treatment and outcome of aquaporin-4 antibody–positive nmosd · treatment and outcome of...

ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Treatment and outcome of aquaporin-4antibodyndashpositive NMOSDA multinational pediatric study

Renata Barbosa Paolilo MD Yael Hacohen MD PhD Elise Yazbeck MD Thais Armangue MD PhD

Arlette Bruijstens MD Christian Lechner MD Samira Luisa Apostolos-Pereira MD PhD

Yana Martynenko MD Markus Breu MD Carolina de Medeiros Rimkus MD PhD Evangeline Wassmer MD

Matthias Baumann MD Laura Papetti PhD Marco Capobianco MD Barbara Kornek MD PhD

Kevin Rostasy MD Jose Albino da Paz MD PhD Olga Ciccarelli MD PhD Ming Lim MD PhD

Albert Saiz MD PhD Rinze Neuteboom MD PhD Romain Marignier MD PhD Cheryl Hemingway MD PhD

Douglas Kazutoshi Sato MD PhD and Kumaran Deiva MD PhD

Neurol Neuroimmunol Neuroinflamm 20207e837 doi101212NXI0000000000000837

Correspondence

Dr Paolilo

renatabpaolilogmailcom

AbstractObjectiveTo describe the clinical phenotypes treatment response and outcome of children with anti-bodies against aquaporin-4 (AQP4-Ab) neuromyelitis optica spectrum disorder (NMOSD)

MethodsRetrospective multicenter and multinational study of patients with AQP4-Ab NMOSD agedlt18 years at disease onset from a center in Brazil and 13 European centers Data on de-mographics clinical findings and laboratory results were analyzed calculation of annualizedrelapse rates (ARRs) pre- and on-treatment with disease-modifying therapies (DMTs) and ofORs for predictors of poor outcome was performed

ResultsA total of 67 children were identified At last follow-up (median 4 years interquartile range2ndash10 years) 3767(578) were found to have permanent disability A more severe diseasecourse was seen in the non-White ethnicity with both a shorter time to first relapse (p = 0049)and a worse Expanded Disability Status Scale score at last follow-up (p = 0008) The medianARR on treatment was 018 on azathioprine (n = 39 range 0ndash4) 0 on mycophenolate mofetil(n = 18 range 0ndash3) and 0 on rituximab (n = 29 range 0ndash2) No patient treated with rituximabas first-line therapy relapsed Optic neuritis at onset was associated with a poor visual outcomebelow 20200 (OR 8669 95 CI 1764ndash42616 p = 0008) and a younger age at onset wasassociated with cognitive impairment (OR 0786 95 CI 0644ndash0959 p = 0018)

These authors have contributed equally to this manuscript

From the Department of Neurology (RBP SLA-P JAdP) and Department of Radiology (INRAD) (CdMR) Hospital das Clınicas Faculty of Medicine University of Satildeo Paulo(HCFMUSP) Brazil Queen Square MS Centre (YH OC) UCL Institute of Neurology Faculty of Brain Sciences University College London Department of Paediatric Neurology (YHCH) Great Ormond Street Hospital for Children London United Kingdom Assistance Publue-Hopitaux de Paris (EY KD) University Hospitals Paris South Bicetre Hospital LeKremlin Bicetre France Neuroimmunology Program (TA) and Neurology Service (AS) Institut drsquoInvestigacions Biomediques August Pi i Sunyer (IDIBAPS) Hospital Clınic andPediatric Neuroimmunology Unit (TA) Sant Joan de Deu (SJD) Childrenrsquos Hospital Universitat de Barcelona Spain Department of Neurology (AB RN) Erasmus University MedicalCenter Rotterdam the Netherlands Division of Paediatric Neurology (CL MB) Department of Pediatrics I Medical University of Innsbruck Austria Medical Center of PhysicalTherapy and Pain Medicine INNOVO (YM) Lviv Ukraine Division of Pediatric Neurology (MB) Department of Pediatrics and Adolescent Medicine and Department of Neurology(BK) Medical University of Vienna Austria Pediatric Neurology (EW) Birmingham Women and Childrenrsquos Hospital United Kingdom Department of Neuroscience (LP) PediatricMultiple Sclerosis Center Bambino Gesu Children Hospital IRCCS Rome Italy Department of Neurology (MC) and Regional Multiple Sclerosis Centre (MC) University Hospital SanLuigi Gonzaga Orbassano Italy Department of Pediatric Neurology (KR) Vestische Kinder und JugendklinikWittenHerdeckeUniversity Datteln Germany ChildrenrsquosNeurosciences(ML) Evelina London Childrenrsquos Hospital at Guyrsquos and St ThomasrsquoNHS Foundation Trust Kingrsquos Health Partners Academic Health Science Centre Faculty of Life Sciences andMedicine(ML) Kingrsquos CollegeHospital London United Kingdom NeurologyDepartment (RM) Hopital Neurologique PierreWertheimer Hospices Civils de Lyon French Reference Network ofRare Inflammatory Brain and Spinal Diseases (RM KD) Le Kremlin Bicetre France School of Medicine (DKS) Brain Institute of Rio Grande do Sul (Brains) Pontifical CatholicUniversity of Rio Grande Do Sul (PUCRS) Porto Alegre Brazil and Inserm UMR 1184 (KD) Immunology of Viral Infections and Autoimmune Diseases CEA IDMIT Le Kremlin BicetreFrance

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

The Article Processing Charge was funded by Assistance Publique-Hopitaux de Paris Hopitaux Universitaires Paris Saclay

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

ConclusionsAQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort All DMTswere associated with a reduction of ARR First-line rituximab prevented further clinical relapses International consensus ontreatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide

Classification of evidenceThis study provides Class IV evidence that for children with AQP4-Ab NMOSD all DMTs particularly first-line rituximabreduced the ARR and prevented further clinical relapses

Antibodies against aquaporin-4 (AQP4-Ab) were first describedin 2004 in patients with neuromyelitis optica (NMO)1 allowingthe expansion of the phenotype2 The most recent criteria forthe diagnosis of NMO spectrum disorder (NMOSD) stratifypatients by the presenceabsence of AQP4-Ab3 AQP4-Ab se-ropositivity is associated with relapsing disease45 This led to theuse of B-cell targeting therapies which clearly reduce relapserates6 This reduction is not seen when therapies known to beeffective for MS7 are used in NMOSD

The clinical features and MRI abnormalities in children withAQP4-Ab NMOSD are similar to the adult phenotype8ndash11

The prevalence of AQP4-Ab was reported in 07 (2279)12

to 45 (364)13 of children presenting with a first pre-sentation of acquired demyelinating syndrome (ADS) and 8102 (78) of children with relapsing syndromes14 Childrenare reported to have a less severe disease course and may takelonger to reach disability than adults15 Children are at ahigher risk of visual impairment compared with adults but areless likely to acquire motor deficits16 Previous pediatricpublications highlighted that AQP4-Ab NMOSD in Europe israre9 whereas the prevalence in South America8 is higher

With the rarity of pediatric presentation treatment is derived fromadult guidelines and can be influenced by medication availabilityand cost Current available treatments used such as azathioprine

GlossaryADS = acquired demyelinating syndrome AQP4-Ab = antibodies against aquaporin-4 ARR = annualized relapse rateAZA = azathioprine CRF = case reporting form DMT = disease-modifying therapy EDSS = Expanded Disability StatusScale IQR = interquartile range MMF = mycophenolate mofetil MOG-Ab = myelin oligodendrocyte glycoproteinantibody NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritis TM = transverse myelitis

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 NeurologyorgNN

(AZA) mycophenolate mofetil (MMF) and rituximab have notreceived regulatory approval for NMOSD In this retrospectivemulticenter and multinational study patientsrsquo demographics firstattack features paraclinical characteristics and disease course aredescribed to ultimately evaluate responses to different treatmentstrategies in children with AQP4-Ab NMOSD

MethodsParticipantsIn this multicenter multinational study we collected de-mographic clinical and radiologic data of 67 patients from asingle center in Brazil (Satildeo Paulo n = 20) and from 13 centersin 7 countries as part of the EU Paediatric DemyelinatingDisease Consortium (United Kingdom [n = 18] France [n =11] Spain [n = 6] GermanyAustria [n = 5] theNetherlandsBelgium [n = 4] Italy [n = 2] and Ukraine [n =1]) This consortium was initiated to study children withADS as part of the European Reference Network for RareImmunodeficiency Autoinflammatory and AutoimmuneDisease

We retrospectively identified participants who wererecruited into the respective centers or national de-myelination programs and fulfilled the following inclusioncriteria (1) NMOSD fulfilling the 2015 International Panelfor NMO diagnosis criteria3 (2) AQP4-Abs detected atonset or at the time of a clinical relapse using live cell-basedassays in the local laboratories and (3) age lt18 years at firstpresentation

Standard protocol approvals registrationsand patient consentsPatients included in this study had been enrolled in nationalprograms with respective review boardethical committeeapprovals (Brazil [Hospital das Clınicas Faculty of MedicineUniversity of Satildeo Paulo Satildeo Paulo] France [Hopital BicetreParis] the Netherlands [Medisch Ethische Toetsingscom-missie Erasmus Medical Centre Rotterdam] United King-dom [West Midlands-South Birmingham Research EthicsCommittee] Germany and Austria [University of InnsbruckEthics Committee] and Spain [Hospital Clinic and by SantJoan de Deu Childrenrsquos Hospital] or provided verbal andorwritten informed consent to the respective referring physician(Italy Ukraine) All data were deidentified

ProcedureClinical data already collected as part of national de-myelination programs were deidentified and entered by eachparticipating investigator onto a unified case reporting form(CRF) detailing selected demographics clinical findings andlaboratory results (AQP4-Abs CSF cell count protein andoligoclonal bands) first and subsequent attack characteristicsand treatment information Demyelinating phenotype at on-set and relapses were clinically determined according toestablished criteria18 as being optic neuritis (ON) transversemyelitis (TM) brainstem andor cerebellar andor

hemispheric syndromes (associated with encephalopathy orwithout encephalopathy)

Brain and spinal cord MRI were performed in 61 and 50patients respectively at disease onset All patients had un-dergone brain and spinal cord imaging according to local MRIprotocols (not routinely including orbits) Gadolinium-enhanced imaging was performed in 54 patients Lumbarpuncture for CSF analysis was performed in 5767 (850)patients

The acute treatment for each of these patients at presentationand subsequent episodes of relapses was decided by thetreating pediatricians on the basis of protocols influenced bytheir regional andor national reference center for CNS de-myelination guided by severity and persistence of symptomsDisease-modifying therapies (DMTs) referred to all forms ofmaintenance immunomodulation or immunosuppressiontherapies

Annualized relapse rates (ARRs) on retrospective data werecalculated as number of relapses per year and only includedpatients with at least 6 months of follow-up after initiation oftreatment If time to treatment was less than 6 months thepretreatment ARR was calculated over a 6-month period Theoutcomes as measured by a range of difficulties the patientswere experiencing (cognitive visual and motor) at lastfollow-up were retrieved from the patientrsquos medical records torepresent the most contemporary assessment of disability Ifunavailable this assessment was obtained directly from thepatientrsquos primary treating physician Patients were consideredto have motor disability if they were a wheelchair user neededcrutches (or a cane) to walk or could walk for less than 500 mwithout support Cognitive performance was estimated bylooking at their school performance at last follow-up patientswere considered to have cognitive difficulties if there wassignificant school support grade repetition or needing ofspecial education schools Patients were considered to havevisual sequelae if the logMAR scale was lt03 (Snellen lt2040) or persistent visual field defects The Expanded DisabilityStatus Scale (EDSS) scores were documented at first attacknadir and at final follow-up (at point of disease stability at least3 months from acute or relapsing events)

All CRFs were initially reviewed by the respective nationalleads and subsequently analyzed by 3 investigators (RBPYH and KD)

AQP4-Ab testingWithin 1 month of an acute event (either onset or relapse)clinically symptomatic children underwent testing for serumAQP4-Ab using live cell-based assays in the respective ref-erence laboratories of the following referring countries(France18 Brazil19 United Kingdom20 Spain21 theNetherlands2223 in GermanyAustria in the Clinical De-partment of Neurology Medical University of InnsbruckInnsbruck Austria and in Italy and Ukraine anti-AQP4

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 3

antibodies testing were performed with commercial IFA[Euroimmun]) Routine assessments of antibody testing inthe CSF were not performed

Statistical analysisWe tested the hypothesis that patients treated with AZAMMF andor rituximab experienced a reduction in ARRproviding Class IV evidence for therapeutic decision

Descriptive data of demographic clinical radiologic and se-rologic characteristics were reported for children with AQP4-Ab NMOSD To compare between the different ethnicitiesparametric or nonparametric statistical tests (Mann-WhitneyU and Kruskal-Wallis tests) were used for continuous distri-butions as appropriate given normality and χ2 or Fisher exacttests for nominal data In particular comparisons betweenWhite and non-White ethnicities and stratified EDSS score atlast follow-up were performed Logarithm transformation wasperformed for nonparametric data Effect sizes were calculatedby OR Cohen d and eta-squared (η2) measures

In addition parametric or nonparametric statistical tests wereused for continuous distributions as appropriate and χ2 orFisher exact tests for nominal data to compare patients whowere treated with AZA MMF and rituximab as first-linetreatment A paired 2-tailed t test was used to compare ARRsbefore and during treatment

Univariate logistic regression was used to evaluate age atonset sex ethnicity demyelinating phenotype at onset ab-normal MRI at onset time to treatment number of relapsesbefore treatment and follow-up duration as potential pre-dictors of motor (wheelchair or walking aid) visual (blind-ness) and cognitive outcomes at last follow-up Multivariableanalyses were modeled for the same outcomes including ascovariates those variables significant at the (p lt 005) level inthe univariate analysis Results were presented as ORs and95 CIs A 2-sided p lt 005 was considered significant Datawere analyzed using SPSS 20 software and GraphPad Prism 5

Data availabilityAnonymized data will be shared by request from qualifiedinvestigators

ResultsPatientsA total of 67 children with AQP4-Ab NMOSD were includedin this study (table 1) Mean age at onset was 102 plusmn 36 years(range 2ndash16 years) The femalemale ratio was 411 Of the67 children 29 (433) were White 14 (209) Black 13(194) Brazilian mixed ethnicity and 11 (164) otherethnicities Of the 67 children 29 (433) were White 14(209) Black 13 (194) Brazilian mixed ethnicity and11 (164) other ethnicities (Asian Indians Nepali Afro-Caribbean Omani) Non-White ethnicity was more commonin both European (2547) and Brazilian (1320) populations

Family history of autoimmune diseases was reported in 9(137) patients personal history of inflammatory diseases in7 (104) and 8 (119) had a preceding infection Patientsrsquodemographic clinical and paraclinical features and EDSSscores stratified to ethnicities are summarized in table 1 Thegroups were similar except for shorter time to first relapse (η2

= 0071 p = 0049) and higher EDSS score at last follow-up(η2 = 0056 p = 0008) in the non-White population

First attack featuresThemost frequent phenotype at onset was isolatedON (n = 2029) followed by isolated TM (n = 15 22) and isolated areapostrema syndrome (n = 11 164) Of the children presentingwith ON 920 (45) had bilateral ON Of the 15 childrenpresenting with isolated TM 10 (667) had longitudinallyextensive TM Six (9) patients had simultaneousON andTMSix (9) patients presented with ADEM 1 (15) patient withisolated diencephalic syndrome 3 (45) with isolated brain-stem syndrome and 5 (75) patients with multifocal syn-dromes involving the spinal cord optic nerve and brain(brainstem area postrema or diencephalic syndromes)

At onset 4461 (721) patients had abnormal brain MRI3250 (64) patients had abnormal spinal cordMRI and 1654 (296) had contrast-enhancing lesions Abnormal CSFwas reported in 3757 (649) children with oligoclonalbands detected in 757 (122) CSF pleocytosis was presentin 3550 (70) examinations with a median of 10 cells(interquartile range [IQR] 25ndash385 cells) Elevated CSFprotein was found in 1327 (48) examinations with a me-dian of 0030 gdL (IQR 0002ndash0850 gdL) Myelin oligo-dendrocyte glycoprotein antibodies (MOG-Abs) werenegative in the 60 patients who were tested

Disease course and outcomeA total of 297 attacks were reported in the cohort Themediantime to first relapse was 4 months (range 17ndash1005 months)At last follow-up (median disease duration of 4 years IQR2ndash10 years) 58 (866) patients had a second clinical eventwith a median ARR of 105 relapses per year and median(IQR) EDSS score = 20 (10ndash35) Moderate disability withEDSS score ge3 was reported in 2967 (432) Visual im-pairment was seen in 32 (478) patients of which 20 wereregistered blind (visual acuity lt20200 logMAR gt1) motordeficits were found in 14 (212 of which 5 were wheelchairusers and 2 used a walker) and cognitive impairment wasdetected in 17 (254) patients

A more severe disease course was seen in the non-Whiteethnicity with worse EDSS score at last follow-up (p = 0008)and a shorter time to first relapse (p = 0049)

Response to immunotherapyDMTs were given in 6367 (95) children A total of 41patients were treated with 1 DMT 12 with 2 7 with 3 DMTs2 with 4 DMTs and 1 with 5 sequential DMTs Patients werecommenced on DMTs at a median of 6 months from


symptom onset (IQR 2ndash135 months) and a median of 2clinical attacks (IQR 1ndash3 clinical attacks) Of the 4 untreatedpatients at a median follow-up of 5 years (range 2ndash10 years)only 1 patient relapsed despite persistent antibody positivity

A total number of 139 relapses on treatment were observed inthe cohort Relapses occurred on all treatments except the 2patients treated with ofatumumab and the 1 patient whounderwent hematopoietic stem cell transplantation (HSCT)The clinical course and disease activity in patients who un-derwent therapy with maintenance treatment are illustrated infigure 1 Most frequently used treatments were AZA (totaltreatment duration 2095 patient years relapses = 92 043relapsestreated year) rituximab (total treatment duration 88years relapses = 13 015 relapsestreated year) and MMF(total treatment duration 462 years relapses = 23 049relapsetreated year) Patient characteristic stratified to first-line treatments is summarized in table 2 and table e-4 linkslwwcomNXIA287

Thirty-nine children were treated with AZA 35 (897) asfirst-line therapy and 4 as second-line treatment AZA

treatment was associated with a mean reduction in the ARR of110 (mean ARR pretreatment 169 vs 059 on treatment meandifference 110 95CI 054ndash166 t = 401 Cohen d = 063 p lt0001) Twenty-five of 39 (641) patients relapsed on treat-ment Of these treatment was escalated in 16 patients toMMF(n = 6) rituximab (n = 8) cyclosporine (n = 1) and glatirameracetate (n = 1) Of the 4 who were treated with AZA as secondline 3 previously failed treatment withmethotrexate glatirameracetate and cyclophosphamide and in 1 treatment was de-escalated after being relapse free on rituximab

Twenty-nine children were treated with rituximab 14(483) first line 9 (310) second line 5 (172) third lineand 1 (34) fourth line The treatment with rituximab wasassociated with a mean reduction in the ARR of 236 (meanARR pretreatment 250 vs 014 on treatment mean difference236 95 CI 157ndash315 t = 613 Cohen d = 114 p lt 0001)All 14 patients treated with rituximab as first line did not havefurther relapses Of these 1 patient had prolonged oral ste-roids (for 1 year) before commencing rituximab and a secondpatient had additional intravenous immunoglobulin for thefirst 6 months Seven of 29 patients (241) treated with

Table 1 Clinicalparaclinical features and outcome in childrenwith AQP4-AbNMOSD stratified to the different ethnicities

White (N = 29) Non-White (N = 38) All (N = 67)

Age at onset y mean (SD) 106 (35) 99 (37) 102 (36)

Female sex n () 2529 (862) 2938 (763) 5467 (80)

EDSS score at nadir median (IQR) N = 17 30 (2ndash45) N = 30 47 (33ndash75) N = 47 40 (3ndash65)

Baseline attack

Area postrema syndrome (all) n () 829 (276) 638 (158) 1467 (21)

Optic neuritis presentation (all) n () 1529 (517) 1438 (368) 2967 (43)

Transverse myelitis presentation (all) n () 1029 (345) 1438 (368) 2467 (36)

Brainstemcerebral involvement (all) n () 929 (31) 1738 (447) 2667 (39)

Abnormal brain MRI at onset n () 2027 (741) 2434 (706) 4461 (72)

Abnormal spinal cord MRI at onset n () 1421 (667) 1729 (586) 3150 (62)

Intrathecal OCB n () 322 (136) 423 (174) 747 (15)

Time to first relapse mo median (IQR) 55 (3ndash142) 4 (2ndash5) 4 (2ndash10)

No of attacks median (IQR) 3 (2ndash57) 2 (2ndash5) 3 (2ndash5)

No of attacks in the first 2 y mean (SD) 22 (13) 21 (09) 22 (11)

Time to treatment mo median (IQR) 6 (2ndash17) 45 (1ndash102) 5 (1ndash135)

FU y median (IQR) 6 (4ndash107) 35 (2ndash62) 4 (2ndash10)

Visual sequelae n () 1429 (483) 1835 (514) 3264 (50)

Motor sequelae n () 529 (172) 937 (243) 1466 (21)

Cognitive sequelae n () 528 (179) 1238 (316) 1766 (26)

EDSS score at last FU median (IQR) 20 (0ndash3) 25 (1ndash4) 20 (1ndash35)

Abbreviations EDSS Expanded Disability Status Scale FU follow-up IQR = interquartile range OCB = oligoclonal band


rituximab relapsed on treatment and these patients werepreviously treated with AZA (n = 5) andMMF (n = 2) In the4 children in whom the CD19 count was measured acutely 1relapsed with absent B cells and 3 during B cell reconstitution

Eighteen children were treated with MMF 10 (556) firstline 6 (333) second line 1 (56) third line and 1 fifth line(56) MMF treatment was associated with a mean re-duction in the ARR of 032 (mean ARR pretreatment 104 vs072 on treatment mean difference 032 95 CI minus057 to122 t = 077 Cohen d = 018 p = 0452) Ten patientsremained relapse free on treatment Of the 8 who relapsed ontreatment 5 were changed to rituximab

Tocilizumab was used in 2 patients as third-line DMT andboth relapsed and satralizumab in 2 patients (who wereenrolled in the open-label SAkuraSky trial as an add-ontreatment to MMF) who have not relapsed Two patients

were treated with ofatumumab following infusion reactionwith rituximab and have not relapsed Three patients treatedwith cyclophosphamide 2 with methotrexate and 1 withcyclosporine all continued to relapse with worsening ARRTwo patients were treated with glatiramer acetate for apresume diagnosis of MS and both relapsed on treatmentARRs before and after treatment initiation are shown infigure 2

Adverse eventsOf the 37 patients treated with AZA 5 (135) developedlymphopenia (lt05 times 109L) without infectious complica-tions 3 developed infections (viral meningitis pneumoniaand varicella) and 3 did not tolerate the treatment in view ofgastrointestinal symptoms or raised liver function test Onechild developed lymphopenia (lt05 times 109L) on MMF In-fusion reactions with rituximab occurred in 3 of 29 (103)children of which 2 were switched to ofatumumab due to the

Figure 1 Disease course in relation to respective therapies

Patient relapsed on all treatments with a total of 139 relapses on treatment reported in the cohort Forty-three (693) remained relapse free on treatment1035 (286) treated with azathioprine (AZA) 1017 (588) treated with mycophenolate mofetil (MMF) and 2329 (793) treated with rituximab Onepatient who relapsed AZA and cyclosporine underwent hematopoietic stem cell transplantation (HSCT) and has not relapsed (follow-up 2 years)


side effects One child developed persisted neutropenia onrituximab and was changed to AZA

Predictors of poor outcomeORs to estimate the effects of parameters at onset on theoccurrence of disability (EDSS score ge3) are illustrated intable 2 Children with an EDSS score ge3 (n = 29 432) wereyounger presented with ON and had a higher EDSS score atnadir Patients with a better outcome at last follow-up (EDSSscore lt30) were more commonly girls and presented withcerebral syndrome (table 3) Logistic regression looking atage at onset ethnicity demyelinating phenotype at onsetabnormal MRI at onset time to treatment and number ofrelapses before treatment were evaluated as predictors ofmotor visual and cognitive outcomes (table e-1 linkslwwcomNXIA284 table e-2 linkslwwcomNXIA285 andtable e-3 linkslwwcomNXIA286) Multivariable analysis

did not identify any predictors for motor disabilities (wheel-chair or walking aid) ON at onset was associated with worsevisual outcome below 20200 (p = 0008 OR 8669 95 CI1764ndash42616) and younger age at onset was associated withworse cognitive impairment (p = 0018 OR 0786 95 CI0644ndash0959)

DiscussionAQP4-Ab NMOSD is now well recognized in children Nat-ural history studies suggest an attack-related stepwise accu-mulation of disabilities Therefore attack preventionstrategies are used as maintenance treatment In this multi-national cohort of children with AQP4-Ab NMOSD thephenotype observed was overall similar to that reportedpreviously in children or adults3 The time to first relapse was

Table 2 Patients characteristic stratified to first-line treatment

Azathioprine(n = 35)

Mycophenolatemofetil (n = 10)

Rituximab(n = 14)

Other treatmentnotreatment (n = 8)

Age when starting treatment ymedian (range)

11 (4ndash17) 9 (3ndash17) 12 (5ndash15) 11 (9ndash15)

Non-White ethnicity n () 2135 (60) 410 (40) 814 (571) 38 (375)

Country of origin n ()

Brazil (n = 20) 1720 (85) 120 (5) 0 220 (10)

United Kingdom (n = 18) 718 (389) 518 (278) 318 (167) 318 (167)

France (n = 10) 210 (20) 110 (10) 610 (60) 110 (10)

Spain (n = 6) 26 (333) 16 (167) 36 (50) 0

GermanyAustria (n = 5) 45 (80) 0 15 (20) 0

Belgiumthe NetherlandsItalyUkraine (n = 8) 38 (375) 28 (25) 18 (125) 28 (25)

Demyelinating phenotype at onset n ()

Optic neuritis (n = 29) 1629 (551) 729 (241) 429 (137) 229 (68)

Transverse myelitis (n = 24) 1324 (541) 224 (83) 724 (291) 224 (83)

All area postrema syndrome (14) 714 (50) 114 (71) 414 (285) 214 (142)

All brainstemencephalic (n = 26) 1326 (50) 326 (115) 626 (23) 426 (153)

Time to treatment mo median (range) 6 (0ndash84) 6 (0ndash16) 1 (0ndash9) mdash

No of attacks before treatmentmedian (range)n ()

2 (1ndash6) 2 (2ndash4) 2 (1ndash9) mdash

Median duration on treatment y median(range)


ARR median (range) 018 (0ndash4) 0 (0ndash2) 0 mdash

No of patients who relapsed on treatment n () 2235 (628) 310 (30) 0 mdash

No of patients who changed treatment n () 1435 (40) 210 (20)additionalone stopped

214 (142) mdash

Abbreviation ARR = annualized relapse rate


short and the ARR pretreatment was high indicating a highrisk of relapses and permanent disability in children withAQP4-Ab NMOSD

We detected cognitive impairment in 254 of the cohortAbnormal brain MRI was not a risk factor but younger age atonset and brainstemcerebral attacks were associated with

Figure 2 The efficacy of various disease-modifying therapies in children with AQP4-Ab NMOSD

Annualized relapse rates (ARRs) before and after treatment initiation with the most frequently used medications (A) Azathioprine (AZA) (B) Mycophenolatemofetil (MMF) (C) Rituximab (D) After escalation from treatment with AZA or MMF to rituximab

Table 3 Univariable analysis and OR for parameters associated with the EDSS score (EDSS ge3) at final follow-up

EDSS score lt3 (n = 38) EDSS score ge3 (n = 29) OR (95 CI) p Value

Sex (FM) 344 209 0261 (0071ndash0960) 0043

Age at presentation y mean (SD) 111 (31) 91 (39) 0847 (0732ndash0980) 0026

Ethnicity (Whitenon-White) 1919 1019 1900 (0702ndash5141) 0206

Optic neuritis presentation n () 1238 (316) 1729 (586) 3069 (1121ndash8402) 0029

Transverse myelitis presentation n () 1238 (316) 1229 (414) 1529 (0559ndash4186) 0408

Brainstemcerebral presentation n () 1938 (50) 729 (241) 0318 (0110ndash0920) 0035

Abnormal brain MRI n () 2535 (714) 1926 (731) 1096 (0349ndash3379) 0887

Intrathecal OCBs n () 728 (25) 017 NA gt0999

EDSS score at nadir mean (SD) N = 26 40 (23) N = 21 54 (22) 1303 (1004ndash1690) 0046

Time to treatment mo median (IQR) 6 (15ndash16) 45 (1ndash107) 1003 (0967ndash1041) 0859

No of relapses before treatment median (IQR) 1 (02ndash2) 1 (0ndash2) 1061 (0749ndash1503) 0739

FU y median (IQR) 4 (3ndash6) 5 (2ndash12) 11109 (1009ndash1218) 0032

Abbreviations CI = CI for OR calculated for nominal variables EDSS = Expanded Disability Status Scale FU = follow-up IQR = interquartile range OCB =oligoclonal band


cognitive deficits Cognitive impairment had not been sys-tematically addressed in pediatric NMOSD and our resultshighlight its importance Although no objective cognitivemeasure was used in this study we selected measures that areconsistent across the diverse educational systems that reflectclear difficulties and thus would be a reasonable surrogate forcognitive performance ON at onset was a risk for visual im-pairment and blindness in keeping with previous report thatyoung children do not recover well following ON16 Of in-terest time to starting treatment and number of relapsesbefore starting treatment were not associated with worstoutcome As previously reported24 non-White ethnicity wasassociated with a more aggressive disease course but was notpredictive of moderate disabilities at last follow-up

Patients were treated according to each center experience andthe choices of treatment were additionally influenced by theaccess to treatments in each country and their related costsAlmost all of the Brazilian children were commenced on AZAand none were given rituximab as first-line treatment Incontrast the European children were frequently commencedon rituximab and MMF (table 3) A previous pediatric co-hort10 (only 2058 patients were treated with DMTs)reported residual disability in 4348 (90) with 2648(54) having visual impairment and 2148 (44) withmotordeficits Comparing to this cohort the visual but not themotor outcome is similar which might be related totreatment

A key observation from our study was that all treatmentsknown to reduce relapses in adults (AZA MMF and ritux-imab) were associated with a reduction in the ARR More-over rituximab treatment resulted in the lowest ARR and itis remarkable that all 14 patients who started on rituximab asfirst line did not have any further relapses Treatment esca-lation fromAZA andMMF to rituximab was beneficial in 1213 with only 1 child maintaining the same ARR (figure 2)The benefit of early treatment with rituximab was previouslydemonstrated in a pediatric cohort with a range of CNSdisorders including NMOSD25 This apparent superioritycould be partially explained by the early treatment effect ofrituximab In addition in our cohort patients were alsoinitiated with rituximab sooner compared with AZAMMF(1 month vs 6ndash10 months) after the attack CD19 count wasnot performed in all 7 patients who relapsed with rituximabMonitoring B-cell repopulation and redosing rituximabmight prevent relapses as demonstrated in a pediatricstudy26 Three patients treated with rituximab changedtherapy due to adverse effect and none had severe infectionProspective follow-up was not performed to check onhypogammaglobulinemia27

Although we did not perform a direct comparison the treat-ment effect observed in this pediatric cohort appeared greaterthan reported in adults with AQP4-Ab NMOSD628ndash30 Thegreater reduction in the ARR following initiation of DMTs isalso reported in children with MS compared with adults and

likely reflects the more inflammatory disease seen in theyounger patients31 Of interest in comparison to a cohort ofchildren with MOG-Abndashassociated disease32 despite thehigher ARR before treatment the ARR on treatment waslower across all treatments in the AQP4-Ab NMOSD group

Our cohort was not optimal for a direct evaluation of anindividual treatment or a sequence of treatment effect whichis better suited to a study design where the sequence ofDMTs the lag phase of efficacy or washout period of specifictherapies are prospectively controlled One particular treat-ment that deserves specific attention would be the cumulativeuse of corticosteroids often used in conjunction with DMTsand at low doses but also during acute attacks Time to ini-tiation of acute treatment the choice of treatment andtreatment escalation are major predictors of long-term out-come in AQP4-Ab NMOSD33ndash35 As many of the childrenpresented initially to district general hospital timing dura-tion and sequence of acute treatment were not included inthe analysis

A major limitation of this study is that not all patients weresystematically managed with possible biases in treatmentinitiation andor escalation Nevertheless these real-worldclinical data from multiple countries allowed us to make im-portant observations about the treatment responsiveness ofchildren with AQP4-Ab NMOSD The important questionour study raises is whether rituximab should be first-linetreatment for children Moreover should children who arealready stable on AZA and MMF be changed to the moreefficacious therapies with a higher risk profile Furthermorewith new monoclonal antibodies (satralizumab36 inebilizu-mab37 and eculizumab38) likely to become available treat-ment algorithms that accommodate risk stratification ofpoorer prognosis (such as the patients age and severity of theattack) and grouping of treatments with similar efficacy withinthe sequence and choice of treatments in pediatric AQP4-AbNMOSD are urgently required

AcknowledgmentThe authors thank all collaborators who worked in this study inthe collection of data Austria and Germany M Reindl ClinicalDepartment of Neurology Medical University of InnsbruckInnsbruck Austria Brazil Dr Dagoberto Callegaro (Depart-ment of Neurology Hospital das Clınicas Faculty of MedicineSatildeo Paulo Brazil) Laboratory of Brain Institute of Rio Grandedo Sul (Brains) Pontifical Catholic University of RioGrandeDoSul (PUCRS) Porto Alegre Brazil France Dr MaureyAssistance Publique-Hopitaux de Paris University HospitalsParis South Bicetre Hospital Pediatric Neurology DepartmentLe Kremlin Bicetre Dr Pascale Chretien University HospitalsParis South Bicetre Hospital Immunology Department LeKremlin Bicetre Dr Aubart Assistance Publique-Hopitaux deParis Necker Hospital Paris Dr Cheuret Hopital des EnfantsPediatric Neurology Department Toulouse Dr Lepine CentreHopitalo-Universitaire de Marseille Marseille Pr Laugel CHUde Strasbourg - Hopital de Hautepierre Pediatric Neurology


Department Strasbourg Spain Dr Maria Sepulveda (Neuro-immunology Program Hospital Clinic-IDIBAPS University ofBarcelona Spain) Dr Victor Soto-Insuga (Pediatric NeurologySection Pediatric Service Fundacion Jimenez Dıaz MadridSpain) Maria C Miranda-Herrero (Pediatric NeurologySection Pediatric Service Hospital Gregorio Marantildeon MadridSpain) Montserrat Garcia-Puig (Pediatric Neurology SectionPediatric Service Hospital Parc Taulı Sabadell Spain) TheNetherlands Prof Rogier Hintzen MD PhD was involved inthis study before his sudden death Dorte Hamann and KyraGelderman from the Department of Immunopathology andBlood Coagulation Sanquin Diagnostic Services Amsterdamthe Netherlands AQP4 antibodies were routinely assayed in acell-based assay using a fluorescence-activated cell sorter (FACSLSRII and DIVA software Becton Dickinson San Jose) UnitedKingdom UK Childhood Inflammatory Disorders (UK-CID)Study Group Antonia Clarke MD (Department of PaediatricNeurology St Georgersquos Hospital London) Katherine ForrestMD (Department of Paediatric Neurology SouthamptonChildrenrsquos Hospital Southampton) Andrex Lux MD (De-partment of Paediatric Neurology University Hospitals BristolBristol) Saleel Chandratre MD (Department of PaediatricNeurology John Radcliffe Hospital Oxford) Kshitij MankadMD and Kling Chong MD (Paediatric Neuroradiology GreatOrmond Street Hospital London) Laboratory Paddy WaterPhD Mark Woodhall PhD and Jackie Palace MD PhD(Oxford Autoimmune Neurology Group and National HealthService National Specialised Commissioning Group for Neuro-myelitis Optica United Kingdom)

Study fundingThis study was supported in part by the Marato TV3 Foun-dation (20141830 to TA and AS) Red Espantildeola de Escle-rosis Multiple (REEM) (RD1600150002 RD1600150003 to AS) and Torrons Vicens Foundation (PFNR0144to TA)

DisclosureRB Paolilo received support for participating in scientificmeetings from Roche and Merck Y Hacohen and E Yazbeckreport no disclosures T Armangue received speaking hono-raria from Novartis and travel expenses for participating inscientific meetings from Roche A Bruijstens and C Lechnerreport no disclosures SL Apostolos-Pereira served as boardadvisory for Novartis and Roche and received support forparticipating in scientific meetings fromGenzyme Roche andNovartis Y Martynenko M Breu C de Medeiros Rimkus EWassmer M Baumann and L Papetti report no disclosuresM Capobianco received personal honoraria for speaking atmeeting or participating in advisory boards from BiogenMerck Novartis Roche Sanofi and Teva B Kornek KRostasy and JA da Paz report no disclosures O Ciccarellireceives research funding from the UKMS Society RosetreesTrust and NIHR UCLH BRC and serves as a consultant forBiogen Novartis Roche and GE Healthcare she is on theeditorial board of Neurology M Lim received consultationfees from CSL Behring received travel grants from Merck

Serono and was awarded educational grants to organizemeetings by Novartis Biogen Idec Merck Serono and BayerA Saiz reports no disclosures R Neuteboom received con-sultation fees from Novartis and Zogenix R Marignier serveson the scientific advisory board for Novartis andMedImmuneand received speaker honoraria and travel funding fromNovartis Biogen Teva Sanofi-AventisGenzyme andMerckC Hemingway received consulting and educational grantsfrom Novartis served on the Global Paediatric MS Steeringcommittee and received educational grants from Biogen andreceived consultation fees from Alexion DK Sato receivedresearch support from CAPESBrasil CNPqBrasilFAPERGSBrasil and Japan Society of Science and re-ceived speaker honoraria from Biogen Novartis GenzymeMerck Sereno QuestAthena Diagnosis Shire and Teva KDeiva received speaking honoraria at meetings and for par-ticipation in advisory boards from Novartis Sanofi andServier Go to NeurologyorgNN for full disclosures

Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 2 2020 Accepted in final form April 28 2020

Appendix Authors

Name Location Contribution

RenataBarbosaPaolilo MD

Department of NeurologyHospital das ClınicasFaculty of MedicineUniversity of Satildeo Paulo(HCFMUSP) Satildeo PauloBrazil

Analyzed data anddrafted the manuscriptfor intellectual content

Yael HacohenMD PhD

Queen Square MS CentreUCL Institute of NeurologyFaculty of Brain SciencesUniversity College LondonDepartment of PaediatricNeurology Great OrmondStreet Hospital forChildren London UnitedKingdom

Designed andconceptualized the studyanalyzed data anddrafted the manuscriptfor intellectual content

Elise YazbeckMD

Assistance Publique-Hopitaux de ParisUniversity Hospitals ParisSouth Bicetre Hospital LeKremlin Bicetre France

Revised the manuscriptfor intellectual content

ThaisArmangueMD PhD

NeuroimmunologyProgram InstitutdrsquoInvestigacionsBiomediques August Pi iSunyer (IDIBAPS) HospitalClınic Universitat deBarcelona BarcelonaSpain PediatricNeuroimmunology UnitSant Joan de Deu (SJD)Childrenrsquos HospitalUniversitat de BarcelonaBarcelona Spain


ArletteBruijstensMD

Department of NeurologyErasmus UniversityMedical CenterRotterdam theNetherlands



Appendix (continued)


ChristianLechner MD

Division of PaediatricNeurology Department ofPediatrics I MedicalUniversity of InnsbruckInnsbruck Austria


Samira LuisaApostolos-Pereira MDPhD



YanaMartynenkoMD

Medical Center of PhysicalTherapy and PainMedicine INNOVO LvivUkraine


Markus BreuMD

Division of PediatricNeurology Department ofPediatrics and AdolescentMedicine MedicalUniversity of ViennaVienna Austria


Carolina deMedeirosRimkus MDPhD

Department of Radiology(INRAD) Hospital dasClınicas Faculty ofMedicine University ofSatildeo Paulo (HCFMUSP) SatildeoPaulo Brazil


EvangelineWassmer MD

Pediatric NeurologyBirmingham Women andChildrenrsquos HospitalBirmingham UnitedKingdom


MatthiasBaumann MD



Laura PapettiPhD

Department ofNeuroscience PediatricMultiple Sclerosis CenterBambino Gesu ChildrenHospital IRCCS RomeItaly


MarcoCapobiancoMD

Department of Neurologyand Regional MultipleSclerosis CentreUniversity Hospital SanLuigi Gonzaga OrbassanoItaly


BarbaraKornek MDPhD

Department of NeurologyMedical University ofVienna Vienna Austria


Kevin RostasyMD

Department of PediatricNeurology VestischeKinder und JugendklinikWittenHerdeckeUniversity DattelnGermany


Jose Albino daPaz MD PhD

Department of NeurologyHospital das Clınicas Facultyof Medicine University ofSatildeo Paulo (HCFMUSP) SatildeoPaulo Brazil




OlgaCiccarelli MDPhD

Queen Square MS CentreUCL Institute of NeurologyFaculty of Brain SciencesUniversity College London

Interpreted the data andrevised the manuscriptfor intellectual content

Ming Lim MDPhD

Childrenrsquos NeurosciencesEvelina London ChildrenrsquosHospital at Guyrsquos and StThomasrsquo NHS FoundationTrust Kingrsquos HealthPartners Academic HealthScience Centre LondonUnited Kingdom Faculty ofLife Sciences andMedicine Kingrsquos CollegeHospital London UnitedKingdom


Albert SaizMD PhD

Neurology ServiceHospital Clinic and InstitutdrsquoInvestigacionsBiomediques August Pi iSunyer (IDIBAPS)University of BarcelonaBarcelona Spain


RinzeNeuteboomMD PhD



RomainMarignierMD PhD

Neurology DepartmentHopital NeurologiquePierre WertheimerHospices Civils de LyonLyon French ReferenceNetwork of RareInflammatory Brain andSpinal Diseases LeKremlin Bicetre France


CherylHemingwayMD PhD

Department of PaediatricNeurology Great OrmondStreet Hospital forChildren London UnitedKingdom


DouglasKazutoshiSato MD PhD

School of Medicine BrainInstitute of Rio Grande doSul (Brains) PontificalCatholic University of RioGrande Do Sul (PUCRS)Porto Alegre Brazil

Interpreted the data anddrafted the manuscriptfor intellectual content

KumaranDeiva MDPhD

Assistance Publique-Hopitaux de ParisUniversity Hospitals ParisSouth Bicetre Hospital LeKremlin Bicetre FranceFrench Reference Networkof Rare InflammatoryBrain and Spinal DiseasesLe Kremlin Bicetre FranceInserm UMR 1184Immunology of ViralInfections andAutoimmune DiseasesCEA IDMIT Le KremlinBicetre France



References1 Lennon VA Wingerchuk DM Kryzer TJ et al A serum autoantibody marker of neu-

romyelitis optica distinction from multiple sclerosis Lancet 20043642106ndash21122 Sato DK Nakashima I Takahashi T et al Aquaporin-4 antibody-positive cases be-

yond current diagnostic criteria for NMO spectrum disorders Neurology 2013802210ndash2216

3 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585177ndash189

4 Rostasy K Reindl M Role of autoantibodies in acquired inflammatory demyelinatingdiseases of the central nervous system in children Neuropediatrics 201344297ndash301

5 Tillema JM McKeon A The spectrum of neuromyelitis optica (NMO) in childhoodJ Child Neurol 2012271437ndash1447

6 Mealy MA Wingerchuk DM Palace J Greenberg BM Levy M Comparison ofrelapse and treatment failure rates among patients with neuromyelitis optica multi-center study of treatment efficacy JAMA Neurol 201471324ndash330

7 Palace J Leite MI Nairne A Vincent A Interferon beta treatment in neuromyelitisoptica increase in relapses and aquaporin 4 antibody titers Arch Neurol 2010671016ndash1017

8 Banwell B Tenembaum S Lennon VA et al Neuromyelitis optica-IgG in childhoodinflammatory demyelinating CNS disorders Neurology 200870344ndash352

9 Huppke P Bluthner M Bauer O et al Neuromyelitis optica and NMO-IgG inEuropean pediatric patients Neurology 2010751740ndash1744

10 McKeon A Lennon VA Lotze T et al CNS aquaporin-4 autoimmunity in childrenNeurology 20087193ndash100

11 Chitnis T Ness J Krupp L et al Clinical features of neuromyelitis optica in childrenUS Network of Pediatric MS Centers report Neurology 201686245ndash252

12 Banwell B Bar-Or A Arnold DL et al Clinical environmental and genetic deter-minants of multiple sclerosis in children with acute demyelination a prospectivenational cohort study Lancet Neurol 201110436ndash445

13 Hacohen Y Absoud M Woodhall M et al Autoantibody biomarkers in childhood-acquired demyelinating syndromes results from a national surveillance cohortJ Neurol Neurosurg Psychiatry 201485456ndash461

14 Hacohen Y Mankad K Chong WK et al Diagnostic algorithm for relapsing acquireddemyelinating syndromes in children Neurology 201789269ndash278

15 Collongues N Marignier R Zephir H et al Long-term follow-up of neuromyelitisoptica with a pediatric onset Neurology 2010751084ndash1088

16 Kitley J Leite MI Nakashima I et al Prognostic factors and disease course inaquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorderfrom the United Kingdom and Japan Brain 20121351834ndash1849

17 Krupp LB Tardieu M Amato MP et al International Pediatric Multiple SclerosisStudy Group criteria for pediatric multiple sclerosis and immune-mediated centralnervous system demyelinating disorders revisions to the 2007 definitions Mult Scler2013191261ndash1267

18 Marignier R Bernard-Valnet RGiraudon P Aquaporin-4 antibody-negative neuromyelitisoptica distinct assay sensitivity-dependent entity Neurology 2013802194ndash2200

19 Sato DK Callegaro D Lana- Peixoto MA et al Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders Neurology 201482474ndash481

20 Waters PJ Pittock SJ Bennett JL Jarius S Weinshenker BG Wingerchuk DMEvaluation of aquaporin-4 antibody assays Clin Exp Neuroimmunol 20145290ndash303

21 Hoftberger R Sepulveda M Armangue T Antibodies to MOG and AQP4 in adultswith neuromyelitis optica and suspected limited forms of the disease Mult Scler 2015211086ndash1094

22 van Pelt ED Wong YY Ketelslegers IA Neuromyelitis optica spectrum disorderscomparison of clinical and magnetic resonance imaging characteristics of AQP4-IgGversus MOG-IgG seropositive cases in the Netherlands Eur J Neurol 201523580ndash587

23 Ketelslegers IA Modderman PW Vennegoor A Antibodies against aquaporin-4 inneuromyelitis optica distinction between recurrent and monophasic patients MultScler 2011171527ndash1530

24 Kim SHMealyMA Levy M et al Racial differences in neuromyelitis optica spectrumdisorder Neurology 201891e2089ndashe2099

25 Dale RC Brilot F Duffy LV et al Utility and safety of rituximab in pediatric auto-immune and inflammatory CNS disease Neurology 201483142ndash150

26 Nosadini M Alper G Riney CJ et al Rituximab monitoring and redosing in pediatricneuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm 20163e188

27 Marcinno A Marnetto F Valentino P et al Rituximab-induced hypo-gammaglobulinemia in patients with neuromyelitis optica spectrum disorders NeurolNeuroimmunol Neuroinflamm 20185e498

28 Costanzi C Matiello M Lucchinetti CF et al Azathioprine tolerability efficacy andpredictors of benefit in neuromyelitis optica Neurology 201177659ndash666

29 Huh SY Kim SH Hyun JW et al Mycophenolate mofetil in the treatment of neu-romyelitis optica spectrum disorder JAMA Neurol 2014711372ndash1378

30 Kim SH Jeong IH Hyun JW et al Treatment outcomes with rituximab in 100patients with neuromyelitis optica influence of FCGR3A polymorphisms on thetherapeutic response to rituximab JAMA Neurol 201572989ndash995

31 Gorman MP Healy BC Polgar-Turcsanyi M Chitnis T Increased relapse rate inpediatric-onset compared with adult-onset multiple sclerosis Arch Neurol 20096654ndash59

32 Hacohen Y Wong YY Lechner C et al Disease course and treatment responses inchildren with relapsing myelin oligodendrocyte glycoprotein antibody-associateddisease JAMA Neurol 201875478ndash487

33 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679206ndash216

34 Kleiter I Gahlen A BorisowN et al Apheresis therapies for NMOSD attacks a retrospectivestudy of 207 therapeutic interventions Neurol Neuroimmunol Neuroinflamm 20185e504

35 Bonnan M Valentino R Debeugny S et al Short delay to initiate plasma exchange isthe strongest predictor of outcome in severe attacks of NMO spectrum disordersJ Neurol Neurosurg Psychiatry 201889346ndash351

36 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 20193812114ndash2124

37 Cree BAC Bennett JL Kim HJ et al Inebilizumab for the treatment of neuromyelitisoptica spectrum disorder (N-MOmentum) a double-blind randomised placebo-controlled phase 23 trial Lancet 20193941352ndash1363

38 Pittock SJ Berthele A Fujihara K et al Eculizumab in aquaporin-4-positive neuro-myelitis optica spectrum disorder N Engl J Med 2019381614ndash625


DOI 101212NXI000000000000083720207 Neurol Neuroimmunol Neuroinflamm

Renata Barbosa Paolilo Yael Hacohen Elise Yazbeck et al pediatric study

positive NMOSD A multinationalminusTreatment and outcome of aquaporin-4 antibody

This information is current as of July 30 2020

ServicesUpdated Information amp

httpnnneurologyorgcontent75e837fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent75e837fullhtmlref-list-1

This article cites 38 articles 5 of which you can access for free at

Subspecialty Collections

httpnnneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnnneurologyorgcgicollectionautoimmune_diseasesAutoimmune diseasesfollowing collection(s) This article along with others on similar topics appears in the

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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

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httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ConclusionsAQP4-Ab NMOSD in children is an aggressive disease with permanent disabilities observed in over half the cohort All DMTswere associated with a reduction of ARR First-line rituximab prevented further clinical relapses International consensus ontreatment protocols for children is required to reduce heterogeneity of treatment regimens used worldwide

Classification of evidenceThis study provides Class IV evidence that for children with AQP4-Ab NMOSD all DMTs particularly first-line rituximabreduced the ARR and prevented further clinical relapses

Antibodies against aquaporin-4 (AQP4-Ab) were first describedin 2004 in patients with neuromyelitis optica (NMO)1 allowingthe expansion of the phenotype2 The most recent criteria forthe diagnosis of NMO spectrum disorder (NMOSD) stratifypatients by the presenceabsence of AQP4-Ab3 AQP4-Ab se-ropositivity is associated with relapsing disease45 This led to theuse of B-cell targeting therapies which clearly reduce relapserates6 This reduction is not seen when therapies known to beeffective for MS7 are used in NMOSD

The clinical features and MRI abnormalities in children withAQP4-Ab NMOSD are similar to the adult phenotype8ndash11

The prevalence of AQP4-Ab was reported in 07 (2279)12

to 45 (364)13 of children presenting with a first pre-sentation of acquired demyelinating syndrome (ADS) and 8102 (78) of children with relapsing syndromes14 Childrenare reported to have a less severe disease course and may takelonger to reach disability than adults15 Children are at ahigher risk of visual impairment compared with adults but areless likely to acquire motor deficits16 Previous pediatricpublications highlighted that AQP4-Ab NMOSD in Europe israre9 whereas the prevalence in South America8 is higher

With the rarity of pediatric presentation treatment is derived fromadult guidelines and can be influenced by medication availabilityand cost Current available treatments used such as azathioprine

GlossaryADS = acquired demyelinating syndrome AQP4-Ab = antibodies against aquaporin-4 ARR = annualized relapse rateAZA = azathioprine CRF = case reporting form DMT = disease-modifying therapy EDSS = Expanded Disability StatusScale IQR = interquartile range MMF = mycophenolate mofetil MOG-Ab = myelin oligodendrocyte glycoproteinantibody NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritis TM = transverse myelitis





































Female sex n () 2529 (862) 2938 (763) 5467 (80)


Baseline attack














Motor sequelae n () 529 (172) 937 (243) 1466 (21)




















Rituximab(n = 14)






Brazil (n = 20) 1720 (85) 120 (5) 0 220 (10)

United Kingdom (n = 18) 718 (389) 518 (278) 318 (167) 318 (167)

France (n = 10) 210 (20) 110 (10) 610 (60) 110 (10)

Spain (n = 6) 26 (333) 16 (167) 36 (50) 0




Optic neuritis (n = 29) 1629 (551) 729 (241) 429 (137) 229 (68)












214 (142) mdash









Sex (FM) 344 209 0261 (0071ndash0960) 0043




























Appendix Authors





Yael HacohenMD PhD



Elise YazbeckMD



ThaisArmangueMD PhD



ArletteBruijstensMD






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints







































Female sex n () 2529 (862) 2938 (763) 5467 (80)


Baseline attack














Motor sequelae n () 529 (172) 937 (243) 1466 (21)




















Rituximab(n = 14)






Brazil (n = 20) 1720 (85) 120 (5) 0 220 (10)

United Kingdom (n = 18) 718 (389) 518 (278) 318 (167) 318 (167)

France (n = 10) 210 (20) 110 (10) 610 (60) 110 (10)

Spain (n = 6) 26 (333) 16 (167) 36 (50) 0




Optic neuritis (n = 29) 1629 (551) 729 (241) 429 (137) 229 (68)












214 (142) mdash









Sex (FM) 344 209 0261 (0071ndash0960) 0043




























Appendix Authors





Yael HacohenMD PhD



Elise YazbeckMD



ThaisArmangueMD PhD



ArletteBruijstensMD






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints



















Rituximab(n = 14)






Brazil (n = 20) 1720 (85) 120 (5) 0 220 (10)

United Kingdom (n = 18) 718 (389) 518 (278) 318 (167) 318 (167)

France (n = 10) 210 (20) 110 (10) 610 (60) 110 (10)

Spain (n = 6) 26 (333) 16 (167) 36 (50) 0




Optic neuritis (n = 29) 1629 (551) 729 (241) 429 (137) 229 (68)












214 (142) mdash









Sex (FM) 344 209 0261 (0071ndash0960) 0043




























Appendix Authors





Yael HacohenMD PhD



Elise YazbeckMD



ThaisArmangueMD PhD



ArletteBruijstensMD






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints










Sex (FM) 344 209 0261 (0071ndash0960) 0043




























Appendix Authors





Yael HacohenMD PhD



Elise YazbeckMD



ThaisArmangueMD PhD



ArletteBruijstensMD






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints


















Appendix Authors





Yael HacohenMD PhD



Elise YazbeckMD



ThaisArmangueMD PhD



ArletteBruijstensMD






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints






ChristianLechner MD






YanaMartynenkoMD



Markus BreuMD









MatthiasBaumann MD



Laura PapettiPhD



MarcoCapobiancoMD



BarbaraKornek MDPhD



Kevin RostasyMD











Ming Lim MDPhD



Albert SaizMD PhD















KumaranDeiva MDPhD



























































Reprints



























































Reprints




treatment and outcome of aquaporin-4 antibody–positive nmosd · treatment and outcome of...

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