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E.U. paediatric MOG consortium consensus: Part 1 – Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

Open AccessPublished:November 03, 2020DOI:https://doi.org/10.1016/j.ejpn.2020.10.006

      Highlights

      • MOGAD include a diverse range of demyelinating and encephalitis-like phenotypes.
      • ADEM in younger and ON and/or TM in older children comprise >90% of presentations.
      • All children with demyelination/encephalitis and abnormal MRI need MOG-ab testing.
      • We recommend an antibody-directed classification: MOG-ab-associated disorders.
      • Followed by addition of the disease course and clinical phenotype.

      Abstract

      Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies.

      Keywords

      Abbreviations

      ADS
      acquired demyelinating syndrome
      ADEM
      acute disseminated encephalomyelitis
      ADEM-ON
      ADEM followed by monophasic or recurrent ON
      AE
      autoimmune encephalitis
      AQP4-ab
      aquaporin-4 antibody
      CNS
      central nervous system
      CRION
      chronic relapsing inflammatory optic neuropathy
      (LE)TM
      (longitudinally extensive) transverse myelitis
      MOG-ab
      myelin oligodendrocyte glycoprotein antibody
      MOGAD
      MOG-antibody-associated disorders
      MOG-ON
      MOG-ab-associated ON
      MOG-TM
      MOG-ab-associated TM
      MDEM
      multiphasic disseminated encephalomyelitis
      NMOSD
      neuromyelitis optica spectrum disorders
      OCT
      optical coherence tomography
      ON
      optic neuritis
      RNFL
      retinal nerve fibre layer
      RON
      relapsing ON

      1. Introduction

      Paediatric acquired demyelinating syndromes (ADS) consist of a broad spectrum of immune-mediated demyelinating diseases of the central nervous system (CNS), including acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM), neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). Diagnosis of the specific phenotype at initial presentation can be challenging, as the situation frequently evolves over time [
      • Banwell B.
      • Kennedy J.
      • Sadovnick D.
      • Arnold D.L.
      • Magalhaes S.
      • Wambera K.
      • et al.
      Incidence of acquired demyelination of the CNS in Canadian children.
      ,
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ,
      • Ketelslegers I.A.
      • Catsman-Berrevoets C.E.
      • Neuteboom R.F.
      • Boon M.
      • van Dijk K.G.
      • Eikelenboom M.J.
      • et al.
      Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.
      ,
      • Neuteboom R.
      • Wilbur C.
      • Van Pelt D.
      • Rodriguez M.
      • Yeh A.
      The spectrum of inflammatory acquired demyelinating syndromes in children.
      ]. The discovery of pathogenic serum autoantibodies targeted against aquaporin-4 (AQP4-abs) in 2004 enables their use as a diagnostic marker for AQP4-ab-positive NMOSD [
      • Lennon V.A.
      • Wingerchuk D.M.
      • Kryzer T.J.
      • Pittock S.J.
      • Lucchinetti C.F.
      • Fujihara K.
      • et al.
      A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
      ]. Over the past few years, there has been increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a candidate biomarker in demyelinating CNS diseases [
      • Reindl M.
      • Di Pauli F.
      • Rostasy K.
      • Berger T.
      The spectrum of MOG autoantibody-associated demyelinating diseases.
      ,
      • Hennes E.M.
      • Baumann M.
      • Lechner C.
      • Rostasy K.
      MOG spectrum disorders and role of MOG-antibodies in clinical practice.
      ]. These antibodies target MOG, which is expressed exclusively on the outer surface of the myelin sheath and plasma membrane of oligodendrocytes [
      • Brunner C.
      • Lassmann H.
      • Waehneldt T.V.
      • Matthieu J.M.
      • Linington C.
      Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the CNS of adult rats.
      ,
      • Hemmer B.
      • Archelos J.J.
      • Hartung H.P.
      New concepts in the immunopathogenesis of multiple sclerosis.
      ]. Although MOG represents only a minor component of myelin (0.5%), it is a likely target for autoantibodies in a demyelinating disease due to its CNS specificity and highly immunogenic location [
      • Reindl M.
      • Di Pauli F.
      • Rostasy K.
      • Berger T.
      The spectrum of MOG autoantibody-associated demyelinating diseases.
      ,
      • Hemmer B.
      • Archelos J.J.
      • Hartung H.P.
      New concepts in the immunopathogenesis of multiple sclerosis.
      ]. While initially MOG-abs were thought to be a possible biomarker for MS, following improvements in assay design [
      • Armangue Thaís.
      • Capobianco Marco
      • et al.
      E.U. paediatric MOG consortium consensus: Part 3 - Biomarkers of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ], multiple studies have established that MOG-abs are present only in a small proportion of MS patients [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ]. Indeed, nowadays it is widely accepted that the presence of MOG-abs indicates a different disease and argues against an MS diagnosis [
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ].
      MOG-abs have consistently been identified in an expanding spectrum of demyelinating syndromes, with predominance and increased heterogeneity in paediatric patients [
      • Ramanathan S.
      • Dale R.C.
      • Brilot F.
      Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination.
      ,
      • Reindl M.
      • Waters P.
      Myelin oligodendrocyte glycoprotein antibodies in neurological disease.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ]. Therefore, this first part of the Paediatric European Collaborative Consensus will focus on the classification of the different paediatric clinical phenotypes within MOG-ab-associated disorders (MOGAD). Furthermore, consensus recommendations on serologic testing for MOG-abs in the paediatric population are included as guidance for clinicians in daily practice, as early diagnosis is relevant for accurate disease monitoring and treatment strategies.

      2. Frequency and general characteristics of paediatric MOGAD

      2.1 Incidence and prevalence of MOG-abs in paediatric ADS and frequency of MOGAD presentations

      MOGAD are rare, with a higher incidence in paediatric compared to adult patients. A recent Dutch study reported a mean incidence of 0.31 per 100.000 children (95% CI 0.17–0.51), compared to 0.13 per 100.000 adults per year (95% CI 0.08–0.19) [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ]. A recent review of 61 studies also described a higher prevalence of MOG-abs in paediatric (40%) compared to mixed (29%) and adult (22%) cohorts [
      • Reindl M.
      • Waters P.
      Myelin oligodendrocyte glycoprotein antibodies in neurological disease.
      ].
      Various studies have determined the prevalence of MOG-abs within paediatric ADS [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Probstel A.K.
      • Dornmair K.
      • Bittner R.
      • Sperl P.
      • Jenne D.
      • Magalhaes S.
      • et al.
      Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.
      ,
      • Rostasy K.
      • Mader S.
      • Schanda K.
      • Huppke P.
      • Gartner J.
      • Kraus V.
      • et al.
      Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • Castro D.A.
      • O'Mahony J.
      • Verhey L.H.
      • 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.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ], using the reliable live cell-based assay (CBA) [
      • Armangue Thaís.
      • Capobianco Marco
      • et al.
      E.U. paediatric MOG consortium consensus: Part 3 - Biomarkers of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ]. According to pooled data of these 11 studies, MOG-abs are present in one third of all paediatric patients with ADS (34%; Fig. 1). Focusing on the different presenting phenotypes, these studies have shown that MOG-abs are predominantly found in patients presenting with ADEM (53%, range 33–65%), ON (40%, range 10–67%), and TM (18%, range 0–35%). An NMOSD-like phenotype with combination of ON and TM as presenting symptom is only reported in a limited number of ADS patients, with MOG-abs detected in 40% of these patients, however varying from 25 to 100% between studies [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • Castro D.A.
      • O'Mahony J.
      • Verhey L.H.
      • 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.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ].
      Fig. 1
      Fig. 1ADS presenting phenotype, divided for MOG-ab-positive and negative patients [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Probstel A.K.
      • Dornmair K.
      • Bittner R.
      • Sperl P.
      • Jenne D.
      • Magalhaes S.
      • et al.
      Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.
      ,
      • Rostasy K.
      • Mader S.
      • Schanda K.
      • Huppke P.
      • Gartner J.
      • Kraus V.
      • et al.
      Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • Castro D.A.
      • O'Mahony J.
      • Verhey L.H.
      • 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.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ].
      ADEM = acute disseminated encephalomyelitis, ADS = acquired demyelinating syndrome, MOG-ab = myelin oligodendrocyte glycoprotein antibody, ON = optic neuritis, TM = transverse myelitis.
      The different clinical presentations of paediatric MOGAD at disease onset are shown in Fig. 2 [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • Castro D.A.
      • O'Mahony J.
      • Verhey L.H.
      • 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.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Salama S.
      • Pardo S.
      • Levy M.
      Clinical characteristics of myelin oligodendrocyte glycoprotein antibody neuromyelitis optica spectrum disorder.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Konuskan B.
      • Yildirim M.
      • Gocmen R.
      • Okur T.D.
      • Polat I.
      • Kilic H.
      • et al.
      Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • D'Indy H.
      • Poulat A.L.
      • Carneiro M.
      • Philippe N.
      • et al.
      MOG antibody-related disorders: common features and uncommon presentations.
      ]. Summarising data of these 13 studies, the most common include ADEM (46%), ON (30%), TM (11%) and NMOSD-like phenotype with simultaneous ON and TM (4%). Together these clinical presentations comprise already more than 90% of all phenotypes encompassed by paediatric MOGAD and will be discussed in detail below.
      Fig. 2
      Fig. 2Presenting clinical phenotypes within the paediatric MOGAD [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • Castro D.A.
      • O'Mahony J.
      • Verhey L.H.
      • 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.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Salama S.
      • Pardo S.
      • Levy M.
      Clinical characteristics of myelin oligodendrocyte glycoprotein antibody neuromyelitis optica spectrum disorder.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Konuskan B.
      • Yildirim M.
      • Gocmen R.
      • Okur T.D.
      • Polat I.
      • Kilic H.
      • et al.
      Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • D'Indy H.
      • Poulat A.L.
      • Carneiro M.
      • Philippe N.
      • et al.
      MOG antibody-related disorders: common features and uncommon presentations.
      ].
      ADEM = acute disseminated encephalomyelitis, MOGAD = MOG-antibody-associated disorders, ON = optic neuritis, TM = transverse myelitis.

      2.2 General characteristics of paediatric MOGAD and age dependency

      The majority of patients in studies with MOGAD are of Caucasian descent [
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ,
      • Hacohen Y.
      • Banwell B.
      Treatment approaches for MOG-ab-associated demyelination in children.
      ], which most likely represents population rather than a true ethnicity bias as seen in AQP4-ab-positive disease [
      • McKeon A.
      • Lennon V.A.
      • Lotze T.
      • Tenenbaum S.
      • Ness J.M.
      • Rensel M.
      • et al.
      CNS aquaporin-4 autoimmunity in children.
      ]. Boys and girls are almost equally distributed, with only a slight preponderance of females in older children [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • Hemingway C.
      • Nytrova P.
      • Woodhall M.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Konuskan B.
      • Yildirim M.
      • Gocmen R.
      • Okur T.D.
      • Polat I.
      • Kilic H.
      • et al.
      Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ,
      • Hacohen Y.
      • Banwell B.
      Treatment approaches for MOG-ab-associated demyelination in children.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ], in contrast to the female preponderance in both MS [
      • Hintzen R.Q.
      • Dale R.C.
      • Neuteboom R.F.
      • Mar S.
      • Banwell B.
      Pediatric acquired CNS demyelinating syndromes: features associated with multiple sclerosis.
      ] and AQP4-ab-positive NMOSD [
      • McKeon A.
      • Lennon V.A.
      • Lotze T.
      • Tenenbaum S.
      • Ness J.M.
      • Rensel M.
      • et al.
      CNS aquaporin-4 autoimmunity in children.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. Comparing paediatric ADS patients with and without MOG-abs, paediatric MOGAD patients are younger [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ]. This difference may be due to the high number of ADEM patients within the MOGAD, who are generally the youngest among all ADS patients, and therefore could skew the age distribution. The fact that paediatric ADEM, ON and NMOSD patients with and without MOG-abs do not differ in age, supports this [
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ,
      • Lopez-Chiriboga A.S.
      • Majed M.
      • Fryer J.
      • Dubey D.
      • McKeon A.
      • Flanagan E.P.
      • et al.
      Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders.
      ,
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Narayan R.N.
      • McCreary M.
      • Conger D.
      • Wang C.
      • Greenberg B.M.
      Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ].
      The presenting clinical phenotype of MOG-ab-positive patients appears to be strongly dependent on age at onset, with brain involvement seen more commonly in younger children (including ADEM and ADEM-like phenotypes), and an opticospinal phenotype (including ON and/or TM or brainstem involvement) more often in older children [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ], and adult patients [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Jurynczyk M.
      • Messina S.
      • Woodhall M.R.
      • Raza N.
      • Everett R.
      • Roca-Fernandez A.
      • et al.
      Clinical presentation and prognosis in MOG-antibody disease: a UK study.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • Maillart E.
      • Audoin B.
      • Zephir H.
      • Bourre B.
      • et al.
      Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study.
      ,
      • Chen L.
      • Chen C.
      • Zhong X.
      • Sun X.
      • Zhu H.
      • Li X.
      • et al.
      Different features between pediatric-onset and adult-onset patients who are seropositive for MOG-IgG: a multicenter study in South China.
      ,
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ]. The transition of this bimodal distribution seems to be around the age of nine [
      • Reindl M.
      • Waters P.
      Myelin oligodendrocyte glycoprotein antibodies in neurological disease.
      ]. As MOG is only expressed during late stages of myelination, it is thought to play a role in maturation of the CNS [
      • Pham-Dinh D.
      • Mattei M.G.
      • Nussbaum J.L.
      • Roussel G.
      • Pontarotti P.
      • Roeckel N.
      • et al.
      Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex.
      ]. This age dependency of presenting clinical phenotype may represent a changing MOG expression during different stages of brain development and CNS maturation in childhood [
      • Hennes E.M.
      • Baumann M.
      • Lechner C.
      • Rostasy K.
      MOG spectrum disorders and role of MOG-antibodies in clinical practice.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ].

      3. Typical clinical phenotypes of paediatric MOGAD

      3.1 Acute disseminated encephalomyelitis (ADEM)

      The heterogeneous clinical syndrome ADEM predominantly occurs in early childhood and is characterised by encephalopathy, polyfocal neurological deficits and typical magnetic resonance imaging (MRI) abnormalities, which can fluctuate during the acute phase (up to three months after disease onset) [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ,
      • Ketelslegers I.A.
      • Visser I.E.
      • Neuteboom R.F.
      • Boon M.
      • Catsman-Berrevoets C.E.
      • Hintzen R.Q.
      Disease course and outcome of acute disseminated encephalomyelitis is more severe in adults than in children.
      ,
      • Wong Y.Y.M.
      • van Pelt E.D.
      • Ketelslegers I.A.
      • Catsman-Berrevoets C.E.
      • Hintzen R.Q.
      • Neuteboom R.F.
      • et al.
      Evolution of MRI abnormalities in paediatric acute disseminated encephalomyelitis.
      ]. The presence of encephalopathy, defined by the International Paediatric Multiple Sclerosis Society Group (IPMSSG) as an altered consciousness or behavioural changes, both not explained by fever, is required for a diagnosis of ADEM [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ]. This requirement is essential, because it distinguishes ADEM from other ADS.
      ADEM is the most frequent type of paediatric MOGAD, but there is only one study comparing paediatric ADEM patients with and without MOG-abs. This study included 19 MOG-ab-positive and 14 negative patients [
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ]. Almost all these ADEM patients presented with altered consciousness due to encephalopathy, which was not different between MOG-ab-positive and negative patients. However, ADEM patients with MOG-abs presented less frequently with emotional or behavioural problems as representation of encephalopathy, compared to patients without MOG-abs (5% vs. 43%). Interestingly, besides a higher number of white blood cells in cerebrospinal fluid (CSF) in MOG-ab-positive patients, the remaining demographic and clinical characteristics at onset of disease, including age, sex ratio and other clinical symptoms, could not discriminate ADEM patients with MOG-abs from those without. Based on the MRI comparison however, the MOG-ab-positive patients more often had spinal cord involvement compared to MOG-ab-negative patients (93% vs. 33%). Remarkably, only 62% of the MOG-ab-positive patients with spinal involvement suffered from spinal symptoms, compared to 100% of the MOG-ab-negative patients with spinal cord involvement [
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ].
      Although ADEM patients generally have a favourable long-term prognosis, mainly based on recovery of motor function, there is a risk of long-term cognitive impairment [
      • Pohl D.
      • Alper G.
      • Van Haren K.
      • Kornberg A.J.
      • Lucchinetti C.F.
      • Tenembaum S.
      • et al.
      Acute disseminated encephalomyelitis: updates on an inflammatory CNS syndrome.
      ,
      • Deiva K.
      • Cobo-Calvo A.
      • Maurey H.
      • De Chalus A.
      • Yazbeck E.
      • Husson B.
      • et al.
      Risk factors for academic difficulties in children with myelin oligodendrocyte glycoprotein antibody-associated acute demyelinating syndromes.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ], and a higher risk of post-ADEM epilepsy in MOG-ab-positive compared to MOG-ab-negative patients [
      • Rossor T.
      • Benetou C.
      • Wright S.
      • Duignan S.
      • Lascelles K.
      • Robinson R.
      • et al.
      Early predictors of epilepsy and subsequent relapse in children with acute disseminated encephalomyelitis.
      ]. While ADEM patients typically have a monophasic disease course, relapses can occur in the MOG-ab-positive ADEM patients [
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ]. These relapsing clinical phenotypes after ADEM are discussed later.
      In conclusion, up to 50% of paediatric ADEM patients are MOG-ab positive and ADEM is the most common presenting clinical phenotype of paediatric MOGAD. Although there are a few clinical and radiological differences between ADEM patients with and without MOG-abs, it still is not possible to distinguish these patients at onset of disease based on these features alone.

      3.2 Optic neuritis (ON)

      The inflammation of the optic nerve(s) in ON causes unilateral or bilateral visual problems, typically including visual loss, central scotoma or reduced visual fields and impaired colour vision, and is often accompanied with painful eye movements [
      • Hintzen R.Q.
      • Dale R.C.
      • Neuteboom R.F.
      • Mar S.
      • Banwell B.
      Pediatric acquired CNS demyelinating syndromes: features associated with multiple sclerosis.
      ]. Paediatric MOG-ab-positive patients presenting with ON predominantly are adolescents between 13 and 18 years of age [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • Healy B.
      • McLaughlin K.
      • Wucherpfennig K.W.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ,
      • Lock J.H.
      • Newman N.J.
      • Biousse V.
      • Peragallo J.H.
      Update on pediatric optic neuritis.
      ]. In patients with ON as clinically isolated syndrome, paediatric ON has different clinical features than ON in adults (most likely representing MS patients), regarding severity, bilateral vs. unilateral, and presence of disc oedema [
      • Lock J.H.
      • Newman N.J.
      • Biousse V.
      • Peragallo J.H.
      Update on pediatric optic neuritis.
      ]. Studies exclusively analysing paediatric patients with MOG-ab-associated ON (MOG-ON) are limited.
      The only three paediatric studies available, one European and two large Asian cohorts, showed that the majority of the paediatric MOG-ON patients had severe visual loss at onset, with a visual acuity (VA) of ≤0.1 at nadir, which is comparable to the vision loss at nadir of paediatric AQP4-ab-positive, double seronegative (i.e. MOG-ab and AQP4-ab-negative) and MS patients with ON [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ,
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ]. However, after six months follow-up the MOG-ab-positive patients made a good recovery with a functional VA of ≥0.5 in 98% of patients [
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ], and ≥0.8 in 89% of patients [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ], which is significantly better than AQP4-ab-positive, but comparable with double seronegative and MS patients with ON [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ,
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ].
      Simultaneous bilateral optic nerve involvement has been reported in most studies in more than 50% of paediatric MOG-ab-positive patients [
      • Dale R.C.
      • Tantsis E.M.
      • Merheb V.
      • Kumaran R.Y.
      • Sinmaz N.
      • Pathmanandavel K.
      • et al.
      Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton.
      ,
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Narayan R.N.
      • McCreary M.
      • Conger D.
      • Wang C.
      • Greenberg B.M.
      Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ,
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ], although lower numbers have also been reported (29–38%) [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ], and mixed paediatric and adult cohorts showed that bilateral involvement is more often seen in adult MOG-ab-positive patients [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Chen L.
      • Chen C.
      • Zhong X.
      • Sun X.
      • Zhu H.
      • Li X.
      • et al.
      Different features between pediatric-onset and adult-onset patients who are seropositive for MOG-IgG: a multicenter study in South China.
      ,
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ]. Such bilateral involvement is atypical for MS [
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • Tantsis E.M.
      • Reddel S.W.
      • Henderson A.P.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ]. In addition, a recent study showed that 73% of paediatric patients presenting with bilateral ON had MOG-abs [
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • Blaschek A.
      • Coelho de Oliveira Koch E.
      • Della Marina A.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. Furthermore, a substantial proportion of paediatric MOG-ON patients presented with prominent optic disc oedema (60–90%), due to anterior involvement of the optic nerve in these patients [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ,
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ]. Unlike in adults, disc oedema did not distinguish MOG-ab-positive from AQP4-ab-positive and double seronegative paediatric ON patients [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ]. Additionally, besides the anterior optic nerve inflammation, MRI images of MOG-ON showed high rates of longitudinal involvement of the optic nerve in mixed paediatric and adults cohorts (90%), with relative sparing of the chiasm and optic tracts [
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ,
      • Lock J.H.
      • Newman N.J.
      • Biousse V.
      • Peragallo J.H.
      Update on pediatric optic neuritis.
      ,
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • Tantsis E.M.
      • Reddel S.W.
      • Henderson A.P.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • Blaschek A.
      • Coelho de Oliveira Koch E.
      • Della Marina A.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ,
      • Chen J.J.
      • Bhatti M.T.
      Clinical phenotype, radiological features, and treatment of myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) optic neuritis.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Xu Q.
      • Sun M.
      • Wei S.
      Clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein antibody-seropositive optic neuritis in varying age groups: a cohort study in China.
      ,
      • Baumann Matthias
      • Bartels Frederik
      • et al.
      E.U. paediatric MOG consortium consensus: Part 2 - Neuroimaging features of paediatric myelin ligodendrocyte glycoprotein antibodyassociated disorders.
      ]. The latter being important since this is different from ON associated with AQP4-abs, where patients more often have chiasmal and optic tract involvement [
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • Tantsis E.M.
      • Reddel S.W.
      • Henderson A.P.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ]. Additionally, perineural enhancement and inflammation of soft orbital tissues on MRI has been described in up to 50% of (mainly) adult patients presenting with MOG-ON [
      • Lee H.J.
      • Kim B.
      • Waters P.
      • Woodhall M.
      • Irani S.
      • Ahn S.
      • et al.
      Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies.
      ,
      • Chen J.J.
      • Flanagan E.P.
      • Jitprapaikulsan J.
      • Lopez-Chiriboga A.S.S.
      • Fryer J.P.
      • Leavitt J.A.
      • et al.
      Myelin oligodendrocyte glycoprotein antibody-positive optic neuritis: clinical characteristics, radiologic clues, and outcome.
      ,
      • Akaishi T.
      • Sato D.K.
      • Nakashima I.
      • Takeshita T.
      • Takahashi T.
      • Doi H.
      • et al.
      MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study.
      ,
      • Akaishi T.
      • Sato D.K.
      • Takahashi T.
      • Nakashima I.
      Clinical spectrum of inflammatory central nervous system demyelinating disorders associated with antibodies against myelin oligodendrocyte glycoprotein.
      ,
      • Kim S.M.
      • Woodhall M.R.
      • Kim J.S.
      • Kim S.J.
      • Park K.S.
      • Vincent A.
      • et al.
      Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS.
      ], distinguishing MOG-ab-positive from AQP4-ab-positive and MS patients with ON [
      • Akaishi T.
      • Sato D.K.
      • Nakashima I.
      • Takeshita T.
      • Takahashi T.
      • Doi H.
      • et al.
      MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study.
      ,
      • Kim S.M.
      • Woodhall M.R.
      • Kim J.S.
      • Kim S.J.
      • Park K.S.
      • Vincent A.
      • et al.
      Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS.
      ]. This phenotype can be referred to as “ON plus phenotype”.
      A proportion of these ON patients will experience further relapses. The relapsing clinical phenotypes following ON are discussed later in more detail. Importantly, although in general the functional VA of MOG-ON patients recovers well, optical coherence tomography (OCT) scans showed signs of severe axonal damage, which was as severe as observed in AQP4-ab-positive patients [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ,
      • Peng A.
      • Kinoshita M.
      • Lai W.
      • Tan A.
      • Qiu X.
      • Zhang L.
      • et al.
      Retinal nerve fiber layer thickness in optic neuritis with MOG antibodies: a systematic review and meta-analysis.
      ], and was not or only partly correlated to the number of ON episodes [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ].
      In conclusion, paediatric MOG-ON patients are mainly adolescents who have severe visual loss at onset of disease, often with optic disc oedema and in about half of them simultaneous bilateral ON. These patients usually have a good functional visual recovery, although OCT scans reveal indication of permanent axonal damage.

      3.3 (Longitudinally extensive) transverse myelitis ((LE)TM)

      Patients with (LE)TM can present with motor and sensory deficits, which are often bilateral and include a sensory level, and/or bladder and bowel dysfunction, progressing within hours to days [
      • Hintzen R.Q.
      • Dale R.C.
      • Neuteboom R.F.
      • Mar S.
      • Banwell B.
      Pediatric acquired CNS demyelinating syndromes: features associated with multiple sclerosis.
      ]. Due to the rarity of MOG-ab-associated TM (MOG-TM) in childhood, literature on this specific MOGAD phenotype in paediatric patients is sparse, without any studies comparing paediatric TM patients with and without MOG-abs.
      However, one retrospective study included 54 patients with MOG-TM patients, among them 16 paediatric patients (30%), with isolated TM (54%) or TM as part of a multifocal disease presentation with ADEM (17%) or ON (6%) [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • Morris P.P.
      • Sechi E.
      • Zalewski N.L.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ]. Similar to the ON patients, almost all TM patients had a severe disease at onset including prominent motor and sensory deficits, with one third of patients being wheelchair bound. Furthermore, 85% of these patients presented with neurological bowel and bladder dysfunction, and additionally 54% of male patients with erectile dysfunction, probably attributable to the often longitudinally extensive lesion with frequent conus involvement observed on MRI in these patients (41%). This conus involvement has also been demonstrated in 37% of all paediatric MOG-ab-positive patients presenting with spinal cord lesions [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • Wendel E.M.
      • Lechner C.
      • Behring B.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ]. While LETM is also characteristic for AQP4-ab-associated TM, conus involvement is more typical for MOG-TM [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ,
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • Morris P.P.
      • Sechi E.
      • Zalewski N.L.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Sato D.K.
      • Callegaro D.
      • Lana-Peixoto M.A.
      • Waters P.J.
      • de Haidar Jorge F.M.
      • Takahashi T.
      • et al.
      Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.
      ,
      • Kitley J.
      • Waters P.
      • Woodhall M.
      • Leite M.I.
      • Murchison A.
      • George J.
      • et al.
      Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study.
      ]. Interestingly, 19% of patients of the above described retrospective study presented with a flaccid areflexia, which can be explained by the predilection for the central grey matter in MOG-TM, also typical for AQP4-ab-associated TM, but atypical for MS-associated TM [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • Morris P.P.
      • Sechi E.
      • Zalewski N.L.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ].
      Regardless of the disease severity at onset, most of these MOG-TM patients showed a good motor recovery [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • Morris P.P.
      • Sechi E.
      • Zalewski N.L.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ], which may be better than the recovery in TM patients without MOG-abs, as previous paediatric TM cohorts with unknown MOG-ab serostatus reported worse outcomes [
      • Deiva K.
      • Absoud M.
      • Hemingway C.
      • Hernandez Y.
      • Hussson B.
      • Maurey H.
      • et al.
      Acute idiopathic transverse myelitis in children: early predictors of relapse and disability.
      ,
      • De Goede C.G.
      • Holmes E.M.
      • Pike M.G.
      Acquired transverse myelopathy in children in the United Kingdom--a 2 year prospective study.
      ]. However, bowel, bladder and/or erectile residual symptoms are common [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • Morris P.P.
      • Sechi E.
      • Zalewski N.L.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ]. A proportion of MOG-TM patients have recurrent episodes during follow-up, described in around 17% of adult [
      • Cobo-Calvo A.
      • Ruiz A.
      • D'Indy H.
      • Poulat A.L.
      • Carneiro M.
      • Philippe N.
      • et al.
      MOG antibody-related disorders: common features and uncommon presentations.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • Maillart E.
      • Audoin B.
      • Zephir H.
      • Bourre B.
      • et al.
      Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study.
      ], and 0–14% of paediatric MOG-TM patients [
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. Furthermore, patients presenting with MOG-TM may have other relapses during follow-up, e.g. ON, extending the MOGAD phenotype to an NMOSD-like phenotype, also reported in around 14% of paediatric patients [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ].
      In conclusion, isolated TM only covers a small part of the paediatric MOGAD. MOG-TM often causes severe deficits at onset, including motor, sensory, and bowel, bladder and/or erectile impairment. Patients often have a LETM, in contrast to MS patients. Moreover, conus involvement can distinguish them from AQP4-ab-positive patients. Although patients make a good motor recovery, bowel, bladder and/or erectile residual symptoms are common and important features to discuss with the patient and to monitor during follow-up, besides the long-term monitoring for potential relapses.

      3.4 Neuromyelitis optica spectrum disorders (NMOSD)-like phenotype

      Neuromyelitis optica (NMO) initially was characterised by recurrent uni- or bilateral ON and (LE)TM. In 2015, the spectrum was broadened by inclusion of brainstem syndromes and limited forms of NMO, altogether referred to as NMO spectrum disorders (NMOSD) [
      • Neuteboom R.
      • Wilbur C.
      • Van Pelt D.
      • Rodriguez M.
      • Yeh A.
      The spectrum of inflammatory acquired demyelinating syndromes in children.
      ,
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • Cabre P.
      • Carroll W.
      • Chitnis T.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ]. Although the presence of AQP4-abs was added as a supportive diagnostic criterion, these antibodies are rare in childhood, only found in 3–6% of ADS [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ] and 11% of NMOSD patients [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. In contrast, MOG-abs are found in one third of paediatric ADS and in 56% of paediatric patients with an NMOSD-like phenotype [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ].
      As described above, ON and (LE)TM can occur either as isolated clinical MOGAD phenotypes, or simultaneously, representing an NMOSD-like phenotype at onset of disease. Interestingly, in a study analysing paediatric NMOSD(-like) patients, none of the AQP4-ab-positive patients had concomitant ON and (LE)TM, in contrast to 85.7% of MOG-ab-positive patients [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. This simultaneous phenotype has been observed in adult MOG-ab-positive patients in lower percentages (around 40%) [
      • Kitley J.
      • Waters P.
      • Woodhall M.
      • Leite M.I.
      • Murchison A.
      • George J.
      • et al.
      Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study.
      ,
      • van Pelt E.D.
      • Wong Y.Y.
      • Ketelslegers I.A.
      • Hamann D.
      • Hintzen R.Q.
      Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in The Netherlands.
      ,
      • Jarius S.
      • Ruprecht K.
      • Kleiter I.
      • Borisow N.
      • Asgari N.
      • Pitarokoili K.
      • et al.
      MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.
      ], but still was a discriminative feature from AQP4-ab-positive NMOSD [
      • van Pelt E.D.
      • Wong Y.Y.
      • Ketelslegers I.A.
      • Hamann D.
      • Hintzen R.Q.
      Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in The Netherlands.
      ].
      Since broadening NMO to NMOSD, brainstem involvement with inflammation of the area postrema is included as feature of AQP4-ab-positive NMOSD [
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • Cabre P.
      • Carroll W.
      • Chitnis T.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ]. Area postrema syndrome (APS) causes intractable nausea, vomiting and/or unexplained hiccups, and is thought to be highly specific for AQP4-abs [
      • Shosha E.
      • Dubey D.
      • Palace J.
      • Nakashima I.
      • Jacob A.
      • Fujihara K.
      • et al.
      Area postrema syndrome: frequency, criteria, and severity in AQP4-IgG-positive NMOSD.
      ]. However, adult studies with MOG-ab-positive patients also reported brainstem involvement in 10–30% [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Jarius S.
      • Kleiter I.
      • Ruprecht K.
      • Asgari N.
      • Pitarokoili K.
      • Borisow N.
      • et al.
      MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: brainstem involvement - frequency, presentation and outcome.
      ], e.g. with cranial nerve deficits, ataxia, respiratory insufficiency, and also nausea and vomiting as clinical symptoms [
      • Jarius S.
      • Kleiter I.
      • Ruprecht K.
      • Asgari N.
      • Pitarokoili K.
      • Borisow N.
      • et al.
      MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: brainstem involvement - frequency, presentation and outcome.
      ]. In contrast, in paediatric MOG-ab-positive patients, isolated brainstem syndromes or brainstem involvement ever during disease course were only rarely observed (0–3% and 0–4%, respectively) [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • Wokke B.
      • Siepman T.
      • Neuteboom R.F.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ], and evidently more often seen in the paediatric AQP4-ab-positive patients (20% and 60%, respectively) [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. Lastly, as described above, both AQP4-ab and MOG-ab-positive patients can experience symptoms of APS (nausea, vomiting and/or hiccups), but in MOG-ab-positive patients these symptoms rarely seem to be attributed to inflammation of the area postrema, as seen in AQP4-ab-positive NMOSD, but may be due to disruption of anatomical connections to the vomiting centre [
      • Kunchok A.
      • Krecke K.N.
      • Flanagan E.P.
      • Jitprapaikulsan J.
      • Lopez-Chiriboga A.S.
      • Chen J.J.
      • et al.
      Does area postrema syndrome occur in myelin oligodendrocyte glycoprotein-IgG-associated disorders (MOGAD)?.
      ]. Therefore, pure APS with inflammation of the area postrema remains a typical feature for AQP4-ab-positive NMOSD.
      Despite clinical overlap between AQP4-ab-positive NMOSD and MOG-ab-associated NMOSD-like phenotypes, differences exist as summarised in Table 1. Importantly, the underlying immunological disease mechanisms of both antibody-associated diseases is different, with AQP4-abs targeting astrocytes and MOG-abs targeting oligodendrocytes, resulting in astrocytopathy and oligodendrocytopathy, respectively [
      • Parratt J.D.
      • Prineas J.W.
      Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes.
      ,
      • Fang L.
      • Kang X.
      • Wang Z.
      • Wang S.
      • Wang J.
      • Zhou Y.
      • et al.
      Myelin oligodendrocyte glycoprotein-IgG contributes to oligodendrocytopathy in the presence of complement, distinct from astrocytopathy induced by AQP4-IgG.
      ,
      • Pittock S.J.
      • Lucchinetti C.F.
      Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later.
      ]. Additionally, differences in human leukocyte antigen association are found, suggestive of a distinctive underlying immunogenetic background [
      • Bruijstens A.L.
      • Wong Y.Y.M.
      • van Pelt D.E.
      • van der Linden P.J.E.
      • Haasnoot G.W.
      • Hintzen R.Q.
      • et al.
      HLA association in MOG-IgG- and AQP4-IgG-related disorders of the CNS in the Dutch population.
      ]. There is an ongoing debate about the nosology of these disorders [
      • Leite M.I.
      • Sato D.K.
      MOG-antibody-associated disease is different from MS and NMOSD and should be considered as a distinct disease entity - Yes.
      ,
      • Fujihara K.
      MOG-antibody-associated disease is different from MS and NMOSD and should be classified as a distinct disease entity - Commentary.
      ], although many argue for a separation of MOGAD from AQP4-ab-positive NMOSD [
      • Ramanathan S.
      • Dale R.C.
      • Brilot F.
      Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ,
      • Lopez-Chiriboga A.S.
      • Majed M.
      • Fryer J.
      • Dubey D.
      • McKeon A.
      • Flanagan E.P.
      • et al.
      Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders.
      ,
      • Cobo-Calvo A.
      • Vukusic S.
      • Marignier R.
      Clinical spectrum of central nervous system myelin oligodendrocyte glycoprotein autoimmunity in adults.
      ,
      • Zamvil S.S.
      • Slavin A.J.
      Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder?.
      ,
      • Pittock S.J.
      Demyelinating disease: NMO spectrum disorders: clinical or molecular classification?.
      ,
      • Hacohen Y.
      • Palace J.
      Time to separate MOG-Ab-associated disease from AQP4-Ab-positive neuromyelitis optica spectrum disorder.
      ].
      Table 1Differences between paediatric AQP4-ab-positive NMOSD and MOG-ab-associated NMOSD-like phenotypes.
      NMOSD-like phenotypes
      MOG-ab+AQP4-ab+
      DemographicsMore often in paediatric patients

      Equal distribution boys/girls

      No association with other AID
      Rare in paediatric patients

      Predominance in girls

      Association with other AID
      Clinical phenotypes
      ∗ON∗ Bilateral, longitudinally extensive with anterior involvement (disc oedema
      Discriminative feature for MOG-abs and AQP4-abs in mixed paediatric and adult studies, but not in paediatric studies exclusively.
      )
      ∗ Longitudinally extensive with chiasma/optic tract involvement
      ∗TM∗ LETM with conus involvement∗ LETM with cervico-thoracic spinal cord involvement
      ∗NMOSD(-like)∗ Often simultaneous ON and TM, area postrema syndrome is rare∗ Area postrema syndrome, isolated brainstem syndrome
      Severity at onsetSevereSevere
      RecoveryPromptly after steroids and often completely, except for axonal damage on OCT (ON) and bowel/bladder problems (TM)High risk for poor recovery
      Disease courseMore often monophasic, but relapses are possibleRelapsing
      AID = autoimmune disease, AQP4-ab = aquaporin-4 antibody, LETM = longitudinally extensive transverse myelitis, MOG-ab = myelin oligodendrocyte glycoprotein antibody, NMOSD = neuromyelitis optica spectrum disorders, OCT = optical coherence tomography, ON = optic neuritis, TM = transverse myelitis, + = positive, – = negative.
      a Discriminative feature for MOG-abs and AQP4-abs in mixed paediatric and adult studies, but not in paediatric studies exclusively.
      In conclusion, AQP4-ab-positive NMOSD is rare in paediatric patients, and NMOSD-like phenotypes with MOG-abs are more common [
      • Lechner C.
      • Breu M.
      • Wendel E.-M.
      • Kornek B.
      • Schanda K.
      • Baumann M.
      • et al.
      Epidemiology of pediatric NMOSD in Germany and Austria.
      ]. Typical for MOGAD is simultaneous ON and TM. While adult patients may have brainstem involvement, this is rare for paediatric patients. An area postrema syndrome attributable to inflammation in the area postrema is rare and remains a typical feature of AQP4-ab-positive NMOSD.

      4. Relapsing phenotypes

      The frequency of relapses among all paediatric MOG-ab-positive patients ranges widely between studies, because of e.g. differences in follow-up time, study design (retro- vs. prospective) and patient selection (nationwide coverage vs. secondary academic centres). Recent studies, with longer follow-up duration, have revealed increasing evidence for a multiphasic disease course in a subset of MOG-ab-positive patients [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Hacohen Y.
      • Mankad K.
      • Chong W.K.
      • Barkhof F.
      • Vincent A.
      • Lim M.
      • et al.
      Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.
      ]. Patients who remain seropositive during follow-up appear at higher risk for relapse compared to the patients who convert to a seronegative status (38% vs. 13%, respectively) [
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ]. Additionally, older age has been found to be strongly associated with a relapsing disease course [
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ].
      In 2018, the European Paediatric Demyelinating Disease Consortium studied 102 MOG-ab-positive patients with a relapsing disease course [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. Median follow-up was five years. This cohort included multiphasic disseminated encephalomyelitis (MDEM; 20%), ADEM followed by one or more ON episode(s) (ADEM-ON; 20%), relapsing ON (RON; 18%) and relapsing NMOSD (43%). Interestingly, the same age dependency of clinical phenotype was observed for the relapses, with MDEM and ADEM-ON in the younger, and RON and NMOSD in the older patients, again with the division between these phenotypes around the age of nine.

      4.1 Multiphasic disseminated encephalomyelitis (MDEM)

      ADEM, whilst usually monophasic, can present as a relapsing form, known as MDEM [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ]. Almost all MDEM patients are MOG-ab positive [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ]. Importantly, clinical symptoms and radiologic features can fluctuate during the acute phase of ADEM (up to three months) [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ], mainly during weaning off immunomodulatory treatment. Therefore, during this acute ADEM period it is important to be aware of the possibility of a “flare-up”, which does not reflect a true relapse [
      • Bruijstens Arlette L.
      • Wendel Eva-Maria
      • et al.
      E.U. paediatric MOG consortium consensus: Part 5 - Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ]. A relapse was defined by the consensus group as a new clinical episode accompanied by radiological evidence depending on the subtype of MOGAD, appearing at least one month subsequently to the last acute attack. On the contrary, a “flare-up” was defined by the consensus group as re-occurrence of symptoms within one month (and up to three months in ADEM patients) after start of acute treatment and not meeting definition of a relapse.
      The first study describing multiple MDEM patients was published in 2016 [
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Karenfort M.
      • Kornek B.
      • Seidl R.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ]. In total, only eight MDEM patients were identified from 295 paediatric ADS patients including 59 ADEM patients, and all eight were MOG-ab-positive. These numbers are comparable to the reported number of MDEM patients in other paediatric ADS cohorts, in whom almost all had positive MOG-abs [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • O'Mahony J.
      • Brown R.A.
      • Castro D.A.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ]. Remarkable is the heterogeneity between MDEM patients, observed in the initial eight patients [
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Karenfort M.
      • Kornek B.
      • Seidl R.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ], but also in the 20 MOG-ab-positive MDEM patients identified from the European Paediatric Demyelinating Disease Consortium [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. Although IPMSSG criteria for MDEM are limited to only two ADEM episodes [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ], studies with MOG-ab-positive MDEM patients have shown that these patients may have only one relapse, but can also have multiple, with more than ten documented in certain cases [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ,
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Karenfort M.
      • Kornek B.
      • Seidl R.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ]. Most patients had a new attack within two years after onset, but new attacks also occurred years later. In these cohorts with MDEM patients, 25–50% of patients had a good recovery, but the remaining patients had mild to moderate impairment, including cognitive deficits, motor deficits or seizures [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ,
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Karenfort M.
      • Kornek B.
      • Seidl R.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ]. Every new relapse with new brain demyelination might increase the risk of secondary neuroaxonal injury, and consequently, risk of poor outcome might depend on number of relapses [
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ]. However, this hypothesis has not been investigated systematically in paediatric patients yet.

      4.2 ADEM-ON

      A subgroup of children with initial ADEM presentation continue to have demyelinating episode(s) limited to the optic nerve (ADEM-ON) [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. As for MDEM, during the acute phase of ADEM (up to three months) the possibility of a “flare-up”, instead of a true relapse, should be considered [
      • Bruijstens Arlette L.
      • Wendel Eva-Maria
      • et al.
      E.U. paediatric MOG consortium consensus: Part 5 - Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ], as optic nerve involvement can also occur during the acute phase of ADEM [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ].
      The majority of these ADEM-ON patients are MOG-ab positive [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • Hennes E.M.
      • Schanda K.
      • Mader S.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ,
      • Huppke P.
      • Rostasy K.
      • Karenfort M.
      • Huppke B.
      • Seidl R.
      • Leiz S.
      • et al.
      Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients.
      ,
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ]. Like MDEM, this ADEM-ON phenotype is rare and characteristics of these patients have only been described previously in detail in seven patients from Germany [
      • Huppke P.
      • Rostasy K.
      • Karenfort M.
      • Huppke B.
      • Seidl R.
      • Leiz S.
      • et al.
      Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients.
      ] and more recently in 20 patients from the European Paediatric Demyelinating Disease Consortium [
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ]. The heterogeneity among ADEM-ON patients is comparable to MDEM patients; the number of relapses ranged from one to nine per patient, and the interval between relapses ranged from three months to even 20 years in one patient [
      • Huppke P.
      • Rostasy K.
      • Karenfort M.
      • Huppke B.
      • Seidl R.
      • Leiz S.
      • et al.
      Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients.
      ,
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ]. Furthermore, relapses occurred in patients after a long steady period without treatment, but also in patients on treatment [
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ]. In a high proportion of patients (60–70%), visual residual deficits were reported [
      • Huppke P.
      • Rostasy K.
      • Karenfort M.
      • Huppke B.
      • Seidl R.
      • Leiz S.
      • et al.
      Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients.
      ,
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ], which were not related to the number of relapses, at least not in this small sample size [
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ]. Importantly, in the ADEM patients with further relapses, a shorter time to first relapse [
      • Wong Y.Y.M.
      • Hacohen Y.
      • Armangue T.
      • Wassmer E.
      • Verhelst H.
      • Hemingway C.
      • et al.
      Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.
      ] as well as a persistent MOG-ab positivity during follow-up [
      • Lopez-Chiriboga A.S.
      • Majed M.
      • Fryer J.
      • Dubey D.
      • McKeon A.
      • Flanagan E.P.
      • et al.
      Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders.
      ] were found to both increase the risk of (further) relapses, the latter arguing for longitudinal MOG-ab testing for prediction of relapse risk [
      • Ketelslegers I.A.
      • Van Pelt D.E.
      • Bryde S.
      • Neuteboom R.F.
      • Catsman-Berrevoets C.E.
      • Hamann D.
      • et al.
      Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ].

      4.3 Relapsing ON (RON)

      As the majority of adult patients already present with ON, RON is the most frequent relapsing phenotype in adulthood [
      • Jurynczyk M.
      • Messina S.
      • Woodhall M.R.
      • Raza N.
      • Everett R.
      • Roca-Fernandez A.
      • et al.
      Clinical presentation and prognosis in MOG-antibody disease: a UK study.
      ,
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ], while in childhood, an ON relapse can result in ADEM-ON, relapsing NMOSD-like phenotype, or RON as final diagnosis [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ,
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ].
      In 2012, a study reported that a proportion of MOG-ab-positive children with ON will experience further relapse(s), and suggested that these patients represent a separate subgroup distinct from MS or NMOSD [
      • Rostasy K.
      • Mader S.
      • Schanda K.
      • Huppke P.
      • Gartner J.
      • Kraus V.
      • et al.
      Anti-myelin oligodendrocyte glycoprotein antibodies in pediatric patients with optic neuritis.
      ]. Subsequently, several studies confirmed that paediatric MOG-ON patients show higher rates of recurrence compared to paediatric MOG-ab-negative [
      • Chen Q.
      • Zhao G.
      • Huang Y.
      • Li Z.
      • Sun X.
      • Lu P.
      • et al.
      Clinical characteristics of pediatric optic neuritis with myelin oligodendrocyte glycoprotein seropositive: a cohort study.
      ,
      • Song H.
      • Zhou H.
      • Yang M.
      • Tan S.
      • Wang J.
      • Xu Q.
      • et al.
      Clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein antibody-seropositive paediatric optic neuritis in China.
      ] and MS patients with ON [
      • Eyre M.
      • Hameed A.
      • Wright S.
      • Brownlee W.
      • Ciccarelli O.
      • Bowman R.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ]. These relapses have been shown to be highly steroid-responsive, or even steroid-dependent. Therefore, relapsing MOG-ab-positive patients often meet criteria for chronic relapsing inflammatory optic neuropathy (CRION) [
      • Ramanathan S.
      • Mohammad S.
      • Tantsis E.
      • Nguyen T.K.
      • Merheb V.
      • Fung V.S.C.
      • et al.
      Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.
      ,
      • Lee H.J.
      • Kim B.
      • Waters P.
      • Woodhall M.
      • Irani S.
      • Ahn S.
      • et al.
      Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies.
      ,
      • Chalmoukou K.
      • Alexopoulos H.
      • Akrivou S.
      • Stathopoulos P.
      • Reindl M.
      • Dalakas M.C.
      Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis.
      ,
      • Ramanathan S.
      • Reddel S.W.
      • Henderson A.
      • Parratt J.D.
      • Barnett M.
      • Gatt P.N.
      • et al.
      Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis.
      ].
      Compared to other paediatric relapsing MOGAD, RON patients had a similar number of relapses, but a slightly longer time to their first relapse, and more often a good outcome, defined as expanded disability status scale (EDSS) score of 0 [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ,
      • Bruijstens Arlette L.
      • Breu Markus
      • et al.
      E.U. paediatric MOG consortium consensus: Part 4 e Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.
      ].

      4.4 Relapsing NMOSD-like phenotype

      Patients who present with an NMOSD-like phenotype at onset of disease can experience further relapses during disease course, mainly ON or simultaneous ON and (LE)TM [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. Furthermore, also patients initially presenting with isolated ON or (LE)TM may have subsequent relapse(s), converting to a relapsing NMOSD-like phenotype during follow-up [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. Finally, some patients presenting with ADEM also convert to this phenotype due to further relapses with for example simultaneous ON and (LE)TM, or sequential relapses with ON as well as (LE)TM [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • Anlar B.
      • Bajer-Kornek B.
      • Blaschek A.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Duignan S.
      • Wright S.
      • Rossor T.
      • Cazabon J.
      • Gilmour K.
      • Ciccarelli O.
      • et al.
      Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes.
      ,
      • Lopez-Chiriboga A.S.
      • Majed M.
      • Fryer J.
      • Dubey D.
      • McKeon A.
      • Flanagan E.P.
      • et al.
      Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders.
      ,
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • Jurynczyk M.
      • Wright S.
      • Konuskan B.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ].
      From all paediatric patients with NMOSD (fulfilling Wingerchuk diagnostic criteria [
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • Cabre P.
      • Carroll W.
      • Chitnis T.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ]) or limited forms of NMOSD (including LETM, bilateral ON, brainstem syndromes or RON), only half of the MOG-ab-positive patients relapsed, compared to 100% of AQP4-ab-positive patients [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. While adult studies have shown better outcome in MOG-ab-positive than AQP4-ab-positive patients [
      • Cobo-Calvo A.
      • Ruiz A.
      • Maillart E.
      • Audoin B.
      • Zephir H.
      • Bourre B.
      • et al.
      Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study.
      ], no differences in outcome between these groups in paediatric patients were observed regarding VA and EDSS, possibly due to limited number of AQP4-ab-positive patients included in this study (n = 5), related to the rarity in childhood [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • Marquard K.
      • Karenfort M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ].

      5. Emerging and atypical clinical phenotypes

      Due to the continuing research in this field, MOG-abs are consistently identified within new disease presentations, thus expanding the spectrum of MOGAD. These disease presentations are overall rare and include less common or atypical demyelinating phenotypes, and phenotypes beyond the demyelinating syndromes.

      5.1 Encephalitis, overlapping syndromes and seizures

      A number of case series [
      • Fujimori J.
      • Takai Y.
      • Nakashima I.
      • Sato D.K.
      • Takahashi T.
      • Kaneko K.
      • et al.
      Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies.
      ,
      • Budhram A.
      • Mirian A.
      • Le C.
      • Hosseini-Moghaddam S.M.
      • Sharma M.
      • Nicolle M.W.
      Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
      ,
      • Hochmeister S.
      • Gattringer T.
      • Asslaber M.
      • Stangl V.
      • Haindl M.T.
      • Enzinger C.
      • et al.
      A fulminant case of demyelinating encephalitis with extensive cortical involvement associated with anti-MOG antibodies.
      ,
      • Ikeda T.
      • Yamada K.
      • Ogawa R.
      • Takai Y.
      • Kaneko K.
      • Misu T.
      • et al.
      The pathological features of MOG antibody-positive cerebral cortical encephalitis as a new spectrum associated with MOG antibodies: a case report.
      ,
      • Mariotto S.
      • Monaco S.
      • Peschl P.
      • Coledan I.
      • Mazzi R.
      • Hoftberger R.
      • et al.
      MOG antibody seropositivity in a patient with encephalitis: beyond the classical syndrome.
      ,
      • Sugimoto T.
      • Ishibashi H.
      • Hayashi M.
      • Tachiyama K.
      • Fujii H.
      • Kaneko K.
      • et al.
      A case of anti-MOG antibody-positive unilaterally dominant meningoencephalitis followed by longitudinally extensive transverse myelitis.
      ,
      • Otani T.
      • Irioka T.
      • Igarashi S.
      • Kaneko K.
      • Takahashi T.
      • Yokota T.
      Self-remitting cerebral cortical encephalitis associated with myelin oligodendrocyte glycoprotein antibody mimicking acute viral encephalitis: a case report.
      ,
      • Tao R.
      • Qin C.
      • Chen M.
      • Yu H.H.
      • Wu L.J.
      • Bu B.T.
      • et al.
      Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.
      ] and retrospective studies [
      • Ogawa R.
      • Nakashima I.
      • Takahashi T.
      • Kaneko K.
      • Akaishi T.
      • Takai Y.
      • et al.
      MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy.
      ,
      • Wang L.
      • ZhangBao J.
      • Zhou L.
      • Zhang Y.
      • Li H.
      • Li Y.
      • et al.
      Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
      ,
      • Hamid S.H.M.
      • Whittam D.
      • Saviour M.
      • Alorainy A.
      • Mutch K.
      • Linaker S.
      • et al.
      Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease.
      ] have reported an association between MOG-abs and encephalitis, mainly in adult, but also more recently in paediatric patients [
      • Hamid S.H.M.
      • Whittam D.
      • Saviour M.
      • Alorainy A.
      • Mutch K.
      • Linaker S.
      • et al.
      Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease.
      ]. ADEM and encephalitis are both characterised by encephalopathy. However, ADEM typically includes demyelinating features with clinically ON and/or TM, and on neuroimaging poorly demarcated widespread lesions of predominantly white matter and deep grey matter, while in typical encephalitis brain MRI shows cortical lesions or no abnormalities at all [
      • Krupp L.B.
      • Tardieu M.
      • Amato M.P.
      • Banwell B.
      • Chitnis T.
      • Dale R.C.
      • et al.
      International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
      ,
      • Graus F.
      • Titulaer M.J.
      • Balu R.
      • Benseler S.
      • Bien C.G.
      • Cellucci T.
      • et al.
      A clinical approach to diagnosis of autoimmune encephalitis.
      ,
      • Salama S.
      • Khan M.
      • Pardo S.
      • Izbudak I.
      • Levy M.
      MOG antibody-associated encephalomyelitis/encephalitis.
      ]. The reported (mainly adult) patients with encephalitis and MOG-abs presented with seizures, headache and/or fever, with uni- or bilateral cortical lesions on brain MRI, also referred to as “cortical encephalitis” [
      • Fujimori J.
      • Takai Y.
      • Nakashima I.
      • Sato D.K.
      • Takahashi T.
      • Kaneko K.
      • et al.
      Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies.
      ,
      • Budhram A.
      • Mirian A.
      • Le C.
      • Hosseini-Moghaddam S.M.
      • Sharma M.
      • Nicolle M.W.
      Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.
      ,
      • Hochmeister S.
      • Gattringer T.
      • Asslaber M.
      • Stangl V.
      • Haindl M.T.
      • Enzinger C.
      • et al.
      A fulminant case of demyelinating encephalitis with extensive cortical involvement associated with anti-MOG antibodies.
      ,
      • Ikeda T.
      • Yamada K.
      • Ogawa R.
      • Takai Y.
      • Kaneko K.
      • Misu T.
      • et al.
      The pathological features of MOG antibody-positive cerebral cortical encephalitis as a new spectrum associated with MOG antibodies: a case report.
      ,
      • Mariotto S.
      • Monaco S.
      • Peschl P.
      • Coledan I.
      • Mazzi R.
      • Hoftberger R.
      • et al.
      MOG antibody seropositivity in a patient with encephalitis: beyond the classical syndrome.
      ,
      • Sugimoto T.
      • Ishibashi H.
      • Hayashi M.
      • Tachiyama K.
      • Fujii H.
      • Kaneko K.
      • et al.
      A case of anti-MOG antibody-positive unilaterally dominant meningoencephalitis followed by longitudinally extensive transverse myelitis.
      ,
      • Otani T.
      • Irioka T.
      • Igarashi S.
      • Kaneko K.
      • Takahashi T.
      • Yokota T.
      Self-remitting cerebral cortical encephalitis associated with myelin oligodendrocyte glycoprotein antibody mimicking acute viral encephalitis: a case report.
      ,
      • Tao R.
      • Qin C.
      • Chen M.
      • Yu H.H.
      • Wu L.J.
      • Bu B.T.
      • et al.
      Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.
      ,
      • Ogawa R.
      • Nakashima I.
      • Takahashi T.
      • Kaneko K.
      • Akaishi T.
      • Takai Y.
      • et al.
      MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy.
      ,
      • Wang L.
      • ZhangBao J.
      • Zhou L.
      • Zhang Y.
      • Li H.
      • Li Y.
      • et al.
      Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
      ,
      • Hamid S.H.M.
      • Whittam D.
      • Saviour M.
      • Alorainy A.
      • Mutch K.
      • Linaker S.
      • et al.
      Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease.
      ].
      Recently, this association between MOG-abs and encephalitis has been explored further in two paediatric studies [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Wegener-Panzer A.
      • Cleaveland R.
      • Wendel E.M.
      • Baumann M.
      • Bertolini A.
      • Hausler M.
      • et al.
      Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.
      ], including one large prospective, multicentre, observational paediatric cohort study from Spain [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ]. In this study, among the 296 patients with definite or possible encephalitis (according to international criteria [
      • Venkatesan A.
      • Tunkel A.R.
      • Bloch K.C.
      • Lauring A.S.
      • Sejvar J.
      • Bitnun A.
      • et al.
      Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.
      ]), 7% had MOG-abs [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ]. Even more interesting, among the 64 patients with autoimmune encephalitis (AE, excluding encephalitis patients with an infectious or unknown cause), 34% of patients had MOG-abs, which was more common than all neuronal antibodies combined (33%; 22% had N-methyl-D-aspartate-receptor (NMDAR)-abs). MOG-ab-positive patients with encephalitis clinically showed impaired consciousness (100%), seizures (64%; 45% with status epilepticus), fever (59%), and abnormal behaviour (50%) and movements (36%). Brain MRI showed cortical involvement in 73% of patients, which was extensive and bilateral in most of these patients (75%), and additional or isolated basal ganglia or thalamic involvement in 41% of patients. Only 9% of these patients had no radiological abnormalities, which is clearly lower than reported for other forms of AE, e.g. in anti-NMDAR encephalitis, 55% of patients had a normal MRI [
      • Armangue T.
      • Titulaer M.J.
      • Malaga I.
      • Bataller L.
      • Gabilondo I.
      • Graus F.
      • et al.
      Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.
      ]. Within a median follow-up of 42 months, 23% of MOG-ab-positive patients with encephalitis had further relapses, including a demyelinating syndrome (ON or TM) in 80% of these relapsing patients [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • Sepulveda M.
      • Ruiz-Garcia R.
      • Munoz-Batista M.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.