Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study

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Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study Thaís Armangue, Gemma Olivé-Cirera, Eugenia Martínez-Hernandez, Maria Sepulveda, Raquel Ruiz-Garcia, Marta Muñoz-Batista, Helena Ariño, Veronica González-Álvarez, Ana Felipe-Rucián, Maria Jesús Martínez-González, Veronica Cantarín-Extremera, Maria Concepción Miranda-Herrero, Lorena Monge-Galindo, Miguel Tomás-Vila, Elena Miravet, Ignacio Málaga, Georgina Arrambide, Cristina Auger, Mar Tintoré, Xavier Montalban, Adeline Vanderver, Francesc Graus, Albert Saiz, Josep Dalmau, on behalf of the Spanish Pediatric anti-MOG Study Group*

Summary

Background Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis.

Lancet Neurol 2020

Methods In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher’s exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity.

See Online/Comment https://doi.org/10.1016/ S1474-4422(20)30032-6

Findings Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7–10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22–67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05–0·59). Interpretation The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. Funding Mutua Madrileña Foundation; ISCIII–Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX. Copyright © 2020 Elsevier Ltd. All rights reserved.

Introduction During the past 10 years, the concept of inflammatory CNS disease associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) has evolved to include a wide variety of syndromes. In children, several studies have shown that MOG antibodies are associated with acquired demyelinating syndromes such as optic neu­ ritis, myelitis, or acute disseminated enceph­ alo­ myelitis (ADEM), which are often monophasic, have

a clinical course different from multiple sclerosis, and although most patients receive immunotherapy, it is rarely used as long-term treatment.1–5 There are cases, however, in which MOG antibodies occur in associ­ation with relaps­ing optic neu­ritis, multiphasic ADEM, ADEM followed by optic neu­ritis (ADEM-ON), or neuro­myelitis optica spect­rum disorder (NMOSD), raising the question of whether these patients might bene­fit from chronic imm­uno­­therapy.6–11 In adults, and exceptionally children,

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Published Online February 10, 2020 https://doi.org/10.1016/ S1474-4422(19)30488-0

*See appendix for a full list of study group members Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain (T Armangue MD, G Olivé-Cirera MD, E Martínez-Hernandez MD, M Sepulveda MD, M Muñoz-Batista BS, H Ariño MD, Prof F Graus MD, Prof A Saiz MD, Prof J Dalmau MD); Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children’s Hospital, University of Barcelona, Barcelona, Spain (T Armangue; V González-Álvarez MD); Neurology Section, Pediatric Service, Hospital Parc Taulí, Sabadell, Barcelona, Spain (G Olivé-Cirera); Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain (R Ruiz-Garcia PhD); Neurology Section, Pediatric Service, Vall d’Hebron Hospital Barcelona, Spain (A Felipe-Rucián MD); Neurology Section, Pediatric Service, Cruces University Hospital, Bizkaia, Spain (M Jesús Martínez-González MD); Pediatric Neurology Section, Hospital Niño Jesús, Madrid, Spain (V Cantarín-Extremera MD); Neurology Section, Pediatric Service, Hospital Gregorio Marañón, Madrid, Spain (M Concepción Miranda-Herrero MD); Neurology Section, Pediactric Service, Hospital

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Miguel Servet, Zaragoza, Spain (L Monge-Galindo MD); Neurology Section, Pediatric Service, Hospital La Fe, Valencia, Spain (M Tomás-Vila MD); Pediatric Neurology Unit, Pediatric Service, Hospital Son Espases Palma de Mallorca, Spain (E Miravet MD); Child Neurology Unit, Hospital Universitario Central de Asturias, Oviedo, Spain (I Málaga MD); Centre d’Esclerosi Múltiple de Catalunya, Department of Neurology (G Arrambide MD, Prof M Tintoré MD, Prof X Montalban MD), and Section of Neuroradiology and Magnetic Resonance Unit, Department of Radiology (C Auger MD), Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Division of Neurology, University of Toronto, St Michael´s Hospital, Toronto, ON, Canada (Prof X Montalban); Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA (A Vanderver MD); Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (A Vanderver, Prof J Dalmau); and Catalan Institute for Research and Advanced Studies, Barcelona, Spain (Prof J Dalmau) Correspondence to: Dr Thaís Armangue, Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children’s Hospital, University of Barcelona, Barcelona 08950, Spain tarmangue@ sjdhospitalbarcelona.org or Prof Josep Dalmau, IDIBAPS, Hospital Clínic, Universitat de Barcelona, Barcelona 08036, Spain [email protected] See Online for appendix

Research in context Evidence before this study We searched MEDLINE and Embase for articles published in English before Sep 30, 2019, using the MeSH terms “myelin oligodendrocyte antibodies” or “MOG antibodies”, alone or in combination with “myelitis”, “optic neuritis”, “acute disseminated encephalomyelitis”, “ADEM”, “neuromyelitis optica spectrum disorders”, “NMOSD”, “NMO”, “children”, “encephalitis”, “pediatric”, “multiple sclerosis”, and “demyelination”. We restricted searches to human studies. We also reviewed the reference lists of the articles identified by this search. According to this search, over the past 10 years, MOG antibodies have become one of the most important biomarkers of several acquired demyelinating syndromes that commonly occur in children. Persistence of MOG antibodies has been suggested to be associated with clinical relapses, although the antibody follow-up has often been short (<6 months) or not done systematically. Although evidence that MOG antibodies are associated with encephalitis (without overt demyelination) exists, the number of reports is limited to a few patients (who are usually adults), the prevalence of MOG antibody-associated encephalitic syndromes is unknown, and the response to treatment and prognosis are unclear. Added value of this study Different from previous studies on MOG antibody-associated syndromes, which mainly focused on demyelinating diseases, our study provides the frequency of MOG antibody-associated syndromes in two large prospective cohorts of paediatric

a few studies12–16 have shown an associ­ation of MOG anti­ bodies with encephalitis other than ADEM. These syndromes and clinical course variants might not yet represent the entire spectrum of MOG antibodyassociated syndromes. Indeed, most previous studies were focused on typical1,3 or atypical8,9,11,17 anti-MOG demye­ linating syndromes, but the spectrum of disorders beyond these syndromes or encephalitis other than ADEM has not been prospectively assessed. The potential identification of novel MOG antibody-associated dis­ orders is important because it might have treatment and prognostic implica­ tions. In this study, we prospect­ ively investigated two cohorts of children with acute demyelin­ating syndromes and encephalitis of any cause to deter­mine the frequency and types of syndromes associated with MOG antibodies. We then focused on the patients who had MOG anti­ bodies, and report the distribution of syndromes at disease onset and relapses, response to treatment and outcome, main imm­uno­logical features, and paediatric phenotypes that were associated with poor prognosis.

Methods

Study design For this prospective observational study, an invitation to participate was sent to the Neuroimmunology and Neuroinfections Study Group and all members of the Spanish Society of Paediatric Neurology. Members and 2

patients affected by acute demyelinating syndromes or encephalitis other than acute disseminated encephalomyelitis (ADEM). We found that among patients with demyelinating disorders, the repertoire of MOG antibody-associated syndromes was broader that that previously reported, with some syndromes unclassifiable according to current criteria or terminology. Among the cohort of patients with encephalitis other than ADEM, MOG antibodies were the most common autoantibodies, surpassing all neuronal antibodies combined. The diagnosis of most of these patients would have been missed if it were not for the systematic screening of our study. The importance of these findings is emphasised by the fact that 85% of all patients with MOG antibody-associated syndromes responded to treatment. Implications of all the available evidence Findings from this study should raise awareness of a broader spectrum of syndromes associated with MOG antibodies. In children, testing for these antibodies should be considered not only in demyelinating syndromes, but also in all types of encephalitis after excluding the infectious causes and others that might be clinically recognisable (eg, anti-NMDA receptor and opsoclonus-myoclonus encephalitis). Recognition of these syndromes, phenotypes of poor outcome, and the value of MOG antibody follow-up in predicting the risk of relapses has important diagnostic and treatment implications. Our findings reveal a need for an update to the current classification and terminology of MOG antibody-associated syndromes.

corresponding centres (n=40) interested in participat­ing were included. All patients identified in each centre with a suspected acquired demyelinating syndrome (cohort A) or an encephalitic syndrome (cohort B) were investigated for MOG antibodies, and those who were positive were then included in our study assessing clinical features, response to treat­ ment, and outcome. Clinical informa­ tion was obtained with structured questionnaires that were com­ pleted at dis­ease onset and every 6 months until the end of the study (appendix pp 11–14). Brain and spinal cord MRIs at disease onset (and when available during the followup) were centrally reviewed at Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clinic (Barcelona). Patients were exclu­ded if the interval between symptom onset and MOG antibody testing was more than 3 months or if the clinical follow-up was shorter than 6 months. Patients with insufficient clinical informa­ tion or those with suspected encephalitis (cohort B) who did not fulfill international criteria of encephalitis were also excluded. Our study was approved by the Internal Review Board of Hospital Clinic, University of Barcelona.

Patients and procedures Encephalitis was defined according to international cri­ teria for inflammatory or infectious encephalitis (appendix pp 1–2).18 Patients were considered to have ADEM if they

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fulfilled criteria previously reported by the International Pediatric Multiple Sclerosis Study Group (IPMSSG; appendix p 2).19 Patients with criteria of enceph­alitis who did not fulfil those of ADEM were defined as encephalitis other than ADEM. Acquired demye­­ lin­ ating syndromes were classified according to IPMSSG criteria,19 except for multiple sclerosis and NMOSD, which were classified according to more recent criteria.20,21 The term ADEM-ON was used to describe ADEM followed by one or more episodes of optic neu­ ritis.22 Relapses were defined as development of new neurological symp­toms 1 month after onset of the initial episode or, in the case of ADEM, 3 months after onset of the initial episode.19 Clinical outcome was assessed with the modified Rankin Scale (mRS).23,24 An mRS score of at least 2 at the last follow-up was considered a poor outcome. Comprehensive neuronal and glial antibody testing was done in serum or CSF of all patients from cohorts A and B at IDIBAPS-Hospital Clinic, as previously reported (appendix pp 2–3).25,26 Among MOG antibody-positive patients (titre ≥1:160), a subset was followed for serum MOG antibodies at months 3 and 6, and then every 6 months until the titre became less than 1:80. Written informed consent was obtained from all patients or proxies.

Statistical analyses Analyses were done using Stata, version 13.1, and the level of significance was established at the two-sided 5% level. Categorical variables were summarised by counts and proportions, and continuous variables by med­ ian and IQR. Demographics and clinical features were analysed using the Fisher’s exact and Wilcoxon rank sum tests as appropriate for the dataset. Time to serum antibody negativity was analysed by survival function and the median (95% CI) by the Kaplan-Meier method. Com­ parison of times to antibody negativity between patients with and without clinical relapses was done using the logrank test. Hazard ratios (HRs, 95% CI) were obtained from the Cox model. Missing values on follow-up serum samples were imputed by last observa­tion carried forward until the last follow-up (appendix pp 7–8).

Role of the funding source The funders of the study had no role in the design, data collection, data analyses, data interpretation, or writing of the Article. The corresponding authors had full access to all the data, and had final responsibility for the decision to submit the study for publication.

Results Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 children with encephalitis other than ADEM (cohort B) were recruited. Controls included 177 patients excluded from cohorts A (n=13) and B (n=164) with non-inflammatory neurological disorders (figure 1), and 187 with other

264 children with suspected acquired demyelinating syndrome (including ADEM) enrolled in cohort A

479 children with suspected encephalitis (excluding ADEM) enrolled in cohort B

25 excluded 12 limited information 13 final diagnosis of non-inflammatory neurological disorders

239 confirmed acute disseminated encephalomyelitis

183 excluded 19 limited information 164 final diagnosis of non-inflammatory neurological disorders

296 definite or possible encephalitis*

145 MOG antibody negative

94 MOG antibody positive

274 MOG antibody negative

22 MOG antibody positive

116 children with MOG antibody-confirmed acquired demyelinating syndrome or autoimmune encephalitis

Figure 1: Patients with MOG antibodies identified from cohorts A and B Diagram showing the total number of patients with MOG antibodies identified from cohorts A and B. MOG=myelin oligodendrocyte glycoprotein. ADEM=acute disseminated encephalomyelitis. *According to International Criteria for inflammatory or infectious encephalitis (appendix pp 1–2).18

diseases (54 brain tumour, 50 stroke, 36 autoimmune neuropathies, 25 genetically confirmed leukodystrophies, and 22 chronic epilepsy). In cohort A, 94 (39%) of 239 patients had MOG antibodies (appendix p 4). The most common syndromes included ADEM (46 [65%] of 71), optic neu­ritis (20 [38%] of 52), myelitis (13 [26%] of 50), and NMOSD (six [43%] of 14). Of 43 children with multiple sclerosis or clinically isolated syndrome with MRI evi­dence of dissemination in space, three (7%) had MOG antibodies (appendix p 4). In cohort B, three categories of encephalitis were established: infectious (100 [34%] patients), autoimmune (64 [22%]), and enceph­ alitis of unclear cause (132 [45%]; appendix p 5). Among the 64 patients with auto­immune encephalitis, MOG anti­ bodies were more common (22 [34%]) than all neuro­nal antibodies combined (21 [33%]). After excluding the causes of encephalitis more frequently considered in paedi­ atrics or easily recog­ nised at bedside (infectious disease, anti-NMDA receptor [NMDAR], and opsoclonus myoclonus), the frequency of MOG antibody-associated encephalitis was 22 (13%) of 170 (appendix p 5). Overall, 116 (22%) of 535 patients from both cohorts had MOG antibody-associated syndromes. The age and sex dis­ tribution, paraclinical findings, treatment, relapses, and outcome for each syndrome are shown in table 1. 57 (49%) patients were female and the median age was 6·2 years (IQR 3·7–10·0). 14 (12%) patients had previous history of personal autoimmune disease (three patients), family autoimmune disease (nine), or both (two). In all patients, MOG antibodies were identified during an acute neurological event, either the first episode of the disease

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All patients (n=116)

ADEM (n=46)

Encephalitis other than ADEM (n=22)

Optic neuritis (n=20)

Myelitis (n=13)

Other† (n=9) Neuromyelitis optica spectrum disorder* (n=6)

p value

Sex Female

57 (49%)

25 (54%)

12 (55%)

7 (35%)

6 (46%)

2 (33%)

5 (56%)

0·69

Male

59 (51%)

21 (46%)

10 (45%)

13 (65%)

7 (54%)

4 (67%)

4 (44%)

0·69

8·5 (5·9–10·0)

8·5 (5·9–10·0)

9·2 (5·1–10·9)

0·0001

Age

6·2 (3·7–10·0)

3·9 (2·3–5·5)

8·3 (4·6–10·7)

9·0 (7·3–12·6)

Cerebrospinal fluid White blood cells, per mm‡

26 (9–58)

30 (15–55)

45 (20–65)

5 (0–20)

57 (40–84)

27 (13–33)

10 (3–10)

0·0004

Protein concentration, mg/dL

31 (23–45)

32 (23–47)

30 (25–44)

22 (18–26)

52 (36–68)

16 (4–67)

33 (28–38)

0·0092

93 (80%)

46 (100%)

21 (95%)

5 (25%)

9 (69%)

4 (67%)

8 (89%)

<0·001

100 (86%)

43 (93%)

16 (73%)

18 (90%)

12 (92%)

5 (83%)

6 (67%)

0·082

23 (20%)3

6 (13%)

5 (23%)

1 (5%)

3 (23%)

1 (17%)

7 (78%)

0·001

5/41 (12%)

Brain MRI abnormalities (excluded cases with optic neuritis without brain MRI findings) First-line immunotherapy at onset Second-line or chronic immunotherapy (any time) Frequency of relapses Cases followed from first episode

17/100 (17%)

4/21 (19%)

3/17 (18%)

4/11 (36%)

0/5 (0%)

1/5 (20%)

0·45

All patients

33 (28%)

10 (22%)

5 (23%)

6 (30%)

6 (46%)

1 (17%)

5 (56%)

0·23

17 (15%)

6 (13%)

8§ (36%)

0

0

1 (17%)

2 (22%)

0·009

mRS ≥2 last follow-up

Data are n, n (%), median (IQR), or n/N (%). p values show association of variable with type of syndrome at presentation. ADEM=acute disseminated encephalomyelitis. mRS=modified Rankin scale. *All presented with simultaneous optic neuritis and myelitis. †Three patients had multiple sclerosis (one was <12 years); and six presented with other non-encephalopathic syndromes with MRI lesions atypical for multiple sclerosis. ‡Includes three patients treated at disease onset, 19 at relapses, and one with asymptomatic radiological activity who was diagnosed with multiple sclerosis during follow-up. §One patient died.

Table 1: Paraclinical features, treatment, and follow-up according to syndrome at presentation

in 100 (86%; 76 from cohort A, 24 from cohort B) or a relapse in 16 (14%; 15 from cohort A, one from cohort B). All patients had brain MRI studies at symptom onset, and 65 (56%) during follow-up (>3 months). Spinal cord MRI studies were obtained according to the syndrome: 64 patients at disease onset and 26 during follow-up (>3 months). Among the 116 patients with MOG antibodies, 68 (59%) presented with clinical features of encephalitis: 46 (68%) fulfilled criteria of ADEM and 22 (32%) did not (figure 2). 29 (63%) patients with ADEM had spinal cord MRI studies, which in 18 (62%) were abnormal; six of those with abnormal spinal MRI did not have spinal cord symptoms (figure 3A–C). The clinical features of the 22 patients with nonADEM encephalitis included decreased level of conscious­ ness (22 [100%] patients), seizures (14 [64%]; ten with status epilepticus), fever (13 [59%]), abnormal behav­ iour (11 [50%]), motor deficits (nine [40%]), abnormal movements (eight [36%]), and brainstem-cerebellar dys­ func­tion (five [23%]). The brain MRI findings were not compatible with ADEM: 12 (55%) patients had extensive bilateral cortical involvement (five with additional basal ganglia or thalamic changes, and two with meningeal enhancement); four (18%) had isolated symmetric thala­ mic or basal ganglia involvement (figure 3); four (18%) had isolated cortical or cortical-subcortical single lesions; and two (9%) had normal brain MRI. 20 (17%) of 116 patients presented with optic neu­ ritis (bilateral in seven of those patients [35%]); 13 (11%) with myelitis (longitudinally extensive in 12 [92%]); and 4

six (5%) fulfilled criteria of NMOSD without aquaporin 4 antibodies. 18 (46%) of these 39 patients with optic neuritis, myelitis, or NMOSD had asymptomatic supra­ tentorial T2-fluid-attenuated inversion recovery abnor­ malities. None fulfilled the McDonald MRI criteria for dissemination in space; however, six (15%) had thalamic or basal ganglia lesions similar to those reported in ADEM but without encephalopathy. Nine (8%) patients initially presented with other syndromes, including three with multiple sclerosis, and six with non-encephalopathic syndromes and brain MRI findings atypical for multiple sclerosis (one later developed multiple sclerosis; figure 2; table 1). At initial diagnosis, 16 (14%) of 116 patients were not treated and 100 (86%) received first-line immuno­ therapy (steroids, intravenous immunoglobulins, or plasma exchange; appendix p 3). Additional treatments inclu­ded rituximab (three patients, one with anakinra). After a median follow-up of 42 months (IQR 22–67; range 8–197 months), 17 (17%) of 100 patients diag­ nosed at disease onset had relapses; four (24%) had more than one relapse. Considering these 17 patients and the 16 whose diagnosis of anti-MOG-associated disease was made during a relapse (totalling 33 patients with relapses, 15 [45%] with more than one relapse), the median time from disease onset to the first relapse was 4·7 months (IQR 2·8–12·0; range 1–63); eight of the 33 patients with relapses developed their first relapse after the 12-month follow-up. The likelihood of having a relapse was similar regardless of the type of syndrome at disease onset, and did not differ between patients who received first-line

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Patient Sex Age number (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70

F M M M F F F F M M M M M F M F F F M M M F F F F M M F F F F F F M F F F M M M F M M F F M F F F M M F M F M M F F M M M F F M F F F M M M

Onset

6 0·9 4 5 4 3 2 1·8 5 6 3 2 4 5 3 3 0·6 6 3 3 2 3 1·5 1·5 4 3 0·4 16 1 4 4 14 2 8 7 5 2 6 1·5 4 2 1·9 6 2 1·4 4 8 12 14 9 13 10 2 3 9 8 6 10 3 15 6 6 12 10 2 5 3 1·5 11 12

ADEM Encephalitis (other than ADEM) Optic neuritis Myelitis NMOSD*

First relapse

Second relapse

Third relapse

Fourth relapse

Five or more Follow-up relapses time (months) 132 197 63 81 75 35 72 38 26 80 30 23 39 67 46 63 20 60 17 34 42 75 54 74 55 43 35 75 80 57 69 64 42 29 59 27 80 7 6 6 80 21 35 40 26 30 17 75 46 67 7 59 44 47 78 27 11 72 78 9 43 41 56 22 54 21 46 9 28 30

mRS at last Diagnosis at last follow-up follow-up 4 4 0 2 0 2 0 0 1 2 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 1 3 0 0 0 0 0 6 2 2 4 3 0 0 0 0 0 0 0 0 1 0

Multiphasic ADEM Multiphasic ADEM Multiphasic ADEM with ON Multiphasic ADEM with ON ADEM-ON Multiphasic ADEM Multiphasic ADEM Multiphasic ADEM Multiphasic ADEM ADEM-ON ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM ADEM Atypical recurrent syndrome Multiple sclerosis NMOSD Atypical recurrent syndrome Atypical recurrent syndrome Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Encephalitis Recurrent optic neuritis Recurrent optic neuritis

Other syndromes, without encephalopathy, with multiple sclerosis-like lesions on MRI† Other syndromes, without encephalopathy, with ADEM-like lesions on MRI‡ Other syndromes, without encephalopathy, with MRI lesions not resembling ADEM or multiple sclerosis§ Asymptomatic radiological activity

(Figure 2 continues on next page)

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Patient Sex number 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116

M M M M M M F M M F F F F M F F M F M M F M M F F M M F F M F M M M F F F M M F F M F M F F

Age (years)

Onset

First relapse

Second relapse

Third relapse

Fourth relapse

8 15 12 12 8 12 6 12 12 3 12 6 8 3 8 9 4 7 5 9 7 13 14 5 2 6 5 11 10 10 8 11 17 4 10 8 7 14 10 14 2 8 9 9 3 5

ADEM Encephalitis (other than ADEM) Optic neuritis Myelitis NMOSD*

mRS at last Diagnosis at last follow-up Five or more Follow-up relapses time (months) follow-up 41 80 39 17 33 50 67 64 17 50 45 11 35 57 81 63 20 17 128 80 122 70 28 12 77 18 62 9 69 6 11 86 59 42 43 18 8 51 15 6 21 33 34 22 38 26

1 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 1 1 0 0 1 0 0 0 0 0 0 0 0 3 0 0 1 0 1 0 1 2 1 0 1 1 2 0

Recurrent optic neuritis Recurrent optic neuritis Recurrent optic neuritis Atypical recurrent syndrome Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (unilateral) Optic neuritis (bilateral) Optic neuritis (bilateral) Optic neuritis (bilateral) Optic neuritis (bilateral) Optic neuritis (bilateral) Optic neuritis (bilateral) Recurrent LETM Recurrent LETM NMOSD NMOSD NMOSD NMOSD Myelitis (LETM) Myelitis (LETM) Myelitis (LETM) Myelitis (LETM) Myelitis (LETM) Myelitis (LETM) Myelitis (no LETM) NMOSD NMOSD NMOSD NMOSD NMOSD NMOSD Multiple sclerosis Multiple sclerosis Multiple sclerosis Atypical recurrent syndrome Atypical recurrent syndrome Multiple sclerosis Atypical monophasic syndrome Atypical monophasic syndrome Atypical monophasic syndrome

Other syndromes, without encephalopathy, with multiple sclerosis-like lesions on MRI† Other syndromes, without encephalopathy, with ADEM-like lesions on MRI‡ Other syndromes, without encephalopathy, with MRI lesions not resembling ADEM or multiple sclerosis§ Asymptomatic radiological activity

Figure 2: Syndromes, relapses, follow-up, and outcome Four patients with multiphasic ADEM (patients 3, 4, 6, and 9 all had more than two episodes) developed several relapsing episodes within the second and third month of the disease; these episodes were not included here as relapses because according to current criteria they are not considered relapses. mRS=modified Rankin scale (at the last follow-up). F=female. M=male. ADEM=acute disseminated encephalomyelitis. NMOSD=neuromyelitis optica spectrum disorder. LETM=longitudinal extensive transverse myelitis. *All with simultaneous optic neu­ritis and longitudinally transverse myelitis. †Includes three patients with brainstem and spinal cord syndromes who fulfilled multiple sclerosis diagnostic criteria for dissemination in space and time at onset (one [patient 109] was younger than 12 years). ‡Includes cerebellar, brainstem, or multifocal involvement without encephalopathy but ADEM-like MRI lesions. §Includes two patients with new onset status epilepticus (patients 111 and 112); one with bilateral optic neuritis along with non-contiguous three segment myelitis (patient 113); one with progressive hemiparesis associated with a contralateral pseudotumoural lesion (patient 114), and one with bilateral optic neuritis and acute onset hemiparesis with multifocal cortical-subcortical enhancing MRI lesions (number 115).

immunotherapy and those who did not (28 [28%] of 100 vs five [31%] of 16; p=0·77). During relapses, 32 (97%) of 33 patients received first-line immunotherapy and 19 (58%) other immuno­ therapies, mainly rituximab (11 patients; appendix p 3). Only one (7%) of 14 patients treated with rituximab at disease onset (three patients) or at a relapse (11 patients) developed further relapses (median follow-up since rituximab treatment 18 months, IQR 8–30). 6

In 18 (55%) of 33 patients with relapses, the syndromes were different from the initial or previous episodes (figure 2). Among 33 (28%) of 116 patients with relapses and one additional case who developed asymptom­ atic radio­logical activity (patient 113), the diagnoses at the last follow-up included the following: multiphasic ADEM (eight [24%]; five of them with more than two rel­ apses), NMOSD (six [18%]), multiple sclerosis (five [15%]), recurrent optic neu­ritis (five [15%]), recurrent myelitis

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(two [6%]), ADEM-ON (two [6%]), and non-classifiable or atypical recurrent syndromes (six [18%]; figure 2). Overall, 99 (85%) of the 116 patients had complete (78 patients) or near complete (21) recovery (mRS <2), and 17 had moderate to severe deficits (mRS≥2; one died). The outcome was similar for the 100 patients followed from disease onset (data not shown). Of 93 patients with abnormal MRI at disease onset, 65 had radiological followup, which showed resolution of findings in 42 (65%) of these patients. The outcome at the last follow-up varied according to the syndrome presentation (p=0·009; table 1). Patients with encephalitis other than ADEM had the highest frequency of poor outcome (eight [36%] of 42 patients), which was worse than that of patients with ADEM (six [13%] of 46; p=0·051). Among the 17 (15%) patients with moderate or severe deficits (mRS ≥2), including the patient who died, two distinct clinicoradiological patterns of progress­ion were identified. One pattern was seen in four patients (patients 1, 2, 4, and 6; 3% of the series) who presented with ADEM and subsequently developed fre­ quent relapses and diffuse involvement of the white matter (table 2). In two patients, the symmetry and extension of white matter changes sug­ gested a genetic leukodystrophy (figure 4; table 2) lead­ ing to whole genome sequencing that did not reveal abnormalities. The second clinicoradiological pattern was seen in six patients (patients 50 and 56–60; 5% of the series) who presented with encephalitis other than ADEM; two devel­ oped severe cranial hypertension that caused the death of one (patient 56). In five patients, the MRI showed extensive bilateral cortical involvement, and one who initially had a normal MRI rapidly developed bilateral thalamic involve­ment. Only one (17%) of these six patients had relapses, but all developed relentless progression towards general cortical atrophy and irreversible deficits (figure 4; table 2). The other seven patients with moderate or severe deficits (mRS ≥2) did not have a unifying syndrome: two had mul­tiple sclerosis (patients 48 and 110), one NMOSD (patient 102), one ADEM-ON (patient 10), one ADEM and intra­­­ cranial hypertension that required decom­ pressive cran­i­­ectomy (patient 18), one cortical-subcortical gadolinium-enhancing MRI abnormalities (patient 115; figure 4), and one non-classifiable syndrome (patient 47; table 2). Paired serum and CSF samples were available from 83 patients, serum alone from 29, and CSF from four. Among those with paired samples, 51 (61%) had MOG antibodies in both, 27 (33%) in serum alone, and five (6%) in CSF alone. Four (80%) of five patients (patients 48, 108, 110, and 113) with antibodies in CSF alone were diag­nosed with multiple sclerosis compared with one (2%) of 49 patients (patient 109) with anti­ bodies in both samples and none of 27 with antibodies in serum alone (p<0·001). None of the patients with

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Figure 3: MRI features in four representative patients with good outcome (mRS <2) Patient 35: Girl, aged 7 years, with clinical-radiological presentation of ADEM including multifocal white matter lesions (A, B) and longitudinally extensive spinal cord involvement (C). Patient 32: girl, aged 14 years, with clinicoradiological presentation of ADEM including multifocal bilateral cortical-subcortical lesions and asymmetric involvement of basal ganglia (D–F). Patient 13: boy, age 4 years, with clinicoradiological presentation of ADEM associated with bilateral thalamic (G, I) and cerebellar peduncle (H, I) involvement. The three patients showed full clinicoradiological recovery (data not shown). Patient 53: boy, aged 2 years, with clinical presentation of basal ganglia encephalitis associated with isolated symmetric basal ganglia and thalamic involvement on MRI (J); despite full clinical recovery, follow-up MRI studies showed bilateral residual symmetric atrophy of the striatum (K, L). Fluid-attenuated inversion recovery sequences were used in A–E, G, H, and J. T2 sequences were used in F, I, J and K.

high titres of MOG antibodies had multiple sclerosis (appendix p 6). All control samples were MOG antibody negative. Of 100 patients diagnosed during the first episode of the disease, 93 had MOG antibodies in serum (the other

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Sex

Age at Initial syndrome, onset, number of years episodes

Symptoms

MRI finding at onset

MRI finding at last follow-up

Follow-up Second-line or chronic immunotherapy or both (response)

mRS at last follow-up

EDSS* at last follow-up

Residual symptoms at last follow-up

Leukodystrophy-like pattern 1

Female 7

ADEM, >10

Encephalopathy, brainstem symptoms

Brainstem and basal ganglia

Leukodystrophylike pattern

11 years Interferon beta 1-alpha (no response), monthly intravenous immunoglobulins and rituximab (no further relapses)

3

3, 5

Cognitive impairment, bladder dysfunction, cerebellar symptoms, epilepsy

2

Male

1·9

ADEM, >10

Encephalopathy, brainstem symptoms: in some relapses optic neu­ritis

Brainstem and bilateral symmetric basal ganglia

Leukodystrophylike pattern

16 years Since fourth episode: steroiddependency, cyclophosphamide, MMF (partial response)

4

5, 5

Cognitive impairment, spastic tetraparesis, cerebellar symptoms, epilepsy, visual loss (visual acuity OD <20/200, OS 20/40)

4

Male

5

ADEM, 4

First, second, and fourth episodes: encephalopathy, brainstem and cerebellar symptoms; third episode: severe unilateral optic neu­ ritis

Brainstem, cerebellar Leukodystrophyand basal ganglia like pattern

Oral steroids, cyclophosphamide and MMF (transient response), rituximab (good response)

7 years

2

2

Cognitive impairment, visual loss (visual acuity D 20/50, OS 20/20)

6

Female 3

ADEM, 4

First to third episodes: brainstem, cerebellar symptoms, and encephalopathy; fourth episode: same symptoms without encephalopathy

Diffuse asymmetric white matter with intense contrast enhancement

Leukodystrophylike pattern

From fourth episode rituximab (good response)

3 years

2

2

Cognitive impairment, mild cerebellar symptoms

Predominant cortical involvement with progression to cortical atrophy 50

Male

9

Non-ADEM encephalitis, 2

Encephalopathy, seizures and abnormal behaviour

In both episodes: multifocal cortical and basal ganglia; interval with normal MRI

Generalised cortical atrophy

rituximab (no further relapses)

5·5 years

3

NA

Cognitive impairment, epilepsy

56

Male

8

Non-ADEM encephalitis, 1

Encephalopathy, decreased level of consciousness, cranial hypertension

Diffuse cortical involvement with restriction diffusion, basal ganglia, and transtentorial herniation

NA

No

4 days

6

NA

Died

57

Female 6

Non-ADEM encephalitis, 1

Encephalopathy, seizures, abnormal behaviour

Cortical-subcortical lesions that progressed along with signs of cranial hypertension

Generalised cortical atrophy

Rituximab (good response)

10 months 2

NA

Cognitive impairment, epilepsy

58

Female 10

Non-ADEM encephalitis, 1

Encephalopathy, status epilepticus (clonic seizures)

Bilateral cortical with Generalised restriction diffusion cortical atrophy

No

6 years

2

NA

Cognitive impairment, epilepsy

59

Male

Non-ADEM encephalitis, 1

Encephalopathy, refractory myoclonic seizures, status epilepticus

Diffuse cortical enhancement with restriction diffusion

Generalised cortical atrophy

No

6 years

4

NA

Cognitive impairment, bladder dysfunction, tetraparesis, epilepsy (VNS)

3

(Table 2 continues on next page)

8

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Sex

Age at Initial syndrome, onset, number of years episodes

Symptoms

MRI finding at onset

EDSS* at last follow-up

Residual symptoms at last follow-up

3

NA

Cognitive impairment, epilepsy

MRI finding at last follow-up

Follow-up mRS at Second-line or last chronic follow-up immunotherapy or both (response)

Generalised cortical atrophy

Rituximab, anakinra (without response); plasma exchange (partial response)

9 months

(Continued from previous page) 60

Male

15

Non-ADEM encephalitis, 1

Initially normal; FIRES-like onset: super-refractory status repeat MRI 20 days epilepticus after fever later: mild isolated bilateral thalamic involvement

Other patterns 10

Male

6

ADEM, 2

Encephalopathy, pyramidal signs; 6 months later optic neu­ritis

Multifocal thalamic and cerebellar peduncle abnormalities

Normal

No

6 years

2

1

Behavioural problems

18

Female 6

ADEM, 1

Encephalopathy, brainstem symptoms, cranial hypertension

Multifocal white matter and basal ganglia abnormalities

Generalised cortical atrophy, hydrocephalus (ventricular shunt)

Plasma exchange (no response)

5 years

4

5, 5

Cognitive impairment, spastic tetraparesis, epilepsy

47

Female 8

Non-ADEM encephalitis, 4

Isolated bilateral First episode: symmetric basal encephalopathy and ganglia seizures; second episode: optic neu­ritis; third and fourth episodes encephalopathy

Normal

Interferon beta 1a (no response), from fourth episode rituximab (good response)

1·5 years

2

NA

Cognitive impairment

48

Female 12

Non-ADEM encephalitis, 3

Isolated corticalFirst episode: subcortical frontal encephalopathy and lesion myoclonus; second and third episodes: typical isolated clinical syndromes (optic neu­ ritis, brainstem, cerebellar) without encephalopathy

Typical of multiple sclerosis (fulfilled DIT and DIS criteria), along with pseudotumoural lesions

Glatiramer acetate 6 years (no response), teriflunomide (good response)

2

1

Cognitive impairment

NMOSD, >10

Simultaneous optic neu­ritis and myelitis; sometimes isolated optic neu­ritis

Optic nerve enhancement and LETM

Normal

Interferon beta 1a, glatiramer acetate, azathioprine (no response)

7 years

3

2

Visual loss (visual acuity OD 20/40, OS 20/50)

Typical of multiple sclerosis (fulfilled DIT and DIS criteria) along with pseudotumoural lesions

Same as initial MRI

Rituximab (good response)

6 months

2

3, 5

Cerebellar ataxia, sensory deficits, nystagmus

Two large corticalsubcortical lesions with intense contrast enhancement

Local cortical atrophy

Rituximab (good response)

3 years

2

2

Visual loss (visual acuity OD 20/60, OS 20/20)

102 Male

11

110 Female 14

First and second Other, without episodes: brainstem, encephalopathy; multiple sclerosis, 1 cerebellar, and spinal cord involvement without symptoms of encephalopathy

115

Other, without encephalopathy; different from multiple sclerosis, 1

Female 3†

1 month of fever and bilateral optic neu­ritis, sudden onset of hemiparesis without encephalopathy

ADEM=acute disseminated enceph­alomyelitis. DIS=disseminated in space. DIT=disseminated in time. EDSS=Expanded Disability Status Scale. FIRES=febrile-induced refractory epilepsy syndrome. LETM=longitudinally extensive transverse myelitis. MMF=mycophenolate mofetil. mRS=modified Rankin scale. NA=not applicable. NMOSD=neuro­myelitis optica spect­rum disorder. OD=right eye. OS=left eye. VNS=vagus nerve stimulation. *Assessed in patients with demyelinating disease. †Previous history of type 1 neurofibromatosis and optic glioma.

Table 2: Clinical features of patients with poor outcome by patient number (mRS ≥2)

seven had antibodies in CSF alone or the serum was not available) and 66 (71%) had longitudinal MOG antibody studies (median time to last sample 12 months, IQR 7–27). The median time to become MOG antibody negative was 12 months (IQR 6–36) for patients without relapses and 46 months (IQR 41–73) for those with relapses (p=0·0013; HR 0·18, 95% CI 0·05–0·59; appendix p 9).

The percentage of patients who developed relapses at any time during follow-up according to MOG antibody serostatus is shown in the appendix (p 7); for example, at 6 months follow-up, 11 (24%) of 46 patients who remained MOG antibody positive and none of 20 patients who were MOG antibody negative developed relapses during the entire follow-up (p=0·026). A similar analysis showing

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Figure 4: MRI features in four representative patients with poor outcome (mRS ≥2) Patient 1: girl, aged 6 years, who, 2 weeks after chickenpox, developed encephalopathy and a left cerebellar peduncle lesion (A), which was subsequently followed by multiple ADEM-like episodes. An MRI from the second episode (B) shows bilateral extensive white matter abnormalities. From the third episode onwards the patient developed bilateral confluent white matter changes resembling a genetic leukodystrophy (C) associated with gadolinium contrast enhancement (D). Patient 50: boy, aged 9 years, with clinical presentation of encephalitis and MRI showing multifocal cortical abnormalities (E). A follow-up MRI 1 year later was normal (F), but during the next year he developed a clinicoradiological relapse similar to the initial episode (G), evolving to severe cortical atrophy, as shown in a follow-up MRI 6 months later (H). Patient 59: boy, aged 3 years, who presented with encephalitis and extensive bilateral cortical MRI abnormalities (I–K) associated with gadolinium contrast enhancement suggesting cortical necrosis (L). A follow-up MRI showed generalised atrophy (not shown). Patient 115: girl, aged 3 years, who presented with 1 month history of fever and bilateral optic neuritis, followed by acute onset left hemiparesis. The brain MRI showed a large cortical-subcortical lesion in the right frontal region (M) that along other brain lesions showed contrast enhancement in a vasculitic-like pattern (N). A follow-up MRI showed a decrease of the size of the lesions (O) that no longer enhanced after gadolinium administration (P). Fluid-attenuated inversion recovery sequences were used in B, C, E–H, and I. T2 sequences were used in A, J, K, M, and O. T1 sequences with gadolinium were used in D, L, N, and P.

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the percentage of patients who were going to develop a first relapse according to MOG antibody serostatus at different times of follow-up is shown in the appendix (p 8). In addition to MOG antibodies, five (4%) patients had gly­­cine receptor antibodies. The presence of these anti­ bodies did not associate with distinct symptoms (two devel­oped optic neuritis and three ADEM). No other neu­ ro­nal or glial antibodies were identified.

Discussion In this prospective study of 535 children with acquired demyelinating syndromes or encephalitis, 116 (22%) had MOG antibodies. These antibodies were more prevalent in the cohort with demyelinating disorders than in the cohort with encephalitis, but the prevalence was similar when the first cohort was compared with the group of patients with autoimmune encephalitis other than

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O

P

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ADEM. Regarding the cohort of patients with acute demye­linating diseases, our findings confirm the high prevalence of MOG anti­ bodies in children with new onset ADEM, NMOSD, optic neu­ ritis, and myelitis. However, as far as the cohort of encephalitis is con­ cerned, we found that MOG antibodies were the most common autoantibodies, surpassing all neuronal anti­ bodies combined, and that after excluding the causes of encephalitis more frequently considered in paedi­ atrics or recognised at bedside (infectious, anti-NMDAR, opsoclonus-myoclonus) the frequency of MOG antibodies was 13% (22 of 170 patients). When focusing on the group of 116 patients with MOG antibodies, the most common syndromes included ADEM, encephalitis other than ADEM, optic neu­ ritis, myelitis, NMOSD, and other syndromes. Although sev­ eral of these MOG antibody-associated syndromes were already well known,1,3,6,9,11 28 (24%) of the 116 patients devel­ oped synd­romes different from those typically considered within the spectrum of MOG antibody-associated dis­ orders. The detection of atypical syndromes was more notable in the cohort with encephalitis. Indeed, most of these patients presented with atypical symptoms or MRI findings such as extensive bilateral cortical encephalitis, isolated involve­ment of the basal ganglia or thalamus, or minimal MRI changes with refractory status epilepticus. These findings are important because MOG antibody testing is infrequently included in the diagnostic workup of patients with suspected autoimmune encephalitis other than ADEM, and many of these cases would have been mis­diagnosed if it were not for the prospective design of our study. Moreover, the MRI findings of some patients resembled those of patients with anti-GABAA receptor or dopamine 2 receptor-associated enceph­alitis, which might further complicate the diagnosis.27,28 We did not find substantial differences regarding sex distribution, paraclinical findings, and treatments used among the main MOG antibody-associated syndromes. However, patients presenting with ADEM were younger compared with those with other syndromes, and patients with optic neuritis were less likely to have CSF pleocytosis and brain MRI abnormalities compared with the other patients. Similar findings regarding the age-related distrib­ u­tion of syndromes have been previously reported.3–5,29,30 The frequency of clinical relapses among 100 patients followed from disease onset was 17 (17%). Considering these patients and 16 additional cases diagnosed at relapse, the frequency of relapses did not change according to the initial syndrome. In other prospective studies focused on paediatric demyelinating syndromes, the frequency of relapses ranged from 18% (18 of 99 patients)1 to 38% (25 of 65).3 99 (85%) of 116 patients had complete or almost complete recovery at the last follow-up. In most respects, the treatments used were similar to those reported by others,9,11 although in our study rituximab was used more frequently during relapses (eg, 11 [33%] of 33 patients

compared with nine [13%] of 71 patients11 or seven [13%] of 56 patients9). Two clinicoradiological patterns of progression were associated with poor outcome. One included a subset of patients who presented with ADEM, frequent relapses, and progression towards extensive bilateral white matter changes resembling a genetic leukodystrophy.10 The other clinicoradiological pattern included a subset of patients who presented with non-ADEM encephalitis (five with exten­­ sive cortical involvement, one with basal ganglia abnor­ malities), sometimes associated with potentially lethal intracranial hypertension, and relentless progress­ ion towards severe brain atrophy and refractory epilepsy, motor impairment, or cognitive changes. This outcome is very different from that described in adults with MOG antibody-associated unilateral cortical involve­ ment, which is usually considered a benign phenotype.12,16 The clini­coradiological features of these subphenotypes often led to early misdiagnoses, such as febrile infectionrelated epilepsy syndrome or genetic leukodystrophy. One can argue that in these cases, MOG antibodies could be an epiphenomenon, but we did not find MOG antibodies in 364 controls (including 25 genetic­ally confirmed leuko­ dystrophies) making a coincidental association unlikely. At the last follow-up, only five (4%) patients were diagnosed with multiple sclerosis. These data, along with that of other paediatric series showing a frequency of MOG antibodies in patients with multiple sclerosis rang­ ing from 4% to 13%,1,2,5 support the concept that MOG antibody-associated syndromes and multiple sclerosis are different clinicopathological entities. The observation that four of five patients with antibodies solely detected in CSF developed multiple sclerosis compared with only one of 75 patients with antibodies in both serum and CSF or serum alone (p<0·001) should be confirmed in future studies, but suggests that these patients should be mon­ itored for multiple sclerosis. In our study, patients who became MOG antibody negative were less likely to develop relapses than those who remained seropositive, as reported by Waters and colleagues.5 Yet, a subset of patients who remained sero­ positive for 1 year or longer did not develop relapses. This study has some limitations. First, this is not a registry-based study and therefore we could not assess the incidence and prevalence of MOG antibody-associated syndromes. Second, the prospective follow-up (median 42 months, IQR 22–67) was short; therefore, it is possible that we underestimated the frequency of relapses or the number of patients who might have developed multiple sclerosis. Third, the outcome was assessed with mRS, which is widely used in autoimmune encephalitis, but does not accurately assess cognitive impairment. Fourth, although radiological follow-up was obtained in many patients, this was not systematically done, particularly assessments of the spinal cord. Finally, only 66 (71%) of 93 patients diagnosed at first episode (and with MOG antibodies in serum) had longitudinal antibody studies,

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which could suggest selection bias; however, the number who relapsed among these 66 patients (11 [17%]; appendix p 7) was similar to that of all patients diagnosed at first episode, with MOG antibodies in serum or CSF (17 [17%] of 100), suggesting that the 66 patients are representative of the cohort. Findings from this study have important implications. The spectrum of MOG antibody-associated syndromes in children is wider than that currently considered in clinical practice and includes multiple demyelinating or enceph­ alitic syndromes. Among encephalitic syndromes, MOG antibodies were the most frequent biomarkers, surpassing the frequency of NMDAR antibodies (or showing a similar frequency if cases of anti-NMDAR post-herpes simplex encephalitis were included); the current definition of multiphasic ADEM or even the classification of paediatric acquired demyelinating syndromes should be updated. For example, existing criteria of multiphasic ADEM only consider a relapse if new symptoms develop 3 months after onset, and only allow two episodes.19 However, five of eight patients reported here with multiphasic ADEM had multiple episodes within the first 3 months and afterwards; MOG antibody testing should be included in the initial workup of paediatric encephalitis (after exclud­ ing infectious causes or if the clinicoradiological fea­ tures are different from anti-NMDAR encephalitis). This is particularly important for the encephalitides that mani­ fest with MRI findings similar to those of some MOG antibody-positive patients (eg, multifocal corticalsubcortical lesions in anti-GABAA receptor, or basal ganglia lesions in anti-dopamine 2 receptor) and for the paedi­atric phenotypes associated with bilateral cortical involve­ment or leukodystrophy-like features, which have a poor prog­ nosis. Overall, our findings are important because 85% of patients in this study had substantial recovery, illus­trating the need for an update of the existing classification and terminology of MOG antibody-associ­ated syndromes. Contributors TA did the study design, literature search, data collection, data interpretation, radiological analysis, statistical analysis, and antibody analysis, developed the figures, wrote the Article, approved the final Article, and obtained funding for the study. GO-C did the figures, radiological analysis, and data interpretation and critically reviewed and approved the final Article. EM-H, RR-G, and HA did the antibody analysis and data interpretation and approved the final Article. MM-B, VG-A, AF-R, MJM-G, VC-E, MCM-H, LM-G, MT-V, EM, and IM did the data collection and approved the final Article. MS, GA, CA, and MT obtained funding, did data interpretation, and approved the final Article. XM did data interpretation and approved the final Article. AV did the genetic analysis and data interpretation and approved the final Article. FG and AS obtained funding, participated in the study design and data interpretation, and critically reviewed and approved the final Article. JD participated in the study design, data interpretation, and writing, critically reviewed and approved the final Article, and obtained funding. Declaration of interests TA reports grants from Mutua Madrileña Foundation, ISCIII-FEDER (Spain), Dodot Procter & Gamble, the Pediatrics Spanish Society, PERIS (Generalitat de Catalunya), Marato TV3 Foundation, Red Española de sclerosis múltiple, and Fundació CELLEX; personal fees and non-financial support from Novartis; and non-financial support from

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Roche. MS reports grants from Departament de Salut de la Generalitat de Catalunya; personal fees from Biogen and Genzyme; and other non-financial support from Novartis. GA reports grants from Marato TV3 Foundation; personal fees and other from Sanofi-Genzyme, Merck, and Roche; grants and other non-financial support from Novartis; and personal fees and other non-financial support from Stendhal. CA reports personal fees from Novartis, Biogen, and Stendhal. MT reports grants from Marato TV3 Foundation; personal fees and other non-financial support from Bayer Schering Pharma, Merck, Biogen, Teva, Sanofi-Genzyme, Novartis, Almirall, and Roche. XM reports personal fees and non-financial support from Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society. AV reports grants from Eli Lilly, Gilead, Takeda, Biogen, Ionis, Foundation to Fight H-ABC, PMD Foundation, and Calliope Joy Foundation. FG has a patent test for diagnosis of Iglon5 antibodies licensed. AS reports other from Merck-Serono, Sanofi-Genzyme, Novartis, Biogen Idec, Teva, Bayer-Shering, and Roche. JD reports grants from La Caixa Foundation (Spain), Instituto Carlos III/FEDER, CIBERER—Instituto Carlos III, AGAUR Generalitat de Catalunya, and Fundació CELLEX. In addition, JD has a patent (number US6387639 B1) with royalties paid to Athena Diagnostics, and patents (numbers US7972796, US8685656, US9719993 B2, PCT/EP2014/072252, and EP2905622 A1) with royalties paid to Euroimmun. All other authors declare no competing interests. Acknowledgments We thank Georgina Casanovas and Gemma Domenech (Medical Statistics Core Facility, IDIBAPS-Hospital Clinic, Barcelona) for their assistance in statistical analyses, and Maria Rodes, Mercè Alba, Eva Caballero, and Esther Aguilar (Neuroimmunology Laboratory, IDIBAPS-Hospital Clinic, Barcelona) for their excellent technical support. We thank patients and families who participated in the study. References 1 Fadda G, Brown RA, Longoni G, et al. MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study. Lancet Child Adolesc Health 2018; 2: 191–204. 2 Hacohen Y, Absoud M, Deiva K, et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm 2015; 2: e81. 3 Hennes EM, Baumann M, Schanda K, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 2017; 89: 900–08. 4 Fernandez-Carbonell C, Vargas-Lowy D, Musallam A, et al. Clinical and MRI phenotype of children with MOG antibodies. Mult Scler 2016; 22: 174–84. 5 Waters P, Fadda G, Woodhall M, et al. Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes. JAMA Neurol 2019; published online Sept 23. DOI:10.1001/jamaneurol.2019.2940. 6 Rostasy K, Mader S, Schanda K, et al. Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis. Arch Neurol 2012; 69: 752–56. 7 Duignan S, Wright S, Rossor T, et al. Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes. Dev Med Child Neurol 2018; 60: 958–62. 8 Rostásy K, Mader S, Hennes EM, et al. Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica. Mult Scler 2013; 19: 1052–59. 9 Ramanathan S, Mohammad S, Tantsis E, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry 2018; 89: 127–37. 10 Hacohen Y, Rossor T, Mankad K, et al. ‘Leukodystrophy-like’ phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. Dev Med Child Neurol 2018; 60: 417–23. 11 Hacohen Y, Wong YY, Lechner C, et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol 2018; 75: 478–87.

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