

1 on 1 nurse or parent required for safety

d. Psychiatry Suicidal thoughts Psychiatric symptoms are not

immediate compromise to safety

Dangerous impulse control issues (risk of injury)

Self-injurious behavior

e. Self-care Unable to self-care, requiring complete assistance Able to self-care (with some
(toileting, dressing, and feeding) assistance or not)

f. Communication Unable to communicate to make themselves Able to communicate and make

understood (including confusion and mutism/ needs understood
aphasia)

g. Alertness Unresponsive to the immediate environment; blank Generally able to attend to events in
staring/severe catatonia the immediate environment

h. Epilepsy Frequent requirement for rescue medication to Seizures not requiring intervention
terminate seizures with rescue medication

i. Adapted mRS score Adapted mRS score 4–5 Adapted mRS score 0–3

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

Score Description Comments

0 No symptoms —

1 Nondisabling symptoms that do not interfere with Playing/learning habits includes

the daily activity and playing/learning habits of the attending school or kindergarten
child

2 Minor symptoms that lead to some restriction in Basic functions: drinking, eating,
daily activity and playing/learning habits of the child, dressing, undressing, combing,
but do not interfere with the age-appropriate basic washing, and bathing
functions

Symptoms: may include minor

physical, cognitive, and/or
relational symptoms

3 Moderate symptoms that significantly interfere with Basic functions and symptoms as
the daily activity and playing/learning habits or above
prevent total independence in age-appropriate basic
functions

Continued

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 Table 1 Definitions Used in the Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody
Encephalitis (NMDARE) (Tables 2 and 3) (continued)
4 Moderately severe symptoms that clearly prevent Basic functions and symptoms as
independence in basic functions as would be above
appropriate for age, although the patient does not
need a constant attention

5 Severely disabled, totally dependent, and requires Bed bound; may have impaired
constant attention consciousness, agitation,
dysautonomia, and severe
movement disorder

6 Dead —

1.2. Failure to improve 92 (24)

During the clinical course, a “failure to improve”

(required to determine need for escalation of
therapy) is defined as failure to achieve
significant gains in function.

1.3. Relapse 96 (25)

Return of previous resolved symptoms and signs,

or appearance of new symptoms or signs,
associated with change in function, lasting more
than 1 wk (or shorter if associated with change in
safety), that cannot be explained by adverse
reactions to current medications or intercurrent
illness, after a period of stability or improvement
of 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 in
eAppendix 1 (links.lww.com/NXI/A530).

The first Delphi questionnaire (Delphi 1, eAppendix 1, Face-to-Face Meeting

links.lww.com/NXI/A530) included key statements on The drafted recommendations were then voted on during a
the treatment of pediatric NMDARE, which were created 2-hour online consensus meeting via the platform Zoom
based on the steering committee’s clinical practice and the (zoom.us) on November 3, 2020, and included 26 partici-
available literature and was sent out to the Panel in Feb- pants from the expert Panel, with representatives from all
ruary 2020 using a web-based survey tool (SurveyMonkey. continents. Each recommendation was voted on via the
com). The Panel members were asked to vote on each platform sli.do with the outcomes agree, do not agree, or
statement of the first Delphi questionnaire according to a abstain. The definitions used in the recommendations and the
5-point Likert scale (strongly agree/agree/neither agree drug regimens were also voted on for consensus. As before,
nor disagree/disagree/strongly disagree) and provide open consensus was defined as an agreement by at least 75% of the
text comments as appropriate. Consensus was defined participants.
as an agreement by at least 75% of the participants
(i.e., ≥75% agree/strongly agree or ≥75% disagree/strongly The number of voters varied (22-26 panelists) for the state-
disagree). ments due to connectivity issues during the meeting. The
statements that reached consensus were collated and are
Twenty-six of 27 experts completed Delphi 1; then, the presented.
statements were revised according to the Panel’s responses
and comments, and statements that reached consensus were Data Availability
collated into a second Delphi document (Delphi 2). In this The Delphi questionnaires used to create the consensus-
second Delphi survey, time durations were added (i.e., total based recommendations for the treatment of pediatric
duration of immunotherapy in NMDARE or timing of NMDARE are provided in eAppendix 1 (links.lww.com/
treatment escalation), and median, interquartile range NXI/A530).
(IQR), and range were calculated. The Delphi 2 statements
were shared with 2 adult experts (J.D. and S.R.I.), with the
Autoimmune Encephalitis Alliance representative and family Results
representatives for further input. Delphi 2 was completed
by 26 of the 27 experts by online survey in May 2020 eAppendix 1 (links.lww.com/NXI/A530) provides the Del-
(eAppendix 1, links.lww.com/NXI/A530), and final drafted phi 1 and Delphi 2 questionnaires and answers. Only final
recommendations were created. recommendations that reached consensus at the final face-to-

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Table 2 Consensus-Based Recommendations on the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis
(NMDARE): General Principles (2.1), First-Line Immunotherapy (2.2), Second-Line Immunotherapy (2.3),
Maintenance Immune Suppression (2.4), and Overall Duration of Immunotherapy (2.5)
Agree % (number
Statements reaching consensus voting)a

2.1. General principles in pediatric NMDARE

2.1.1. The management of children with NMDARE should ideally be guided by a pediatric neurology team in a center with 100 (26)
multidisciplinary expertise in NMDARE.

2.1.2. Priorities are to make an accurate and early diagnosis (exclude alternative diagnoses), initiate appropriate and 100 (24)
timely treatment, manage symptoms and complications, support recovery, identify and treat ongoing sequelae, and
prevent/treat relapses.

2.1.3. All treatment recommendations are subject to absence of contraindications, local experience and availability, and 100 (25)
discussion and approval by family.

2.1.4. Appropriate management of pediatric NMDARE includes accurate communication and updates with the family, 100 (24)
especially regarding suspected diagnosis, uncertainty in treatment responses, need for symptomatic treatment as well as
immunotherapy, and challenges in the clinical course.

2.2. First-line immunotherapy at first event of pediatric NMDARE

2.2.1. First-line immunotherapy should be offered to all children with NMDARE, unless they are already back to baseline at 100 (25)
the time of diagnosis (i.e., late diagnosis or rapid improvement and remission).

2.2.2. If NMDARE is suspected, immunotherapy should be started promptly, even before antibody results are available, if 100 (25)
alternative diagnoses have been reasonably excluded (i.e., infectious encephalitis).

2.2.3. IV corticosteroids should be the first immunotherapy used (i.e., IV methylprednisolone, IVMP). If IV corticosteroids 96 (25)
are not available or are contraindicated, oral corticosteroids (prednisone, OP or dexamethasone, DEX) should be used.

2.2.4. Oral prednisone, oral DEX pulses, or IVMP pulses can be given as an extended taper following an initial course of 96 (25)
IVMP, depending on severity, treatment response, and adverse reactions.

2.2.5. Therapeutic plasma exchange (TPE) should be strongly considered in patients with severe disease. TPE should 84 (25)
precede IV immunoglobulin (IVIg) if both are used.

2.2.6. IVIg should be part of the first-line immunotherapy options for all children, especially in severe disease, and can be 88 (25)
given with corticosteroids at diagnostic suspicion.

2.2.7. In a child who has only received one first-line immunotherapy and who has severe disease or is failing to improve 96 (25)
after 1 wk postinitiation of corticosteroids, another first-line immunotherapy (i.e., corticosteroids + TPE or corticosteroids
+ IVIg) should be considered.

2.2.8. In patients who are failing to improve approximately 2 wk after initiation of 2 or more first-line therapies, second- 92 (25)
line therapy is favored over further first-line therapies.

2.2.9. Prolonged first-line immunotherapy can be offered for up to 3–12 mo, depending on severity and improvement (i.e., 92 (24)
especially in countries without access to second-line therapies).
Prolonged first-line immunotherapy: corticosteroids (OP, monthly IVMP, and oral DEX pulses), and/or 3–4 weekly IVIg (regardless of
initiation of second line).

2.3. Second-line immunotherapy at first event of pediatric NMDARE

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

2.3.2. Rituximab (RTX) is generally the second-line therapy of choice. Cyclophosphamide (CYC) may be considered if RTX is 100 (25)
contraindicated or not available.

2.3.3. Another second-line therapy (i.e., CYC, if RTX was used first, or vice versa) can be used in any patient with severe 96 (25)
disease who fails to improve adequately 1–3 mo following initiation of the first second-line immunotherapy.

2.3.4. Escalation to IV tocilizumab should be considered only in the most refractory patients who fail to improve 80 (25)
adequately after about 1–3 mo of treatment with RTX and/or CYC.

2.4. Maintenance (>6 mo) immune suppression with mycophenolate mofetil (MMF) or RTX redosing after first event of pediatric NMDARE

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

2.4.2. Maintenance (>6 mo) immune suppression can be considered in any patient who fails to improve adequately despite 96 (25)
conventional second-line or escalation therapy.

2.4.3. RTX redosing (when repopulation of CD19 occurs) and MMF are appropriate treatments if maintenance (>6 mo) 96 (25)
immune suppression is required.

Continued

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 Table 2 Consensus-Based Recommendations on the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis
(NMDARE): General Principles (2.1), First-Line Immunotherapy (2.2), Second-Line Immunotherapy (2.3),
Maintenance Immune Suppression (2.4), and Overall Duration of Immunotherapy (2.5) (continued)
Agree % (number
Statements reaching consensus voting)a

2.4.4. Prolonged first-line therapy (with IVMP, DEX, and IVIG) can be used as an alternative form of maintenance (>6 mo) 96 (25)
immunotherapy if RTX and mycophenolate are not available (i.e., in countries without access to other maintenance
immunotherapies).

2.5. Overall duration of immunotherapy during first event of pediatric NMDARE

2.5.1. In the absence of clinical relapse, the overall duration of total immunotherapy (including all first line, second line, 96 (24)
and maintenance, i.e., IVMP to completion of MMF, or to B-cell repopulation after RTX) depends on the severity of the
clinical picture, the response to first- and second-line or escalation immunotherapy, and treatment adverse reactions.
As a guidelineb,c:
• Median 3 mo (IQR 3–6 mo, range 1–18 mo), in the best responders (without relapse or adverse reactions)
• Median 9 mo (IQR 6–12 mo, range 1–24 mo), in the average responders (without relapse or adverse reactions)
• Median 18 mo (IQR 12–24 mo, range 1–25 mo), in the poorest responders (without relapse or adverse reactions).

Abbreviations: IQR = interquartile range; OP = oral prednisone.

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 in
eAppendix 1 (links.lww.com/NXI/A530).
b
A general guide toward understanding clinical response in children with NMDARE (in the absence of clinical relapse), and its role in determining the overall
duration of total immunotherapy, can be found in Table 5.
c
The timelines were voted on during the Delphi process (eAppendix 1).

face meeting are presented in Tables 1–4 and the Figure. definitions of failure to respond, and timing of treatment esca-
Table 1 shows the key definitions in pediatric NMDARE lation. Indeed, although the management of pediatric
(disease severity, failure to improve, and relapse), which NMDARE should ideally be guided by a pediatric neurology
reached consensus support. In addition, to aid clinicians with team in a center with multidisciplinary expertise in NMDARE,
less experience in the management of NMDARE, definitions this may not always be possible, particularly in the acute phase
for best, average, and poorest responders are described (Table of the disease.
5). Tables 2 and 3 show the recommendations for the treat-
ment of pediatric NMDARE and are subdivided into general Our recommendations begin with general management princi-
management principles (Table 2, 2.1), treatment of first en- ples, highlighting the importance of early diagnosis and careful
cephalitis event including first-line, second-line, and mainte- communication with the family (Table 2, 2.1). The importance of
nance immunotherapy (Table 2, 2.2–2.4), overall duration of raising awareness of this disorder, which may present to psychi-
immunotherapy at first event (Table 2, 2.5), treatment at atrists and emergency physicians as well as neurologists, cannot be
relapse (Table 3, 3.1), treatment of NMDARE triggered by overemphasized, and the diagnostic criteria26 and modification for
preceding herpes simplex virus encephalitis (HSE) (Table 3, children,27 along with the distinctive clinical characteristics,12,28,29
3.2), symptomatic treatments (Table 3, 3.3), and oncologic may aid an expeditious diagnosis. Similarly, families need to be
searches (Table 3, 3.4). Table 4 shows the recommendations informed of the expected or potential disease evolution, the
for immunotherapy doses and regimens.23-25 The Figure treatment possibilities, and the often long and demanding course
provides a therapeutic pathway for guidance. of the illness. Understanding the timeline of the disease and the
speed of recovery is one of the greatest challenges of this disease,
and it is essential for clinicians and family members to appreciate
Discussion that the typical course is of little change (or worsening) in the
Evidence on treatment of NMDARE is restricted to retro- first weeks and slow improvements in the following months, and
spective and some prospective descriptive studies. No improvements may continue into the second year.
consensus-based treatment guidelines have previously been
proposed. Hence, our purpose was to create international As regards first-line immunotherapy (Table 2, 2.2), there was
consensus-based recommendations for the treatment of pedi- consensus that corticosteroids are the first agent to be used in
atric NMDARE, with expertise from an international group of pediatric NMDARE, with IV use (i.e., IV methylprednisolone)
clinical and academic pediatric neurologists and rheumatolo- preferred over oral use (i.e., oral prednisone), although high-dose
gists. Our vision was to have a global approach with applicability oral administration of corticosteroids is a good alternative, par-
across all health care settings; therefore, the expert Panel in- ticularly if IV access is a problem. In high-income countries,
cluded representatives from all continents. We also wanted this therapeutic plasma exchange (TPE) and/or IV immunoglobulin
document to be useful for clinicians less experienced in the (IVIg) are often used in conjunction with corticosteroids.30 Al-
treatment of autoimmune encephalitis; hence, a practical and though some physicians use TPE or IVIg at the same time as
detailed approach was adopted wherever possible, including corticosteroids, other administer them sequentially, with more

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Table 3 Consensus-Based Recommendations on the Table 3 Consensus-Based Recommendations on the
Treatment of Pediatric NMDAR Antibody Treatment of Pediatric NMDAR Antibody
Encephalitis (NMDARE): NMDARE Relapse (3.1), Encephalitis (NMDARE): NMDARE Relapse (3.1),
Herpes Simplex Virus Encephalitis Followed by Herpes Simplex Virus Encephalitis Followed by
NMDARE (3.2), Symptomatic Therapies (3.3), and NMDARE (3.2), Symptomatic Therapies (3.3), and
Oncologic Searches (3.4) Oncologic Searches (3.4) (continued)
Agree % (number Agree % (number
Statements reaching consensus voting)a Statements reaching consensus voting)a

3.1. Pediatric NMDARE relapse: first-line, second-line immunotherapy, 3.3.2. Use of antipsychotics and management of 96 (25)
and maintenance (>6 mo) immune suppression psychiatric symptoms should be undertaken in
collaboration with a child psychiatrist. It should
3.1.1. First-line immunotherapy should be offered 96 (25) be remembered that the use of antipsychotics in
to all children with NMDARE relapse, even if they children with NMDARE may be associated with a
are improving at the time of diagnosis (i.e., late worsening of dyskinesia or result in neuroleptic
diagnosis or rapid improvement and remission). malignant syndrome.
First-line immunotherapy and combinations can
be used as per Table 2, 2.2. 3.3.3. In descending order of recommendation, 92 (25)
the following agents can be useful in the
3.1.2. In patients who relapse, second-line 100 (25) symptomatic management of agitation:
immunotherapy and/or maintenance (>6 mo) benzodiazepines, sleep induction agents (chloral
immunotherapy (mycophenolate mofetil or hydrate or melatonin), alpha adrenergic agents
rituximab [RTX] redosing) should be considered, (clonidine and dexmedetomidine), and atypical
started within median 2 wk after initiation of first- antipsychotics (risperidone, olanzapine, and
line treatment (range 1–3 wk).c quetiapine).d

3.1.3. Although generally only one second-line 100 (25) 3.3.4. In descending order of recommendation, 88 (24)
treatment is used, another second-line treatment the following agents can be useful in the
(i.e., cyclophosphamide [CYC], if RTX was used symptomatic management of dyskinesia and
first, or vice versa) can be used in patients who fail stereotypy: alpha adrenergic agents (clonidine
to improve after relapse. and dexmedetomidine), benzodiazepines,
antiepileptics (valproate, carbamazepine, and
3.1.4. In patients with NMDARE relapse, escalation 84 (25) gabapentin), anticholinergic agents, and sleep
to IV tocilizumab should be considered only in the induction (chloral hydrate or melatonin).d
most refractory patients who fail to improve
adequately after about 1–3 mo of treatment with 3.4. Oncologic searches
RTX and/or CYC.
3.4.1. Tumor searches for ovarian teratoma and 100 (25)
3.1.5. Duration of maintenance 88 (25) other tumors are mandatory in all children with
immunosuppression in patients with relapse NMDARE, should be started early, and be
should be 12–24 mo depending on the severity of completed in the first days to weeks after
the clinical picture, the response to first- and admission. If tumor is found, removal is required
second-line immunotherapy, the number of as this can result in rapid improvements.
relapses, and treatment adverse reactions.
3.4.2. Generally recommended tumor searches 88 (25)
3.1.6. If NMDARE relapse occurs while on 84 (25) include the following:
maintenance immunosuppression (RTX Ovarian/testicular ultrasound and/or MRI abdomen
redosing, mycophenolate, or prolonged first- and pelvis (in all patients)
line treatment) given for first event, prompt first- Urinary catecholamines and/or CT or MRI of the chest
line immunotherapy should be administered (i.e., (in very young patients aged <5 y)b
IV methylprednisolone and/or therapeutic It is important to consult oncologists and radiologists
plasma exchange/IV immunoglobulin), for best imaging modality to search occult tumors.
followed by second-line treatment and
alternative maintenance immunosuppression. 3.4.3. Recommended duration for tumor searches 92 (26)
(if no tumor found on initial searches) is:
3.2. Herpes simplex virus encephalitis (HSE) followed by NMDARE in • In patients with good recovery:
children o Prepubertal females and all males: only at diagnosis
o Postpubertal females: annually up to 2 y
3.2.1. Patients with relapse of neurologic 84 (25) • In all patients who fail to improve adequately, or
symptoms after HSE should be given acyclovir relapse: annually up to 5 y (or at the time of relapse).
promptly (until HSE can be excluded based on
clinical picture and negative CSF herpes a
The agreement percentage shown in the last column refers to the final
simplex virus PCR), while maintaining a high index
face-to-face agreement; the Delphi 1 and 2 agreement percentages are
of suspicion for an underlying autoimmune shown in eAppendix 1 (links.lww.com/NXI/A530).
etiology. b
Due to the possible presence of neural crest tumor.
c
The timelines were voted on during the Delphi process (eAppendix 1).
3.2.2. Patients with NMDARE following HSE should 96 (25) d
These agents were voted on during the Delphi process (eAppendix 1). All
be treated with immunotherapy in a similar way the listed agents were supported by different members of the Panel, but
to those with naive NMDARE. only benzodiazepines and sleep induction agents reached 75% consensus
support (eAppendix 1).
3.3. Symptomatic therapies for pediatric NMDARE

3.3.1. Assessment of improvement following 100 (25)

immunotherapy (i.e., failure to improve) is
severe patients often prompting a more aggressive combined
contingent on optimization of treatments for treatment or rapid escalation. TPE was recommended for pa-
sleep, agitation, mood/behavior, dyskinesia, and
seizures.
tients with severe disease, although it is recognized that TPE can
be associated with more severe complications (e.g., central line

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 Table 4 Treatment Regimens and Doses for Pediatric NMDAR Antibody Encephalitis (NMDARE) (95% Agreement, 22
Voting—Final Face-to-Face Agreement)
Treatment regimens and doses

Immunotherapies Type of use Dose/mode of administration

IV First-line immunotherapy 20–30 mg/kg/d (max 1 g/d) for 3–5 d

methylprednisolone
Prolonged first-line 20–30 mg/kg/d (max 1 g/d) for 1–3 d, monthly
immunotherapy

Oral prednisone First-line immunotherapy: 2 mg/kg/d (max 60 mg/d) for 1 wk, then gradually tapered (see main guideline)
alternative to IV corticosteroids
First-line immunotherapy: taper
after IV corticosteroids
Prolonged first-line
immunotherapy

Oral First-line immunotherapy: 20 mg/m2/d (divided into 2 or 3 doses, max 12 mg tid) for 3 d
dexamethasone alternative to IV corticosteroids

First-line immunotherapy: taper 20 mg/m2/d (divided into 2 or 3 doses, max 12 mg tid) for 3 d, every 3–4 wk
after IV corticosteroids
Prolonged first-line
immunotherapy

Therapeutic plasma First-line immunotherapy One course is typically 5–7 single or double plasma volume exchanges over 7–10 d
exchange

IV immunoglobulin First-line immunotherapy 2 g/kg over 2–5 d

Prolonged first-line 1–2 g/kg over 1–2 d, monthly

immunotherapy

IV rituximab Second-line immunotherapy The following doses are acceptable:

• 500–1,000 mg (500 mg for <40 kg, 1,000 mg for >40 kg) given twice separated by 2 wk, or
• 375–750 mg/m2 (max 1 g), given twice separated by 2 wk, or
• 375 mg/m2 (max 1 g) weekly for 4 wk

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

IV Second-line immunotherapy 500–1,000 mg/m2 (max 1,500 mg)23–25 monthly pulses for up to 6 mo
cyclophosphamide

Oral Maintenance (>6 mo) immune 600 mg/m2/dose (max 1 g/dose) twice a day
mycophenolate suppression
mofetil

IV tocilizumab Escalation second-line 12 mg/kg/dose (<30 kg), 8 mg/kg/dose (≥30 kg) (max 800 mg) given monthly over 6 mo or more
immunotherapy (duration of required immunosuppression)

infection) compared with IVIg.31,32 TPE was recommended over immunotherapy improves outcome in patients failing to im-
immunoadsorption, where there is less evidence.33,34 In general, prove after first-line therapy2 and that second-line therapy
ongoing corticosteroids are continued in the first months of reduces the risk of relapses.8,9,13 Moreover, earlier initiation of
disease, preferably as pulses, or alternatively oral tapers. Longer or rituximab also seems more favorable compared with late
repeated IVIg courses may be continued monthly for 3–6 treatment.7
months, depending on severity and availability, whereas monthly
pulsed oral dexamethasone or IV methylprednisolone, or even The use of second-line immunotherapy is still variable glob-
ACTH, for 3-6 months may be used in resource-limited settings. ally and considerably less frequent in some countries. For
instance, rituximab use is 0%–5.5% in Chinese cohorts35-37
In patients who are failing to improve (definition in Table 1) and more variable in India (0%–61%),38-40 although with
approximately 2 weeks after initiation of 2 or more first-line generally favorable outcomes, which suggests the outcomes
therapies, second-line treatment is recommended over further described in the published literature may be affected by re-
first-line therapies. Second-line treatments are recommended ferral bias, publication bias, or ethnic vulnerability to worse
especially in patients with severe disease, with rituximab now outcomes.41 The specific approaches toward the use of
generally preferred over cyclophosphamide (Table 2, 2.3). second-line immunotherapy varied within the Panel, with
Rituximab dosing protocols were all equally accepted (Table some clinicians supporting the use of rituximab in all patients
4) as there are no data to support one protocol over another. with NMDARE and others reserving it to cases with severe
There is evidence suggesting that use of second-line disease or failure to improve (Table 1). The consensus

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

opinion was that second-line therapy is not needed in all One of the greatest challenges is deciding the timing of es-
patients, but only in patients with severe disease and those calation after 1 second-line therapy. There was consensus that
who fail to improve. in the patient failing to improve 1-3 months (generally >6

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 Table 5 Definition of Responder to Immunotherapy
Definition of response to immunotherapy

Best responder: These patients, regardless of severity, improve rapidly after immunotherapy (within weeks) and are clearly making functional gains in the first
2 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 treatment
commencement, but in the second and third month start to make clear functional gains. By 6 mo, the patient is home and may still have deficits, but continues
to make slow improvements.

Poorest responder: These patients fail to make substantial and functionally useful improvements in the first 3 mo after treatment commencement, remain
impaired, and have significant care needs. These patients require prolonged rehabilitation and inpatient care, often for >3 mo.

The following definitions of responder to immunotherapy are generated as a general guidance for a global audience and to support clinicians less familiar
with the treatment of pediatric NMDAR antibody encephalitis, especially with regard to the duration of total immunotherapy (Table 2, 2.5).

weeks) following initiation of the first second-line immuno- sequelae from ongoing inflammation. In this situation, CSF re-
therapy, another second-line therapy such as cyclophospha- examination for ongoing neuroinflammation (i.e., persistent
mide if rituximab was used first can be considered. pleocytosis, intrathecal oligoclonal bands, elevated immuno-
globulin G [IgG] index, or CSF neopterin)58 may help with
In the patient who fails rituximab, cyclophosphamide is gen- decision making and the risk vs benefit consideration of an
erally recommended as an escalation agent, although some empiric retrial or immunotherapy (pulsed corticosteroid for 3
members of the Panel have increasing interest in tocilizumab months, IVIg monthly, rituximab reinduction, or tocilizumab).
as an alternative escalation therapy due to a more favorable CSF NMDAR antibody titers seem to correlate better with
perceived safety profile.42-44 Other escalation treatments have disease course compared with serum antibodies,59,60 but there is
been reported in the literature, such as IV/intrathecal meth- not a strong correlation between titer and clinical course in the
otrexate with intrathecal corticosteroids and subcutaneous/IV individual patient, and antibodies can persist long after recov-
bortezomib; these have more limited evidence, but can be ery.60,e1,e2 Although all stages of management of NMDARE
used according to the local treating center’s expertise.41,43-57 may be challenging even for experienced physicians, this is es-
pecially true when dealing with a severe patient failing to im-
The patient who has severe disease and is failing to improve prove, and a second opinion may be useful and help the clinician
remains a major challenge. The clinician needs to balance the make further therapeutic decisions. Organizations such as the
risk of severe disease (such as being on the intensive care unit) Autoimmune Encephalitis Alliance (aealliance.org/), the En-
with the risk of treatment side effects, in the knowledge that cephalitis Society (encephalitis.info/), and the Anti NMDA
NMDARE symptoms may take many weeks or months to Receptor Encephalitis Foundation Inc. (antinmdafoundation.
improve.2,7 Indeed, unlike in acute disseminated encephalo- org/) may help connect with experts.
myelitis, when treatment often results in rapid improvements
within days, in NMDARE, the improvements are slow and There was overall agreement that maintenance immune sup-
continue for ≥24 months after the acute phase.2 Therefore, pression beyond 6 months from onset is generally not needed
allowing treatments to have their effect, including their (Table 2, 2.4), apart from patients with more severe course or
combined actions, is important to avoid hasty therapeutic prolonged impairments and hospitalization. Indeed, literature
decisions. In general, second-line agents such as rituximab or data show that early and adequate treatment, including use of
cyclophosphamide should be given 1-3 months before making second-line therapies when appropriate, is the priority,2 rather
judgment on effect, with 6 weeks being a broadly accepted than prolonged maintenance immune suppression. Moreover,
guideline. The timing of escalation is very challenging and the relatively low relapse rate of NMDARE is in significant
influenced by severity, age, risk-benefit ratio, treating center’s contrast with that of other disorders such as neuromyelitis
experience, and access to treatments. Overall, for patients in optica, where chronic immune suppression is recommended
the intensive care unit, where there may be multiple additional from the first event. When giving immune suppression for
risk factors,7 earlier escalation seems reasonable. Anecdotal more than 6 months, rituximab redosing was generally pre-
reports from our expert group of benefit of treatment with ferred, although mycophenolate mofetil is also used,9,36,e3-e5
rituximab or tocilizumab years after onset suggest that in the and there is little evidence to suggest superiority of either. With
patient who continues to have major impairments, further regard to rituximab redosing, most experts recommend
immunotherapies are warranted within reason, although there redosing when CD19 cells repopulate, in view of the variability
are likely to be diminishing returns when treatment is used in the time to B-cell repopulation between individuals.e6 An
later in the disease course. alternative approach is to redose rituximab at regular 6-month
intervals similar to practice in adult patients with neuromyelitis
In the patient who has failed to improve a year or more after optica.e7,e8 There was no consensus in the dosage and fre-
treatment, it is sometimes difficult to determine residual quency of redosing, with some experts using the same dose/

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regimen used at induction and others using lower doses (Table of behavior agitation and dyskinesia (full list of medications
4). As regards mycophenolate mofetil, given its slow onset of considered is detailed in eAppendix 1, links.lww.com/NXI/
efficacy, there should initially be overlap with other immuno- A530). Caution was also drawn to the observation that the use
therapies (i.e., oral corticosteroids) for 3-6 months after com- of antipsychotics in pediatric NMDARE may worsen dyski-
mencement.e3 Other maintenance agents, such as oral nesia or induce a neuroleptic malignant syndrome.
azathioprine and methotrexate, are sometimes used for main-
tenance immune suppression, although the paucity of experi- Although paraneoplastic etiology is rare in prepubertal children
ence precluded consensus recommendations from our expert and in boys,2,9,e12 oncologic searches for ovarian teratoma (and
group. In resource-poor countries, the Panel also agreed that neural crest tumors in children aged <5 years) are mandatory in
prolonged first-line therapy (with IV pulsed methylpredniso- all children with NMDARE, should be performed early, and be
lone, dexamethasone, or IVIg) can be used as an alternative completed in the first days-weeks after admission (Table 3, 3.4).
form of maintenance (>6 months) immunotherapy, if ritux- Ultrasound or MRI of the abdomen and pelvis and CT or MRI
imab and mycophenolate mofetil are not available. of the chest are the recommended imaging modalities, and
collaboration with local oncologists and radiologists will help
There was agreement in the need for a more aggressive and guide the need for additional studies (e.g., PET scan) to optimize
prolonged treatment approach in patients with relapsing diagnostic yield in patients with severe disease or a failure to
disease (Table 3, 3.1), with a lower threshold for second-line improve. The timely identification of a tumor and its subsequent
and maintenance treatments (rituximab or mycophenolate) removal may improve the outcome considerably, although the
and more prolonged overall immunotherapy duration. In- prognosis also depends on the type of tumor.2,e12 The Panel
deed, the median overall duration of immunotherapy at first reached agreement on oncologic searches that should be per-
event of pediatric NMDARE was recommended to be about 3 formed in all patients, both at baseline and in patients who fail to
months (IQR 3–6 months) in the best responders, 9 months improve or relapse, with particular focus on postpubertal females
(IQR 6–12 months) in the average responders, 18 months in whom ovarian teratoma screening and longitudinal surveil-
(IQR 12–24 months) in the poorest responders (Table 2, lance for ovarian teratoma should be strongly pursued.
2.5), and 12–24 months after a relapse, acknowledging patient
severity and management variables (Table 3, 3.1). We ac- Although not the main aim of this consensus document, the
knowledge that the definition of “best,” “average,” and Panel acknowledged that adequate rehabilitation after the
“poorest” is dependent on experience of the clinician; there- acute phase of NMDARE is essential and may improve out-
fore, some guidance is provided in Table 5. comes. We strongly support the need for rehabilitation to be
provided in a center familiar with rehabilitating young people
Although not the focus of this work, the Panel acknowledges with acquired brain injury such as encephalitis or traumatic
that infectious risk mitigation strategies are key to ensure the brain injury, acknowledging that improvements may continue
patients’ safety while receiving immunotherapy, especially for up to 24 months. Rehabilitation often includes focus on
close monitoring for infections and adherence to hospital cognitive and behavioral problems (including executive dys-
infection control protocols to prevent hospital acquired in- function and fatigue) post-NMDARE.
fection. In selected patients on prolonged high-dose cortico-
steroids, multiple second-line or escalation immunotherapies, In view of the relative rarity of this condition, any recom-
prophylactic trimethoprim-sulfamethoxazole for Pneumocystis mendation or guideline for the treatment of pediatric
carinii pneumonia may be required. In patients with low IgG NMDARE is inevitably based on limited evidence; therefore,
levels and recurrent infections despite prophylactic antibi- this document should be intended as a recommendation
otics, immunoglobulin supplementation may be required. meant to provide guidance rather than absolute rules, and it
should not be used to prevent access to therapies if these are
As regards patients with relapse of neurologic symptoms after recommended by a patient’s physician. Moreover, by putting
HSE (Table 3, 3.2), acyclovir should be administered promptly together international experts from very different settings, the
until HSE recurrence is excluded, while maintaining a high present work highlighted heterogeneity in the management of
index of suspicion for an underlying autoimmune etiology. The this condition. The differences stimulated discussion and re-
Panel agreed that if autoimmune encephalitis is confirmed after flection, and there was still consensus around most aspects of
HSE, immunotherapy should be used in a similar way to pediatric NMDARE treatment. Although the experts included
idiopathic/naive NMDARE.e9,e10 people with broad international expertise, the opinions re-
main vulnerable to anecdote and potential bias related to
The Panel acknowledged that although immunotherapy is the referral of complicated or atypical patients.
therapeutic priority to treat the underlying disease, symptom-
atic management (such as antiseizure medications) is equally Despite these limitations, we strove to create an international
important (Table 3, 3.3). However, symptom management consensus-based recommendation aimed at supporting the
may be challenging and requires multidisciplinary expertise.e11 clinician in the treatment of pediatric NMDARE, with a
As stated in the recommendations, there was consensus on a dedicated global approach for all health care settings. We hope
preferred list of medications found to be useful in the treatment that with the aid of recently released diagnostic criteria,26,27

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 the present treatment recommendation may contribute to a assays for LGI1 and other VGKC-complex antibodies) and on
more systematic approach, resulting in more comparable data an unlicensed patent to improve detection of autoantibodies.
internationally, which may generate better quality evidence. J. Dalmau reports no disclosures relevant to the manuscript.
Nonetheless, there are still major unresolved issues, which M. Lim has received consultation fees from CSL Behring,
should represent the focus of future research. Novartis, and Octapharma; travel grants from Merck Serono;
and was awarded educational grants to organize meetings by
Acknowledgment Novartis, Biogen Idec, Merck Serono, and Bayer. R.C. Dale
The authors thank Kimberley de Haseth from AEA and the reports no disclosures relevant to the manuscript. Go to
De Vivero family for support and advice. Neurology.org/NN for full disclosures.

Study Funding Publication History

There was funding commitment for the face to face meeting by Received by Neurology: Neuroimmunology & Neuroinflammation
the Autoimmune Encephalitis Alliance (AEA), which due to February 14, 2021. Accepted in final form May 21, 2021.
COVID-19 was not needed, as the face-to-face meeting was
virtual. AEA has supported costs of open access for journal
publication. M. Eyre is supported by Action Medical Research
and the British Paediatric Neurology Association. T. Armangue is Appendix Authors
supported by research grants Instituto Carlos III/FEDER, Spain Name Location Contribution
(PI18/00486) and Generalitat de Catalunya PERIS (SLT006/
Margherita Paediatric Neurology and Literature review;
17/00362). S.R. Irani is supported by the Wellcome Trust Nosadini, Neurophysiology Unit, participation to the Delphi
(104079/Z/14/Z), the UCB-Oxford University Alliance, BMA MD, PhD Department of Women’s process and the final online
and Children’s Health, face-to-face meeting for
Research Grants Vera Down grant (2013) and Margaret Temple University Hospital of creation of the consensus
(2017), Epilepsy Research UK (P1201), the Fulbright UK-US Padova, Italy treatment statements;
preparation of the
commission (MS-Society research award), and by the NIHR recommendation draft;
Oxford Biomedical Research Centre. The views expressed are editing and approval of the
final draft; and access to all the
those of the author(s) and not necessarily those of the NHS, the data and responsibility for
NIHR, or the Department of Health). RCD is supported by the data, accuracy of the data
NHMRC Investigator grant (Australia) and Petre Foundation. analysis, and the conduct of
the research

Disclosure Terrence Department of Paediatrics, Participation to the Delphi

Thomas, MD Neurology Service, KK process and the final online
M. Nosadini, T. Thomas, M. Eyre, B. Anlar, T. Armangue, Women’s and Children’s face-to-face meeting for
S.M. Benseler, T. Cellucci, K. Deiva, and W. Gallentine report Hospital, Singapore creation of the consensus
treatment statements;
no disclosures relevant to the manuscript. G. Gombolay re- technical support, data
ceives part-time salary support from the Centers for Disease analysis; preparation of the
recommendation draft; and
Control and Prevention to review acute flaccid myelitis cases editing and approval of the
for surveillance. M.P. Gorman has received research funding final draft
from Pfizer and Roche for research unrelated to the current Michael Eyre, Department of Paediatric Participation to the Delphi
topic. Y. Hacohen, Y. Jiang, B.C. Lim, E. Muscal, and A. MD Neurology, Great Ormond process and the final online
Street Hospital for Children, face-to-face meeting for
Ndondo report no disclosures relevant to the manuscript. R. London, United Kingdom creation of the consensus
Neuteboom participates in treatment studies in pediatric MS treatment statements;
preparation of the
by Novartis and Sanofi-Genzyme and received consultation recommendation draft; and
fees from Novartis, Zogenix, and Sanofi-Genzyme. K. Rostásy, editing and approval of the
H. Sakuma, and S. Sharma report no disclosures relevant to final draft

the manuscript. S.N. Tenembaum participates as member of Banu Anlar, Department of Pediatric Participation to the Delphi
the NMO Scientific Advisory Committee (Genentech-Roche MD Neurology, Hacettepe process and the final online
University, Ankara, Turkey face-to-face meeting for
Inc.) and chair of the NMO Relapse Adjudication Committee creation of the consensus
(Alexion Pharmaceuticals Inc.); she has received speaker treatment statements and
revision of the manuscript
honoraria from Biogen Idec Argentina, Merck Serono for intellectual content
LATAM, Genzyme, Novartis Argentina, and Novartis Pharma
Thais Neuroimmunology Program, Participation to the Delphi
Inc. H.A. Van Mater and E. Wells report no disclosures rel- Armangue, Institut d’Investigacions process and the final online
evant to the manuscript. R. Wickstrom has received consul- MD, PhD Biomèdiques August Pi i face-to-face meeting for
Sunyer (IDIBAPS), Hospital creation of the consensus
tation fees from Roche, Novartis, and Octapharma. A.K. Clı́nic, Universitat de treatment statements and
Yeshokumar reports no disclosures relevant to the manu- Barcelona, Spain; Pediatric revision of the manuscript
Neuroimmunology Unit, for intellectual content
script. S.R. Irani is a coapplicant and receives royalties on Neurology Department, Sant
patent application WO/210/046716 (U.K. patent no., PCT/ Joan de Déu (SJD) Children’s
GB2009/051441) entitled “Neurological Autoimmune Dis- Hospital, University of
Barcelona, Spain
orders” (the patent has been licensed for the development of

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Appendix (continued) Appendix (continued)

Name Location Contribution Name Location Contribution

Susanne M. Alberta Children’s Hospital Participation to the Delphi Eyal Muscal, Department of Pediatrics, Participation to the Delphi
Benseler, MD Research Institute, process and the final online MD, MS Section Rheumatology, co- process and the final online
Department of Pediatrics, face-to-face meeting for appointment in the section of face-to-face meeting for
Cumming School of creation of the consensus Neurology and creation of the consensus
Medicine, University of treatment statements and Developmental Neuroscience, treatment statements and
Calgary, Canada revision of the manuscript Texas Children’s Hospital, revision of the manuscript
for intellectual content Baylor College of Medicine, for intellectual content
Houston, TX
Tania Division of Rheumatology, Participation to the Delphi
Cellucci, MD, Department of Pediatrics, process and the final online Alvin Division of Paediatric Participation to the Delphi
FRCPC, McMaster University, face-to-face meeting for Ndondo, MD Neurology, Department of process and the final online
MScCH Hamilton, Ontario, Canada creation of the consensus Paediatrics and Child face-to-face meeting for
treatment statements and Health, Red Cross War creation of the consensus
revision of the manuscript Memorial Children’s treatment statements and
for intellectual content Hospital, University of Cape revision of the manuscript
Town; Faculty of Health for intellectual content
Kumaran Assistance Publique-Hôpitaux Participation to the Delphi Sciences, University of Cape
Deiva, MD de Paris, Pediatric Neurology process and the final online Town Neuroscience
Department, University face-to-face meeting for Institute, South Africa
Hospitals Paris Saclay, Bicêtre creation of the consensus
Hospital, France; French treatment statements and Rinze Department of Neurology, Participation to the Delphi
Reference Network of Rare revision of the manuscript Neuteboom, Erasmus Medical Center, process and the final online
Inflammatory Brain and Spinal for intellectual content MD, PhD Rotterdam, the Netherlands face-to-face meeting for
Diseases, Le Kremlin Bicêtre, creation of the consensus
France and European treatment statements and
Reference Network-RITA, revision of the manuscript
France for intellectual content

William Departments of Neurology Participation to the Delphi Kevin Department of Pediatric Participation to the Delphi
Gallentine, and Pediatrics, Stanford process and the final online Rostásy, MD Neurology, Children’s process and the final
DO University and Lucile face-to-face meeting for Hospital Datteln, University online face-to-face
Packard Children’s Hospital, creation of the consensus Witten/Herdecke, Germany meeting for creation of the
Palo Alto, CA treatment statements and consensus treatment
revision of the manuscript statements and revision of
for intellectual content the manuscript for
intellectual content
Grace Division of Pediatric Participation to the Delphi
Gombolay, Neurology, Department of process and the final online Hiroshi Department of Brain and Participation to the Delphi
MD Pediatrics, Emory University face-to-face meeting for Sakuma, MD Neural Science, Tokyo process and the final online
School of Medicine and creation of the consensus Metropolitan Institute of face-to-face meeting for
Children’s Healthcare of treatment statements and Medical Science, Japan creation of the consensus
Atlanta, GA revision of the manuscript treatment statements and
for intellectual content revision of the manuscript
for intellectual content
Mark P. Department of Neurology, Participation to the Delphi
Gorman, MD Boston Children’s Hospital, process and the final online Suvasini Department of Pediatrics Participation to the Delphi
Harvard Medical School, face-to-face meeting for Sharma, MD (Neurology Division), Lady process and the final online
Boston, MA creation of the consensus Hardinge Medical College face-to-face meeting for
treatment statements and and Associated Kalawati creation of the consensus
revision of the manuscript Saran Children’s Hospital, treatment statements and
for intellectual content New Delhi, India revision of the manuscript
for intellectual content
Yael Department of Participation to the Delphi
Hacohen, MD Neuroinflammation, Queen process and the final online Silvia Noemi Department of Neurology, Participation to the Delphi
Square MS Centre, UCL face-to-face meeting for Tenembaum, National Pediatric Hospital process and the final online
Institute of Neurology, creation of the consensus MD Dr. J. Garrahan, Buenos face-to-face meeting for
University College London; treatment statements and Aires, Argentina creation of the consensus
Department of Paediatric revision of the manuscript treatment statements and
Neurology, Great Ormond for intellectual content revision of the manuscript
Street Hospital for Children, for intellectual content
London, United Kingdom
Heather Ann Department of Pediatrics, Participation to the Delphi
Yuwu Jiang, Department of Pediatrics, Participation to the Delphi Van Mater, Duke University, Durham, process and the final online
MD Peking University First process for creation of the MD NC face-to-face meeting for
Hospital, Beijing, China consensus treatment creation of the consensus
statements and revision of treatment statements and
the manuscript for revision of the manuscript
intellectual content for intellectual content

Byung Chan Department of Pediatrics, Participation to the Delphi Elizabeth Department of Neurology, Participation to the Delphi
Lim, MD Pediatric Clinical process and the final online Wells, MD Children’s National Medical process and the final online
Neuroscience Center, Seoul face-to-face meeting for Center, Washington, DC face-to-face meeting for
National University creation of the consensus creation of the consensus
Children’s Hospital, Seoul treatment statements and treatment statements and
National University College revision of the manuscript revision of the manuscript
of Medicine, South Korea for intellectual content for intellectual content

Continued

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 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-
Appendix (continued)
paraneoplastic disorder of both sexes. Brain. 2010;133(pt 6):1655-1667.
5. Hacohen Y, Absoud M, Hemingway C, et al. NMDA receptor antibodies associated
Name Location Contribution
with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm. 2014;
1(1):e2.
Ronny Neuropaediatric Unit, Participation to the Delphi 6. Byrne S, Walsh C, Hacohen Y, et al. Earlier treatment of NMDAR antibody en-
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Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | 0 0 15

 International Consensus Recommendations for the Treatment of Pediatric NMDAR
Antibody Encephalitis
Margherita Nosadini, Terrence Thomas, Michael Eyre, et al.
Neurol Neuroimmunol Neuroinflamm 2021;8;
DOI 10.1212/NXI.0000000000001052

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