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E.U. paediatric MOG consortium consensus: Part 2 – Neuroimaging features of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

Open AccessPublished:November 03, 2020DOI:https://doi.org/10.1016/j.ejpn.2020.10.002

      Highlights

      • Children with MOGAD present with typical imaging patterns.
      • Imaging patterns are associated with clinical phenotypes and age at presentation.
      • Unusual imaging features include leukodystrophy-like or predominant cortical lesions.
      • In contrast to other acquired demyelinating syndromes, lesions usually resolve.
      • New imaging techniques may aid to understand the neurobiology and varying outcomes.

      Abstract

      Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the ‘leukodystophy-like’ phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD.

      Keywords

      Abbreviations

      ADEM
      Acute disseminated encephalomyelitis
      ADEMON
      ADEM followed by optic neuritis
      ADS
      Acquired demyelinating syndrome
      AE
      Autoimmune encephalitis
      AQP4
      Aquaporin-4
      AQP4-ON
      AQP4-ab-associated ON
      CNS
      Central nervous system
      DTI
      Diffusion tension imaging
      FLAIR
      Fluid-attenuated inversion recovery
      LETM
      Longitudinal extensive transverse myelitis
      MDEM
      Multiphasic disseminated encephalomyelitis
      MOG-abs
      Myelin oligodendrocyte glycoprotein antibodies
      MOG-ON
      MOG-ab-associated ON
      MOGAD
      MOG-ab-associated disorders
      MPRAGE
      Magnetization prepared rapid acquisition gradient echo
      MS
      Multiple sclerosis
      MS-ON
      MS associated ON
      NMOSD
      Neuromyelitis optica spectrum disorders
      ON
      Optic neuritis
      TM
      Transverse myelitis

      1. Introduction

      Myelin oligodendrocyte glycoprotein antibodies (MOG-abs) can be detected in children presenting with a range of paediatric acquired demyelinating syndromes (ADS) such as acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) antibody negative neuromyelitis optica spectrum disorders (NMOSD), ADEM followed by optic neuritis (ADEMON), multiphasic disseminated encephalomyelitis (MDEM), and optic neuritis (ON). Importantly, MOG-abs are rarely detected in children with multiple sclerosis (MS) [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ]. Several studies have addressed the clinical and prognostic relevance of MOG-abs. High-titre and transient serum MOG-abs are predominantly found in young children with ADEM [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ]. Children with high and persisting MOG-abs are at risk of developing further attacks, in particular episodes of ON. Until recently MOG-ab-associated disorders (MOGAD) were thought to have a more benign outcome compared to other recurrent demyelinating diseases including MS or AQP4-ab-positive NMOSD. Nevertheless, recent findings from adult cohorts indicate that patients with MOG-abs may acquire neurological deficits over time, suggesting the need for immunomodulatory treatment especially in relapsing cases [
      • Cobo-Calvo A.
      • Ruiz A.
      • Maillart E.
      • et al.
      Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study.
      ,
      • Liu H.
      • Zhou H.
      • Wang J.
      • Xu Q.
      • Wei S.
      Antibodies to myelin oligodendrocyte glycoprotein in chronic relapsing inflammatory optic neuropathy.
      ,
      • Mariano R.
      • Messina S.
      • Kumar K.
      • Kuker W.
      • Leite M.I.
      • Palace J.
      Comparison of clinical outcomes of transverse myelitis among adults with myelin oligodendrocyte glycoprotein antibody vs aquaporin-4 antibody disease.
      ].
      Imaging plays a crucial role in differentiating the spectrum of ADS, which apart from MOGAD includes paediatric MS, AQP4-ab-positive NMOSD and other less well-defined subgroups. In addition, physicians caring for children with ADS must be aware of the broad differential diagnosis mimicking acute demyelinating attacks such as viral encephalitis, CNS vasculitis, CNS-isolated hemophagocytic lymphohistiocytosis, brain tumors, and mitochondrial diseases [
      • Rostasy K.
      • Bajer-Kornek B.
      • Venkateswaran S.
      • Hemingway C.
      • Tardieu M.
      Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders.
      ,
      • Twilt M.
      • Benseler S.M.
      Childhood inflammatory brain diseases: pathogenesis, diagnosis and therapy.
      ,
      • Yiu E.M.
      • Laughlin S.
      • Verhey L.H.
      • Banwell B.L.
      Canadian Pediatric Demyelinating Disease N. Clinical and magnetic resonance imaging (MRI) distinctions between tumefactive demyelination and brain tumors in children.
      ,
      • Benson L.A.
      • Li H.
      • Henderson L.A.
      • et al.
      Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.
      ,
      • Wells E.
      • Hacohen Y.
      • Waldman A.
      • et al.
      Neuroimmune disorders of the central nervous system in children in the molecular era.
      ].
      Therefore, it is important to delineate the spectrum of MOGAD not only on clinical and laboratory but also on radiological grounds. Compared to the imaging characteristics of children with MS, children with MOGAD present with various imaging patterns which correspond often with the respective subtype as well as age at presentation [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ]. In this review we describe the common neuroradiological features of the main subtypes of MOGAD in addition to unusual presentations, delineate the features, which distinguishes MOGAD from other ADS, and discuss the future role of MR-imaging in aiding therapy decisions and prognosis in children with MOGAD.

      2. MR imaging

      2.1 Brain

      2.1.1 Lesion distribution and characteristics

      Radiological features are heterogeneous and differ depending on the clinical presentation. In paediatric MOGAD ADEM represents the largest subgroup (40–50%) [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ]. MRI typically shows bilateral supratentorial brain lesions mostly affecting the subcortical and deep white matter and the deep grey matter. Lesions are T2-hyperintense, large (>2 cm in size), blurred and poorly demarcated (Fig. 1A and B) [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ,
      • Konuskan B.
      • Yildirim M.
      • Gocmen R.
      • et al.
      Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.
      ]. Well-demarcated lesions, only small lesions, or involvement of just one anatomical area in younger children with ADEM are indicative of MOG-ab-negative disease [
      • Baumann M.
      • Sahin K.
      • Lechner C.
      • et al.
      Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.
      ]. Children with MOG-ab-positive MDEM and NMOSD often present with similar lesion characteristics as ADEM patients, especially if they are of younger age [
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ]. In young patients (<7 years) with MDEM, these T2-hyperintense lesions can be diffuse and symmetrical, mimicking a leukodystrophy like disease process, but contrast medium enhancement and often complete resolution on follow-up scans favours their inflammatory nature (Fig. 1C and D) [
      • Hacohen Y.
      • Rossor T.
      • Mankad K.
      • et al.
      Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
      ].
      Fig. 1
      Fig. 1MRI features of MOGAD. (A, B) Cerebral MRI of a 3-year-old boy with ADEM, who presented with fever, headache, dysarthria, gait disorder and right hemiparesis, showing large and blurred lesions involving both hemispheres and thalami (axial T2). (C, D) Follow-up scans 3 month later showed complete resolution of lesions (axial T2). (E) Juxtacortical curved lesions involving U-fibres in a 4-year-old-girl with ADEM (axial FLAIR). (F) Callosal lesions in a 4-year-old boy with ADEM (sagittal T2). (G) Well-demarcated, ovoid lesions in an 11-year-old girl with MS (axial T2). (H, I) Follow-up scans seven years later reveal new lesions and lesions radiating perpendicularly from the ventricular surface (axial T2, sagittal FLAIR). (J) Extensive and confluent white matter changes in a 4-year-old boy with ADEM, finally diagnosed as ADEMON (axial T2). (K) Cerebral MRI of a 14-year-old girl with encephalitis who presented to the emergency department with severe headache, mental status changes, and seizures showing pronounced signal alterations of the cortical grey matter, particularly in the right temporal-parietal lobe (axial FLAIR). She was finally diagnosed as relapsing MOGAD. (L) Bilateral signal alterations in both hippocampi in a 16-year-old previously healthy boy with severe right-sided headache (coronal FLAIR), categorized as encephalitis with limbic involvement. (M, N) Spinal MRI of a 3-year-old boy with ADEM and LETM with central grey involvement and a distinctive H pattern in the axial plane (sagittal and axial T2). (O, P) Orbital MRI of a 9-year-old girl with unilateral optic neuritis showing signal increase, swelling, and contrast enhancement of the right optic nerve as well as of the perioptic nerve sheath (coronal fat-suppressed T2 and coronal fat-suppressed, postcontrast T1).

      2.1.2 Differentiation of MOGAD from AQP4-ab-positive NMOSD and MS in brain

      Children with AQP4-ab-positive NMOSD, similarly to adults, have lesions following the distribution of AQP4-rich areas in the brain [
      • McKeon A.
      • Lennon V.A.
      • Lotze T.
      • et al.
      CNS aquaporin-4 autoimmunity in children.
      ]. Brain lesions are primarily found in the periventricular region of the third ventricle, in the periaqueductal grey matter, and in the dorsal brainstem adjacent to the fourth ventricle. However, lesions in these ‘NMOSD-specific’ regions are also present in MOG-ab-positive patients [
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ,
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ,
      • Hacohen Y.
      • Mankad K.
      • Chong W.K.
      • et al.
      Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.
      ]. Children and adults with MOGAD show poorly demarcated lesions in the brainstem or cerebellar peduncles, typically adjacent to the fourth ventricle [
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ,
      • Hacohen Y.
      • Mankad K.
      • Chong W.K.
      • et al.
      Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.
      ]. MOGAD and AQP4-ab-positive disease display different imaging characteristics then MS, but overlap in brain lesion distribution despite targeting distinct cell types (oligodendrocytes vs. astrocytes) [
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ]. Potentially lesion quality, such as poorly demarcated lesions, frequent in MOGAD, and T1-hypointense lesions, more frequent in AQP4-ab-positive disease, distinguishes between the two groups [
      • Lechner C.
      • Baumann M.
      • Hennes E.M.
      • et al.
      Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.
      ,
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ]. In addition, in AQP4-ab-positive disease, cortical grey matter is less frequently involved than in MOGAD [
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ,
      • Absoud M.
      • Lim M.J.
      • Appleton R.
      • et al.
      Paediatric neuromyelitis optica: clinical, MRI of the brain and prognostic features.
      ,
      • Salama S.
      • Khan M.
      • Shanechi A.
      • Levy M.
      • Izbudak I.
      MRI differences between MOG antibody disease and AQP4 NMOSD.
      ].
      Curvilinear lesions involving subcortical U-fibres seemed to be a distinguishing feature between MS, AQP4-ab-positive NMOSD, and MOGAD in a cohort of mostly adult patients, but curvilinear lesions appear also in young children with MOG-ab-positive ADEM (Fig. 1E) [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Jurynczyk M.
      • Tackley G.
      • Kong Y.
      • et al.
      Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.
      ]. Lesions in the corpus callosum, absent in certain series [
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ], have also been described in young patients with MOG-ab-positive ADEM or MDEM (Fig. 1F) [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Konuskan B.
      • Yildirim M.
      • Gocmen R.
      • et al.
      Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.
      ,
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • D'Indy H.
      • et al.
      MOG antibody-related disorders: common features and uncommon presentations.
      ]. In addition, periventricular lesions can also be a feature in selected children with MOGAD and do not distinguish these patients from MS or AQP4-ab-positive NMOSD. However, ovoid lesions perpendicular to the major axis of corpus callosum (Dawson finger type lesions) remain characteristic of MS [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ].
      In general, the presence of MOG-abs pleads against the diagnosis of MS. Nevertheless, a very small subgroup of children who are diagnosed with MS does harbour MOG-abs, which are, in general, transient and decrease to undetectable levels over time [
      • Hennes E.M.
      • Baumann M.
      • Schanda K.
      • et al.
      Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.
      ,
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ]. These children have a typical MS-like MRI pattern with well-demarcated lesions (Fig. 1G, H, and I) and short myelitis, which clearly sets them apart from non-MS cases [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Hacohen Y.
      • Mankad K.
      • Chong W.K.
      • et al.
      Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.
      ]. It is important to clearly separate cases initially diagnosed as MS, which show MRI features not typical for MS and on follow-up MRI resolution of lesions, and therefore should be categorized as MOGAD (e.g. NMOSD).
      In pathological studies on brain biopsies, MOG-ab-positive cases show both perivenous and confluent white matter demyelination, with an over-representation of intracortical demyelinated lesions compared to typical MS [
      • Hoftberger R.
      • Guo Y.
      • Flanagan E.P.
      • et al.
      The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Takai Y.
      • Misu T.
      • Kaneko K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.
      ]. The pathology for AQP4-ab-positive NMOSD is distinct from MOGAD. In AQP4-ab-positive NMOSD a severe astrocytic damage and oligodendrocyte loss is seen, whereas in MOG-ab-associated demyelination oligodendrocytes are relatively preserved. Even large demyelinating lesions in MOGAD show relative preservation of oligodendrocytes [
      • Takai Y.
      • Misu T.
      • Kaneko K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.
      ]. These pathological findings are in line with resolution of MRI-lesions in MOGAD and persistence of lesions or cavitation in AQP4-ab-associated disease.

      2.1.3 Newly recognized presentations

      More recently described phenotypes of MOGAD with characteristic clinical and radiological features include a leukodystrophy-like phenotype with confluent white matter lesions and autoimmune encephalitis (AE) with MOG-abs and predominant involvement of cortical and deep grey matter structures [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Hacohen Y.
      • Rossor T.
      • Mankad K.
      • et al.
      Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
      ,
      • Hacohen Y.
      • Mankad K.
      • Chong W.K.
      • et al.
      Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.
      ,
      • Wegener-Panzer A.
      • Cleaveland R.
      • Wendel E.M.
      • et al.
      Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.
      ]. The leukodystrophy-like phenotype occurs in particular in very young children [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Hacohen Y.
      • Rossor T.
      • Mankad K.
      • et al.
      Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. Patients show confluent largely symmetrical white matter lesions with nodular enhancement (Fig. 1J). Despite resolution of lesions, this phenotype is associated with a poor outcome [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Hacohen Y.
      • Rossor T.
      • Mankad K.
      • et al.
      Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
      ].
      In MOG-ab-associated AE, patients fulfil the diagnostic criteria of possible AE but not the IPMSSG criteria for ADEM. Imaging shows a range of cortical (Fig. 1K), and adjacent juxtacortical white matter involvement, partially combined with involvement of deep grey matter structures, or bilateral limbic areas (Figure 1L) [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • 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.
      • et al.
      Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.
      ]. Optic nerves, deep white matter, periventricular white matter, cerebellum, or spine are initially not involved in MOG-ab-associated AE [
      • Wegener-Panzer A.
      • Cleaveland R.
      • Wendel E.M.
      • et al.
      Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.
      ]. Intracranial hypertension can accompany the encephalitis phenotype in children and adults [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Wang L.
      • ZhangBao J.
      • Zhou L.
      • et al.
      Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
      ]. Children with MOG-encephalitis seem to have a higher risk of further relapses, and imaging in children with relapses resembles children with MDEM or NMOSD [
      • Wegener-Panzer A.
      • Cleaveland R.
      • Wendel E.M.
      • et al.
      Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.
      ]. Unilateral cerebral cortical encephalitis with seizures is increasingly recognized in adult patients with MOG-abs [
      • Wang L.
      • ZhangBao J.
      • Zhou L.
      • et al.
      Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single-center cohort study in Shanghai, China.
      ,
      • Ogawa R.
      • Nakashima I.
      • Takahashi T.
      • et al.
      MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy.
      ,
      • Hamid S.H.M.
      • Whittam D.
      • Saviour M.
      • et al.
      Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease.
      ] resembling children with MOG-encephalitis. Pathological studies in patients with MOG-ab-positive cortical encephalitis show subpial demyelination [
      • Takai Y.
      • Misu T.
      • Kaneko K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.
      ].
      MOGAD with sole localization of lesions in one region like brainstem do not fit the criteria of the above-mentioned subgroups but present rare manifestations of the disease [
      • Hacohen Y.
      • Nishimoto Y.
      • Fukami Y.
      • et al.
      Paediatric brainstem encephalitis associated with glial and neuronal autoantibodies.
      ]. Neither do children who present with isolated seizures during the first episode of MOGAD with no or only subtle MRI changes [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Ramanathan S.
      • O'Grady G.L.
      • Malone S.
      • et al.
      Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children.
      ]. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with detection of MOG-abs later in the course has so far only been described in one adult patient [
      • Symmonds M.
      • Waters P.J.
      • Kuker W.
      • Leite M.I.
      • Schulz U.G.
      Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS.
      ].

      2.2 Spinal cord

      2.2.1 Lesion distribution and characteristics

      Spinal cord involvement is often characterized by a longitudinal extensive transverse myelitis (LETM), defined as a contiguous lesion extending over three or more vertebral segments. LETM is a feature of different subgroups of MOGAD such as ADEM and NMOSD but can also occur as isolated LETM. It mainly affects the cervical and thoracic, and less often the lumbar, and conus regions [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ]. The grey matter of the spinal cord is preferentially involved resulting in a characteristic T2-hyperintense line running in the superior-inferior direction on sagittal images and a distinctive H pattern in the axial plane (Fig. 1M, N), although the extension of lesions can change considerably among the different spinal levels [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ]. Short transverse myelitis (TM) is rarely present in teenagers, but more frequent in adult patients [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Ciron J.
      • Cobo-Calvo A.
      • Audoin B.
      • et al.
      Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: a retrospective multicentric study.
      ].

      2.2.2 Differentiation of MOGAD from AQP4-ab-positive NMOSD and MS in myelitis

      The differential diagnosis includes AQP4-ab-positive myelitis, viral myelitis and spinal cord infarction [
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ,
      • Ciccarelli O.
      • Cohen J.A.
      • Reingold S.C.
      • et al.
      Spinal cord involvement in multiple sclerosis and neuromyelitis optica spectrum disorders.
      ]. Contrast enhancement and cavitation favours AQP4-ab-positive myelitis over MOG-ab-positive myelitis [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ]. MOG-ab-positive myelitis usually does not go along with substance defects or spinal cord atrophy. Even MRI-negative MOG-ab-positive myelitis can occur in children and adults [
      • Sechi E.
      • Krecke K.N.
      • Pittock S.J.
      • et al.
      Frequency and characteristics of MRI-negative myelitis associated with MOG autoantibodies.
      ,
      • Perez C.A.
      • Garcia-Tarodo S.
      • Troxell R.
      MRI-negative myelitis associated with myelin oligodendrocyte glycoprotein antibody spectrum demyelinating disease.
      ]. Multiple lesions with long and short segments and conus involvement are more frequent in MOG-ab-positive myelitis than in AQP4-ab-positive myelitis [
      • Mariano R.
      • Messina S.
      • Kumar K.
      • Kuker W.
      • Leite M.I.
      • Palace J.
      Comparison of clinical outcomes of transverse myelitis among adults with myelin oligodendrocyte glycoprotein antibody vs aquaporin-4 antibody disease.
      ,
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ]. Lumbar involvement is more frequent in MOGAD compared to AQP4-ab-positive NMOSD and MS [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ]. Adult patients with MOG-ab-positive myelitis seem to present more frequently with short myelitis than children [
      • Ciron J.
      • Cobo-Calvo A.
      • Audoin B.
      • et al.
      Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: a retrospective multicentric study.
      ]. Multiple short segments are common in MS [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ].

      2.3 Optic nerves

      2.3.1 Characteristics of MOG-ab-positive ON

      Optic neuritis is frequent in children with MOGAD and up to half of the patients present with bilateral ON [
      • 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.
      ]. The percentage of radiological bilateral ON can be even higher than clinically recorded [
      • Zhao Y.
      • Tan S.
      • Chan T.C.Y.
      • et al.
      Clinical features of demyelinating optic neuritis with seropositive myelin oligodendrocyte glycoprotein antibody in Chinese patients.
      ]. Accordingly, in children with bilateral ON, MOG-abs are present in up to 75% [
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. The majority of children with bilateral ON appears to have a monophasic disease course [
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. A small subgroup of children with bilateral ON and MOG-abs continues to have further relapses including NMOSD, ADEM or recurrent ON [
      • Liu H.
      • Zhou H.
      • Wang J.
      • Xu Q.
      • Wei S.
      Antibodies to myelin oligodendrocyte glycoprotein in chronic relapsing inflammatory optic neuropathy.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. In mainly adult patients with chronic relapsing inflammatory optic neuropathy (CRION), MOG-abs are frequently present and should be included in the MOGAD [
      • Liu H.
      • Zhou H.
      • Wang J.
      • Xu Q.
      • Wei S.
      Antibodies to myelin oligodendrocyte glycoprotein in chronic relapsing inflammatory optic neuropathy.
      ]. Children with MOG-ab-positive ON usually show a longitudinally extensive ON (LEON; involving more than half of the prechiasmatic optic nerve length) with a predominantly anterior affection of the optic nerve [
      • 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.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. Perineural enhancement is common (Figure 1P) [
      • 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.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ]. Chiasma and optic tract are only infrequently involved [
      • Liu H.
      • Zhou H.
      • Wang J.
      • Xu Q.
      • Wei S.
      Antibodies to myelin oligodendrocyte glycoprotein in chronic relapsing inflammatory optic neuropathy.
      ,
      • Zhao Y.
      • Tan S.
      • Chan T.C.Y.
      • et al.
      Clinical features of demyelinating optic neuritis with seropositive myelin oligodendrocyte glycoprotein antibody in Chinese patients.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ,
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ,
      • Chen J.J.
      • Flanagan E.P.
      • Jitprapaikulsan J.
      • et al.
      Myelin oligodendrocyte glycoprotein antibody-positive optic neuritis: clinical characteristics, radiologic clues, and outcome.
      ].

      2.3.2 Differentiation from AQP4-ab-positive and MS associated ON

      In a cohort of paediatric and adult patients with a first-episode of ON, bilateral involvement was more common in MOG-ab-associated ON (MOG-ON) and AQP4-ab-associated ON (AQP4-ON) than MS associated ON (MS-ON) [
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ]. Optic nerve head swelling and retrobulbar involvement was more common in MOG-ON, whereas chiasmal and bilateral optic tract involvement was more common in AQP4-ON than in MOG-ON and MS-ON. MOG-ON and AQP4-ON had longer lesion lengths than MS-ON [
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ]. In a study including 42 children with ON (22 MS-ON, 16 MOG-ON and 4 AQP4-ON), patients with MS-ON more frequently (95%) showed an abnormal brain MRI than patients with MOG-ON (6%) and AQP4-ON (25%) [
      • Eyre M.
      • Hameed A.
      • Wright S.
      • et al.
      Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.
      ].

      2.4 Enhancement and diffusion restriction in cerebral and spinal MRI

      Gadolinium enhancement of brain and spine lesions in paediatric MOGAD is less frequent and if present often more diffuse than in MS or AQP4-ab-positive NMOSD [
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ]. Patients with a leukodystrophy-like phenotype of confluent white matter lesions may show a nodular enhancement [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ,
      • Hacohen Y.
      • Rossor T.
      • Mankad K.
      • et al.
      Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. In adult AQP4-ab-positive NMOSD ‘cloud-like enhancement’, multiple patchy enhancing lesions with blurred margin, is frequently seen [
      • Ito S.
      • Mori M.
      • Makino T.
      • Hayakawa S.
      • Kuwabara S.
      Cloud-like enhancement is a magnetic resonance imaging abnormality specific to neuromyelitis optica.
      ]. Optic nerve, and as aforementioned, perineural, enhancement is common in MOG-ON [
      • Zhao Y.
      • Tan S.
      • Chan T.C.Y.
      • et al.
      Clinical features of demyelinating optic neuritis with seropositive myelin oligodendrocyte glycoprotein antibody in Chinese patients.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ,
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ].
      Areas with restricted diffusion suggestive of cytotoxic oedema is not common in paediatric MOGAD but may be present in younger patients with ADEM [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Zuccoli G.
      • Panigrahy A.
      • Sreedher G.
      • et al.
      Vasogenic edema characterizes pediatric acute disseminated encephalomyelitis.
      ].

      2.5 Age-related clinical phenotypes and imaging patterns

      Age seems to play an important role in the presentation of the different clinical phenotypes of MOGAD and is linked to distinct imaging patterns. Younger children (9 years or less) tend to have a manifestation with poorly demarcated widespread lesions in the brain. As above-mentioned, lesions involving the corpus callosum - albeit infrequent -, and curved juxtacortical lesions involving U-fibres, may also be a feature of younger patients with MOGAD. In contrast, older children (10 years or older), who commonly present with ON and/or TM, more often show well-demarcated, no or only small non-specific lesions in their cerebral MRI [
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. These differences are also seen when comparing MRI features in paediatric-onset and adult-onset MOGAD [
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ]. Probably myelin development and compaction have a significant influence on the neuroradiological presentation. Studies of normal white matter maturation using diffusion tensor imaging show region-specific changes in mean diffusivity and fractional anisotropy from infancy to childhood [
      • Mukherjee P.
      • Miller J.H.
      • Shimony J.S.
      • et al.
      Diffusion-tensor MR imaging of gray and white matter development during normal human brain maturation.
      ,
      • Ben Bashat D.
      • Ben Sira L.
      • Graif M.
      • et al.
      Normal white matter development from infancy to adulthood: comparing diffusion tensor and high b value diffusion weighted MR images.
      ].

      3. MR imaging during disease course and in relapsing cases

      In a Dutch study on paediatric ADEM with unknown antibody status, new lesions and enlargement of existing lesions occurred in about 50% of MRI studies performed during clinical recovery in the first three months but was rarely seen three months after the first onset of ADEM [
      • Wong Y.Y.M.
      • van Pelt E.D.
      • Ketelslegers I.A.
      • et al.
      Evolution of MRI abnormalities in paediatric acute disseminated encephalomyelitis.
      ]. On follow-up cerebral and spinal lesions frequently resolve in MOGAD. In relapsing MOGAD, such as MDEM, new episodes are associated with new MRI lesions. However, few patients also develop new lesions while they remain asymptomatic [
      • Baumann M.
      • Hennes E.M.
      • Schanda K.
      • et al.
      Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): extending the spectrum of MOG antibody positive diseases.
      ]. In relapsing MOGAD localization of lesions can change during the disease. In younger patients (9 years or less) the brain is more likely to be affected, whereas in patients older than 9 years optic nerves are more commonly affected [
      • Hacohen Y.
      • Wong Y.Y.
      • Lechner C.
      • et al.
      Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.
      ]. In patients presenting with MOG-encephalitis and extensive bilateral cortical involvement, progression towards general cortical atrophy and irreversible deficits is described [
      • Armangue T.
      • Olive-Cirera G.
      • Martinez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.
      ].

      4. Differential diagnosis

      Differences in lesion location and quality between MOGAD and AQP4-ab-positive NMOSD, respectively MS, are summarized in Table 1. Key imaging features in MOGAD are usually the absence of destructive lesions and resolution of lesions. Differential diagnosis includes viral encephalitis, CNS vasculitis, CNS-isolated hemophagocytic lymphohistiocytosis, brain tumors, and mitochondrial diseases (Fig. 2) [
      • Rostasy K.
      • Bajer-Kornek B.
      • Venkateswaran S.
      • Hemingway C.
      • Tardieu M.
      Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders.
      ,
      • Twilt M.
      • Benseler S.M.
      Childhood inflammatory brain diseases: pathogenesis, diagnosis and therapy.
      ,
      • Yiu E.M.
      • Laughlin S.
      • Verhey L.H.
      • Banwell B.L.
      Canadian Pediatric Demyelinating Disease N. Clinical and magnetic resonance imaging (MRI) distinctions between tumefactive demyelination and brain tumors in children.
      ,
      • Benson L.A.
      • Li H.
      • Henderson L.A.
      • et al.
      Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.
      ,
      • Wells E.
      • Hacohen Y.
      • Waldman A.
      • et al.
      Neuroimmune disorders of the central nervous system in children in the molecular era.
      ].
      Table 1Comparison of magnetic resonance imaging (MRI) characteristics in paediatric patients with MOG antibody associated disorders (MOGAD), AQP4 antibody positive neuromyelitis optica spectrum disorders (NMOSD), and multiple sclerosis (MS).
      MRI characteristicsMOGADAQP4-NMOSDMS
      Brain
      Cortical lesions+(+)++
      Juxtacortical lesions+++++++
      Periventricular lesions+++++++
      Callosal lesions+++++
      Dawson finger type lesions(+)(+)++
      Deep grey matter lesions++++
      Brainstem lesions++++++
      Poorly demarcated lesions++++++
      Well-demarcated lesions++++++
      T1 hypointense lesions++++++
      Lesion enhancement++++++
      Spinal cord
      Longitudinal extensive transverse myelitis+++++++
      Cervical involvement+++++++++
      Thoracic involvement++++++++
      Lumbar involvement+++(+)
      Centrally located+++(+)
      Peripherally located(+)+++
      Optic nerves
      Bilateral optic neuritis++++++
      Longitudinally extensive optic neuritis++++++++
      Anterior optic nerve involvement++++++
      Posterior optic nerve involvement++++++
      Chiasmal involvement++++
      Optic tract involvement(+)++(+)
      (+) rare, + infrequent, ++ frequent, +++ very frequent
      Data summarized from several studies [
      • Hacohen Y.
      • Absoud M.
      • Deiva K.
      • et al.
      Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.
      ,
      • Baumann M.
      • Grams A.
      • Djurdjevic T.
      • et al.
      MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.
      ,
      • Waters P.
      • Fadda G.
      • Woodhall M.
      • et al.
      Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes.
      ,
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ,
      • Absoud M.
      • Lim M.J.
      • Appleton R.
      • et al.
      Paediatric neuromyelitis optica: clinical, MRI of the brain and prognostic features.
      ,
      • Fernandez-Carbonell C.
      • Vargas-Lowy D.
      • Musallam A.
      • et al.
      Clinical and MRI phenotype of children with MOG antibodies.
      ,
      • Cobo-Calvo A.
      • Ruiz A.
      • D'Indy H.
      • et al.
      MOG antibody-related disorders: common features and uncommon presentations.
      ,
      • Dubey D.
      • Pittock S.J.
      • Krecke K.N.
      • et al.
      Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody.
      ,
      • Tantsis E.M.
      • Prelog K.
      • Alper G.
      • et al.
      Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.
      ,
      • Zhao Y.
      • Tan S.
      • Chan T.C.Y.
      • et al.
      Clinical features of demyelinating optic neuritis with seropositive myelin oligodendrocyte glycoprotein antibody in Chinese patients.
      ,
      • Wendel E.M.
      • Baumann M.
      • Barisic N.
      • et al.
      High association of MOG-IgG antibodies in children with bilateral optic neuritis.
      ,
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ,
      • de Mol C.L.
      • Wong Y.
      • van Pelt E.D.
      • et al.
      The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.
      ,
      • Fadda G.
      • Brown R.A.
      • Longoni G.
      • et al.
      MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study.
      ,
      • Papetti L.
      • Figa Talamanca L.
      • Spalice A.
      • Vigevano F.
      • Centonze D.
      • Valeriani M.
      Predictors of evolution into multiple sclerosis after a first acute demyelinating syndrome in children and adolescents.
      ].
      Fig. 2
      Fig. 2Differential diagnosis of MOGAD (selected examples). (A) Cerebral MRI of a 5-year-old boy with viral encephalitis (FSME), presenting with fever, headache, nausea, vomiting, and tonic-clonic seizures. (B) MRI of a 12-year-old girl with CNS vasculitis, presenting with episodes of impaired unilateral vision and hemiparesis. Magnetic resonance angiography and CSF pleocytosis pointed to the diagnosis of CNS vasculitis. After further stroke-like episodes, she was started on cyclophosphamide, leading to significant improvement. (C) MRI of a 9-year-old girl with posterior reversible encephalopathy syndrome, presenting with headache, vomiting, and tonic-clonic seizures. She had nephritis with transient arterial hypertonia. (D) MRI of a 10-year-old boy with anaplastic astrocytoma. (E) So-called ‘UNOs’ (unidentified neurofibromatosis objects), respectively focal altered signal intensity (FASI), in a 2-year-old-girl with neurofibromatosis type 1. (F) MRI of a 5-year-old boy with atypical presentation of X-linked adrenoleukodystrophy. (G) Bilateral basal ganglia lesions in a 9-month-old-boy with mitochondrial disease (M. Leigh) and complex I deficiency. (H) Cerebral MRI of a 10-year-old boy who presented with irritability, vomiting, double vision, and vertigo showing hazy bilateral lesions in the white matter and thalami. A high titre of aquaporin-4 antibodies was detected and he was diagnosed with neuromyelitis optica spectrum disorder. (A-D, axial FLAIR; E-H, axial T2).

      5. Suggested MRI protocol

      5.1 Acute attack

      Depending on the clinical picture, acute imaging will focus either on brain or spine, but imaging of the entire neuroaxis is recommended at the first presentation.
      Brain MRI should be performed using a magnetic field strength of at least 1.5 T, preferably 3.0 T, with a slice thickness of at least 3 mm for 2D sequences. The minimum requirements for clinical routine brain MRI sequences should include (i) T2-weighted spin-echo (SE) sequences in axial plane, (ii) T2 fluid-attenuated inversion recovery (FLAIR) sequences in another plane than T2-SE or (even better) in three-dimensional (3D) acquisition, (iii) T1-weighted SE sequences in at least axial plane or ideally 3D (MPRAGE, Magnetization Prepared Rapid Acquisition Gradient Echo) before, and (iv) after contrast agent administration, and (v) axial diffusion-weighted imaging. Sequences dedicated to the optic nerves, including sequences with fat saturation in frontal plane, are important in the event of a clinical picture of optic neuritis.
      Spinal imaging should include sagittal and axial T2-weighted sequences, and sagittal and axial T1-weighted sequences, only after gadolinium administration if combined with brain MRI. The entire spinal cord should be studied. Additional axial images of the spinal cord should be performed in areas affected by lesions.
      The MAGNIMS (Magnetic Resonance Imaging in MS) network consensus guidelines on the use of MRI in MS provide similar protocols with detailed descriptions [
      • Rovira A.
      • Wattjes M.P.
      • Tintore M.
      • et al.
      Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process.
      ].
      To allow for advanced MRI analyses in research settings, additional sequences can be acquired including 3D T1-weighted MPRAGE sequences for volumetric measurements, diffusion-weighted protocols for diffusion tensor imaging analyses, echo-planar imaging sequences for the acquisition of resting state data to analyse functional connectivity alterations, and quantitative multi-parameter mapping sequences to study quantitative microstructural measures of brain tissue such as iron and myelin content [
      • Kremer S.
      • Renard F.
      • Achard S.
      • et al.
      Use of advanced magnetic resonance imaging techniques in neuromyelitis optica spectrum disorder.
      ]. These advanced sequences take longer time and are therefore not part of the routine MRI protocol, but can be added for dedicated research questions.

      5.2 Follow-up

      Depending on the clinical course, follow-up imaging 3–6 months after the baseline scan is recommended. As younger children may need sedation for longer MRI protocols, a reduction of sequences may be considered to allow for shorter MRI protocols, e.g. imaging may be restricted to brain or spine. Axial T2-FLAIR/T2-weighted sequences are recommended in brain MRI, spinal imaging should at least include sagittal T2-weighted sequences.
      In younger patients with resolution of symptoms and a so far monophasic course, the risks of sedation have to be weighed against the value of an additional MR-imaging study. The application of intravenous gadolinium should be restricted for the differential diagnosis at the initial episode, but not for routine follow-up studies, as evidence for cerebral gadolinium deposition exists [
      • Gulani V.
      • Calamante F.
      • Shellock F.G.
      • Kanal E.
      • Reeder S.B.
      International Society for Magnetic Resonance in M. Gadolinium deposition in the brain: summary of evidence and recommendations.
      ]. The application of intravenous gadolinium may be considered for new clinical episodes.

      6. Future directions

      MR-imaging can point to MOGAD even before results of antibody-testing are available, or uncover unusual features in patients with MOGAD such as leukodystrophy-like lesions or cortical involvement. As some of these radiological phenotypes are associated with a worse outcome, MRI may influence treatment decisions and can provide prognostic clues.
      New aspects of paediatric demyelinating disorders such as MOGAD may be detected with emerging imaging techniques such as diffusion tension imaging (DTI) and volumetric analysis helping to better understand the pathobiology of the disease.
      Investigating DTI measures (e.g. fractional anisotropy and mean diffusivity) in children with monophasic ADS, it was shown that non-lesional, normal-appearing white matter did not demonstrate age-expected maturational change [
      • Longoni G.
      • Brown R.A.
      • MomayyezSiahkal P.
      • et al.
      White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders.
      ]. Importantly, while there was no suggestion of progressive loss of tissue integrity, these monophasic patients failed to ‘catch-up’ to normal diffusivity trajectories after the second year post-ADS, indicative of both an acute and long-lasting impact of transient demyelinating illness on non-lesional white matter integrity [
      • Longoni G.
      • Brown R.A.
      • MomayyezSiahkal P.
      • et al.
      White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders.
      ].
      Volumetric studies show that in paediatric MS patients, brain volume loss is present already at first clinical presentation, and that increased disease activity is associated with more severe brain volume loss [
      • Bartels F.
      • Nobis K.
      • Cooper G.
      • et al.
      Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure.
      ]. Longitudinal volumetric analyses in children with autoimmune encephalitis revealed significant brain volume loss and failure of age-expected brain growth [
      • Bartels F.
      • Krohn S.
      • Nikolaus M.
      • et al.
      Clinical and magnetic resonance imaging outcome predictors in pediatric anti-N-Methyl-D-Aspartate receptor encephalitis.
      ]. Likewise, volume loss and failure of age expected brain growth was also observed in children with ADEM and other monophasic ADS presentations [
      • Aubert-Broche B.
      • Weier K.
      • Longoni G.
      • et al.
      Monophasic demyelination reduces brain growth in children.
      ], (Bartels et al. in preparation). Both MOG-antibody positive and negative ADEM patients show brain volume loss and failure of brain growth. Patients with relapsing MOGAD (MDEM) have more pronounced brain volume loss compared to monophasic patients.
      Future studies might also identify functional network alterations and changes of tissue parameters such as lipid, iron and myelin content using quantitative MRI [
      • Weiskopf N.
      • Mohammadi S.
      • Lutti A.
      • Callaghan M.F.
      Advances in MRI-based computational neuroanatomy: from morphometry to in-vivo histology.
      ,
      • Lutti A.
      • Dick F.
      • Sereno M.I.
      • Weiskopf N.
      Using high-resolution quantitative mapping of R1 as an index of cortical myelination.
      ]. These techniques can provide quantitative histological measures of brain tissue and allow specific monitoring of myelination longitudinally and noninvasively [
      • Heath F.
      • Hurley S.A.
      • Johansen-Berg H.
      • Sampaio-Baptista C.
      Advances in noninvasive myelin imaging.
      ]. Therefore, conventional imaging techniques, showing formation and resolution of lesions, together with advanced imaging techniques, which provide quantitative parameters for maturational changes, white matter integrity or atrophy, appear to be valuable outcome measures for future clinical trials.

      7. Conclusions

      The spectrum of MRI findings in paediatric MOGAD is wider than initially thought. Standard imaging at disease onset and follow-up will identify new aspects of this disease entity demanding adaption of the currently developed classification and search for MOG-abs in unusual demyelinating or encephalitic syndromes. New imaging techniques might help to better understand the neurobiology of MOGAD, age-related differences, and varying outcomes. Furthermore we want encourage the leading European institutions dealing with paediatric MOGAD to use similar MR-imaging protocols in order gain more insights in this complex disease and to establish MRI markers for future treatment trials.

      Funding sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      Matthias Baumann has no conflict of interest to declare.
      Frederik Bartels has no conflict of interest to declare.
      Carsten Finke has no conflict of interest to declare.
      Catherine Adamsbaum has no conflict of interest to declare.
      Yael Hacohen has no conflict of interest to declare.
      Kevin Rostásy has no conflict of interest to declare relevant to this manuscript.

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