VIEWS amp REVIEWS

Dean M WingerchukMD FRCP(C)

Brenda Banwell MDFRCP(C)

Jeffrey L Bennett MDPhD

Philippe Cabre MDWilliam Carroll MDTanuja Chitnis MDJeacuterocircme de Seze MDKazuo Fujihara MDBenjamin Greenberg

MDAnu Jacob MDSven Jarius MDMarco Lana-Peixoto MDMichael Levy MD PhDJack H Simon MDSilvia Tenembaum MDAnthony L Traboulsee

MD FRCP(C)Patrick Waters PhDKay E Wellik MLSBrian G Weinshenker

MD FRCP(C)

Correspondence toDr Wingerchukwingerchukdeanmayoeduor Dr Weinshenkerweinbmayoedu

Editorial page 118

Supplemental dataat Neurologyorg

International consensus diagnostic criteriafor neuromyelitis optica spectrumdisorders

ABSTRACT

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis(MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) PriorNMO diagnostic criteria required optic nerve and spinal cord involvement but more restrictedor more extensive CNS involvement may occur The International Panel for NMO Diagnosis (IPND)was convened to develop revised diagnostic criteria using systematic literature reviews and elec-tronic surveys to facilitate consensus The new nomenclature defines the unifying term NMOspectrum disorders (NMOSD) which is stratified further by serologic testing (NMOSD with orwithout AQP4-IgG) The core clinical characteristics required for patients with NMOSD withAQP4-IgG include clinical syndromes or MRI findings related to optic nerve spinal cord areapostrema other brainstem diencephalic or cerebral presentations More stringent clinical crite-ria with additional neuroimaging findings are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable The IPND also proposed validation strategies andachieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSDand opticospinal MS Neurologyreg 2015851ndash13

GLOSSARYADEM 5 acute disseminated encephalomyelitis AQP4 5 aquaporin-4 IgG 5 immunoglobulin G IPND 5 International Panelfor NMO Diagnosis LETM 5 longitudinally extensive transverse myelitis lesions MOG 5 myelin oligodendrocyte glycopro-tein MS 5 multiple sclerosis NMO 5 neuromyelitis optica NMOSD 5 neuromyelitis optica spectrum disorders SLE 5systemic lupus erythematosus SS 5 Sjoumlgren syndrome

Neuromyelitis optica (NMO) is an inflammatory CNS disorder distinct from multiple sclerosis(MS)12 It became known as Devic disease following a seminal 1894 report3e1e2 TraditionallyNMO was considered a monophasic disorder consisting of simultaneous bilateral optic neuritisand transverse myelitis but relapsing cases were described in the 20th century3 MRI revealednormal brain scans and$3 vertebral segment longitudinally extensive transverse myelitis lesions(LETM) in NMO4e3 The nosology of NMO especially whether it represented a topograph-ically restricted form of MS remained controversial

A major advance was the discovery that most patients with NMO have detectable serum anti-bodies that target the water channel aquaporin-4 (AQP4ndashimmunoglobulin G [IgG])56 arehighly specific for clinically diagnosed NMO and have pathogenic potential7e4ndashe6 In 2006AQP4-IgG serology was incorporated into revised NMO diagnostic criteria that relaxed clinical

From the Departments of Neurology (DMW) and Library Services (KEW) Mayo Clinic Scottsdale AZ the Childrenrsquos Hospital of Phila-delphia (BB) PA the Departments of Neurology and Ophthalmology (JLB) University of Colorado Denver Aurora the Service de Neurologie(PC) Centre Hospitalier Universitaire de Fort de France Fort-de-France Martinique Department of Neurology (WC) Sir Charles GairdnerHospital Perth Australia the Department of Neurology (TC) Massachusetts General Hospital Boston the Department of Neurology (JdS)Strasbourg University France the Department of Multiple Sclerosis Therapeutics (KF) Tohoku University Graduate School of Medicine SendaiJapan the Departments of Neurology and Neurotherapeutics (BG) University of Texas Southwestern Medical Center Dallas The Walton CentreNHS Trust (AJ) Liverpool UK the Molecular Neuroimmunology Group Department of Neurology (SJ) University Hospital HeidelbergGermany the Center for Multiple Sclerosis Investigation (ML-P) Federal University of Minas Gerais Medical School Belo Horizonte Brazil theDepartment of Neurology (ML) Johns Hopkins University Baltimore MD Portland VA Medical Center and Oregon Health and SciencesUniversity (JHS) Portland the Department of Neurology (ST) National Pediatric Hospital Dr Juan P Garrahan Buenos Aires Argentina theDepartment of Medicine (ALT) University of British Columbia Vancouver Canada Nuffield Department of Clinical Neurosciences (PW)University of Oxford UK and the Department of Neurology (BGW) Mayo Clinic Rochester MN

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the articleThe Article Processing Charge was paid by the Guthy-Jackson Charitable Foundation

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially

copy 2015 American Academy of Neurology 1

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Published Ahead of Print on June 19 2015 as 101212WNL0000000000001729

requirements by permitting unilateral opticneuritis or asymptomatic brain MRI lesionsbut retained the requirement for both myelitisand optic neuritis2 The 2006 criteria werevalidated in several different ethnic and racialcohorts worldwide and became the standardfor clinical and research purposes8ndash10e5e7ndashe15

The specificity of AQP4-IgG facilitated ob-servations that further broadened the clinicaland neuroimaging spectrum of NMO In2007 the term NMO spectrum disorders(NMOSD) was introduced to include AQP4-IgG-seropositive patients with limited or inau-gural forms of NMO (eg first-attack LETMor recurrent or bilateral optic neuritis) whowere at high risk for future attacks1 TheNMOSD term also encompassed the cerebraldiencephalic and brainstem lesions that occurin a minority of patients with otherwise typicalNMO It also included AQP4-IgG-seropositivepatients with coexisting autoimmune disorders(eg systemic lupus erythematosus [SLE] orSjoumlgren syndrome [SS]) Finally NMOSDpotentially included patients diagnosed withopticospinal MS an MS phenotype prominentin Asia and distinguished from Western MS11

Further advances have rendered the 2006 cri-teria inadequate for contemporary practice andresearch Improvement in AQP4-IgG sensitivityhas allowed for refinement of the list of non-opticospinal disease characteristics12ndash14e16ndashe18

Moreover loss of AQP4 immunoreactivityand astrocyte pathology in brain and spinalcord NMO lesions distinguish them fromMS lesionse19ndashe23 Together these data sug-gest that non-opticospinal clinical and MRIcharacteristics should be incorporated intothe diagnostic criteria The term NMOSDhas also been used variably in the literatureand needs clarification3 Other outstandingissues include whether there are distinctivefeatures of pediatric NMO the current valueof the term opticospinal MS and whethermonophasic NMO can be defined Finallytreatment strategies for attack prevention inNMO and MS differ Some MS immuno-therapies appear to aggravate NMO indicat-ing an imperative for early accuratediagnosis15ndash18e24ndashe26 The International Panelfor NMO Diagnosis (IPND) was convenedand charged with revising NMO diagnostic

criteria for clinical decision-making and toaddress the ancillary issues outlined aboveThis report represents the Panelrsquos consensusrecommendations

METHODS The IPND consisted of 18 members from 9 coun-

tries and was led by 2 co-chairs (DMW BGW) It convened

7 times between October 2011 and November 2013 Panel

members participated in 6 Working Groups Clinical

Presentation Neuroimaging Laboratory StudiesSerology

Pediatrics Systemic Autoimmunity and Opticospinal MS

Initial consensus was reached on 2 points First NMOwould

be subsumed into the single descriptive term NMOSD because

the clinical behavior immunopathogenesis and treatment of pa-

tients who have NMOSD are not demonstrably different than for

those with NMO and patients with incomplete forms of NMO

frequently later fulfill NMO criteria1141920e27 The entrenched

and historically significant phrase NMO would be retained by

using NMOSD because although the criteria would be broad-

ened to include patients with neither optic neuritis or myelitis21

those syndromes eventually occur in almost all patients Second

revised criteria would define a clinical diagnosis by integrating

clinical serologic and neuroimaging data diagnosis would not be

based solely on detection of AQP4-IgG Moreover the Panel

concluded that criteria must define NMOSD in instances where

AQP4-IgG serologic testing is negative or unavailable especially

because of the treatment implications

The IPND established several goals chief of which was devel-

oping revised consensus NMOSD criteria using the best available

evidence The Clinical Presentation Working Group conducted

the primary task of establishing the spectrum and validity of clin-

ical syndromes described in clinically diagnosed NMO or in asso-

ciation with AQP4-IgG these data were used to establish new

core clinical criteria The other Working Groups each addressed

a roster of focused questions that would contribute to final diag-

nostic criteria

Each Working Group conducted a systematic literature

review with expert librarian assistance to address its assignments

Medical subject heading terms were used when possible and

MEDLINE EMBASE and other databases were searched from

1946ndashJanuary 2012 with quarterly updates through January

15 2014 (see table e-1 on the Neurologyreg Web site at

Neurologyorg for search strategies and results) Two individuals

independently reviewed abstracts for relevance discordant ratings

were resolved by consensus Relevant full-text articles were inde-

pendently rated to identify those used for data extraction Pub-

lications describing sensitivity and specificity of AQP4-IgG were

included if they compared groups diagnosed with clinical NMO

and MS

The Clinical Presentation and Neuroimaging Working

Groups compiled a list of clinical syndromes and MRI character-

istics reported by more than one publication to be associated with

NMOSD or AQP4-IgG Panel members rated the specificity of

these characteristics for NMOSD diagnosis using 2 electronic sur-

veys Two additional surveys presented adult case vignettes that

contained information on clinical symptoms and signs (1ndash3 dis-

crete clinical events) with brain MRI AQP4-IgG serostatus and

other potential supportive criteria (optic nerve or spinal cord MRI

findings) or laboratory results (eg CSF data visual evoked po-

tentials) Panel members assigned a diagnosis for each vignette

definite NMOSD indeterminate (requiring further data or

follow-up for confident diagnosis) or other (eg MS) A roster

of potential supportive clinical MRI and laboratory criteria was

2 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

separately ranked for their influence on confidence in NMOSD

diagnosis Characteristics or scenarios endorsed by a two-thirds

Panel majority as contributing to a confident clinical diagnosis of

NMOSD were used to develop separate requirements for AQP4-

IgG seropositive and seronegative patients Recommendations

from individual Working Groups regarding pediatric NMOSD

opticospinal MS systemic autoimmunity and monophasic dis-

ease were summarized All IPND members endorsed the final

criteria

RESULTS Consensus diagnostic criteria Nomenclature

The Panel reaffirmed the decision to unify the termsNMO andNMOSD Given the greater degree of diag-nostic uncertainty and potential heterogeneity of sero-negative NMOSD criteria were developed for bothNMOSD with AQP4-IgG and NMOSD withoutAQP4-IgG An additional category of NMOSD withunknown AQP4-IgG status may be used for patientsin whom serologic testing is unavailable The nomen-clature allows for future modifications based on poten-tial discovery and validation of other biomarkers inAQP4-IgG-seronegative patients who have otherwisetypical NMOSD clinical syndromes

Clinical presentation Consensus diagnostic criteriafor NMOSD are presented in table 1 Table e-2 containsa glossary of terms to guide interpretation of individualcomponents of the criteria The criteria allow NMOSDdiagnosis with occurrence of at least 1 of 6 core clinicalcharacteristics and detection of AQP4-IgG The core

clinical characteristics each implicate 1 of 6 CNS regionsoptic nerve19e28ndashe31 spinal cord20e27e32ndashe34 area postremaof the dorsal medulla2223e35 brainstem24e35ndashe38 dien-cephalon2526e39ndashe44 or cerebrum2728e45ndashe48 Certain clini-cal presentations are particularly suggestive of NMOSDoptic neuritis that is simultaneously bilateral involves theoptic chiasm causes an altitudinal visual field defect orcauses severe residual visual loss (acuity 20200 orworse)4e49ndashe51 a complete (rather than partial) spinalcord syndrome especially with paroxysmal tonicspasms429e52 and an area postrema clinical syndrome(16ndash43 incidence) consisting of intractable hic-cups or nausea and vomiting2223e35 Clinical judgmentremains necessary because no characteristic is path-ognomonic For example altitudinal visual fielddefects may result from ischemic optic neuropathyand bilateral simultaneous optic neuritis may occurin MSe53

Diagnostic requirements are more stringent forpatients in whom AQP4-IgG is not detected or forwhom testing is unavailable Such individuals mustexperience 2 or more different core clinical character-istics (ie dissemination in space affecting differentneuroanatomic regions) and other supportive MRIcharacteristics meant to enhance diagnostic specificitymust also be present At least one of the clinical eventsmust be one of the 3 most common clinical character-istics of NMOSD optic neuritis transverse myelitis(additional requirement LETM MRI lesion) or anarea postrema clinical syndrome (additional require-ment associated medullary MRI lesion)222330e35

The 2 required core characteristics may occur witha single clinical attack (eg classic Devic syndromewith simultaneous optic neuritis and acute myelitiswith LETM) or multiple attacks

The Panel reached several additional conclusionsFirst at least 1 discrete clinical attack of CNS symp-toms must occur to establish NMOSD diagnosisAlthough asymptomatic AQP4-IgG seropositive sta-tus may exist for years before clinical NMOSD pre-sentatione54 the natural history of asymptomaticseropositivity is poorly understood SecondNMOSD diagnosis is not warranted in asymptomaticpatients with NMOSD-compatible MRI lesionsbecause the expected clinical course in such individualsis unknown Third no clinical characteristic is path-ognomonic of NMOSD Accordingly a single clinicalmanifestation is not diagnostic when AQP4-IgG is notdetected Finally no single characteristic is exclusion-ary but some are considered red flags (table 2) thatsignal the possibility of alternative diagnosese55ndashe63

The main clinical red flags concern the temporal courseof the syndrome rather than the actual manifestationsMost notably a gradually progressive course of neuro-logic worsening over months to years is very uncom-mon (1ndash2) in NMOSD31 However after

Table 1 NMOSD diagnostic criteria for adult patients

Diagnostic criteria for NMOSD with AQP4-IgG1 At least 1 core clinical characteristic2 Positive test for AQP4-IgG using best available detection method (cell-based assay strongly

recommended)3 Exclusion of alternative diagnosesa

Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status1 At least 2 core clinical characteristics occurring as a result of one or more clinical attacks

and meeting all of the following requirementsa At least 1 core clinical characteristic must be optic neuritis acute myelitis with LETM or

area postrema syndromeb Dissemination in space (2 or more different core clinical characteristics)c Fulfillment of additional MRI requirements as applicable

2 Negative tests for AQP4-IgG using best available detection method or testing unavailable3 Exclusion of alternative diagnosesa

Core clinical characteristics1 Optic neuritis2 Acute myelitis3 Area postrema syndrome episode of otherwise unexplained hiccups or nausea and vomiting4 Acute brainstem syndrome5 Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical

diencephalic MRI lesions (figure 3)6 Symptomatic cerebral syndrome with NMOSD-typical brain lesions (figure 3)

Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknownAQP4-IgG status

1 Acute optic neuritis requires brain MRI showing (a) normal findings or only nonspecific whitematter lesions OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium-enhancing lesion extending over 12 optic nerve length or involving optic chiasm (figure 1)

2 Acute myelitis requires associated intramedullary MRI lesion extending over $3 contiguoussegments (LETM) OR $3 contiguous segments of focal spinal cord atrophy in patients withhistory compatible with acute myelitis (figure 1)

3 Area postrema syndrome requires associated dorsal medullaarea postrema lesions (figure 2)4 Acute brainstem syndrome requires associated periependymal brainstem lesions (figure 2)

Abbreviations AQP4 5 aquaporin-4 IgG 5 immunoglobulin G LETM 5 longitudinally exten-sive transverse myelitis lesions NMOSD 5 neuromyelitis optica spectrum disordersa See table 2 and text discussion on serologic considerations for recommendations regard-ing interpretation of clinical and serologic testing

Neurology 85 July 14 2015 3

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

thorough investigation for potential competing disor-ders the weight of evidence may justify NMOSDdiagnosis despite presence of 1 or more red flagsThe presence of systemic autoimmune diseases andcertain CSF data and pathologic findings (see below)may also influence NMOSD likelihood Regardlessof AQP4-IgG serologic status NMOSD should bediagnosed when criteria are fulfilled and alternativediagnoses for the clinical syndrome have beenexcluded

Neuroimaging and neurophysiologic testing MRI lesionpatterns are a major arbiter of CNS demyelinatingdisease differential diagnosis Several brain opticnerve and spinal cord patterns are characteristic orhighly suggestive of NMOSD (table 3 figures 1ndash3)Detection of a LETM spinal cord lesion (figure 1)

associated with acute myelitis is the most specificneuroimaging characteristic of NMOSD and is veryuncommon in adult MS2 Such lesions typicallyinvolve the central gray matter and may be associatedwith cord swelling central hypointensity on T1-weighted sequences and enhancement followingIV gadolinium administration extension of acervical lesion into the brainstem is characteris-tic43233e35e64ndashe67 In contrast MS cord lesions areusually about 1 vertebral segment long or less occupyperipheral white matter tracts such as the dorsal col-umns and may be asymptomatic (see table 3 forneuroimaging red flags relevant to MS and other dis-eases)34ndash36e68ndashe70 Although the LETM pattern is char-acteristic of NMOSD 7ndash14 of initial and 8 ofsubsequent myelitis attacks in AQP4-IgG-seroposi-tive patients do not meet the LETM definition3237

Therefore NMOSD must be considered in the dif-ferential diagnosis in patients presenting with shortmyelitis lesions The timing of an individual MRIscan must be correlated with clinical status Occasion-ally lesions of less than 3 segments are detected inNMOSD because the MRI was performed early inthe evolution of acute myelitis or in clinical remissionduring which a LETM lesion may fragment into dis-continuous lesions37e71 Some patients with progress-ive MS have coalescent cord lesions that cansuperficially suggest a LETM patterne72 both axialand sagittal plane images should be used to judgelesion extent A LETM MRI pattern may also occurin patients with infectious granulomatous neoplas-tic and paraneoplastic diseases acute disseminatedencephalomyelitis (ADEM) spinal cord infarctionand dural arteriovenous fistulae63

During optic neuritis attacks increased signalwithin the optic nerve may be detected with fat-suppressed T2-weighted orbital MRI sequencestypically with gadolinium enhancement seen on T1-weighted sequences (figure 1) Bilateral optic nerveinvolvement posterior nerve predominance (especiallywith extension into the optic chiasm) or extensivelesions of the optic nerve (more than half of its length)are all suggestive of NMOSD (table 3)e51e73e74

According to the 2006 diagnostic scheme a nor-mal brain MRI or detection of only nonspecific whitematter lesions was a key supportive criterion2 Sixtypercent of patients with NMOSD accumulate asymp-tomatic white matter lesions on longitudinal studyand as many as 16 fulfill Barkhof MS MRI crite-ria333839e75ndashe76 Detection of brain MRI white matterlesions compatible with MS does not exclude thediagnosis of NMOSD but is considered a red flagindicating that additional evidence may be requiredto confidently distinguish NMOSD fromMS in indi-vidual cases3338e64e76e77 Analysis of qualitative fea-tures of lesions assists in distinguishing NMOSD

Table 2 Red flags Findings atypical for NMOSD

Red flags (clinicallaboratory)

1 Clinical features and laboratory findings

Progressive overall clinical course (neurologic deterioration unrelated to attacks consider MS)

Atypical time to attack nadir less than 4 hours (consider cord ischemiainfarction) continualworsening for more than 4 weeks from attack onset (consider sarcoidosis or neoplasm)

Partial transverse myelitis especially when not associated with LETMMRI lesion (consider MS)

Presence of CSF oligoclonal bands (oligoclonal bands occur in 20 of cases of NMO vs80 of MS)

2 Comorbidities associated with neurologic syndromes that mimic NMOSD

Sarcoidosis established or suggestive clinical radiologic or laboratory findings thereof (egmediastinal adenopathy fever and night sweats elevated serum angiotensin convertingenzyme or interleukin-2 receptor levels)

Cancer established or with suggestive clinical radiologic or laboratory findings thereofconsider lymphoma or paraneoplastic disease (eg collapsin response mediator protein-5associated optic neuropathy and myelopathy or anti-Ma-associated diencephalic syndrome)

Chronic infection established or with suggestive clinical radiologic or laboratory findingsthereof (eg HIV syphilis)

Red flags (conventional neuroimaging)

1 Brain

a Imaging features (T2-weighted MRI) suggestive of MS (MS-typical)

Lesions with orientation perpendicular to a lateral ventricular surface (Dawson fingers)

Lesions adjacent to lateral ventricle in the inferior temporal lobe

Juxtacortical lesions involving subcortical U-fibers

Cortical lesions

b Imaging characteristics suggestive of diseases other than MS and NMOSD

Lesions with persistent (3 mo) gadolinium enhancement

2 Spinal cord

Characteristics more suggestive of MS than NMOSD

Lesions 3 complete vertebral segments on sagittal T2-weighted sequences

Lesions located predominantly (70) in the peripheral cord on axial T2-weightedsequences

Diffuse indistinct signal change on T2-weighted sequences (as sometimes seen withlongstanding or progressive MS)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions MS 5 multiplesclerosis NMO 5 neuromyelitis optica NMOSD 5 neuromyelitis optica spectrum disordersThese are some common or key findings that should prompt thorough investigation forcompeting differential diagnoses before making a diagnosis of NMOSD

4 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

from MS First at least 7 of patients haveNMOSD-typical patterns that although not pathog-nomonic for NMOSD are considered exceptional forMS (table 3)39 including lesions of the dorsalmedullaarea postrema (figure 2)223340e36e73e78

and periependymal regions in the brainstem(figure 2)3340e36e73 and diencephalic struc-tures3940e79 or cerebral hemispherese80 (figure 3)or long lesions spanning much of the length of thecorpus callosum3941 or corticospinal tracts(figure 3)3334 Large confluent or tumefactivecerebral lesions may suggest NMOSD but in isola-tion may not be discernable from atypical MSlesions especially in AQP4-IgG-seronegative pa-tients27333942e46e812e83 Second some MRI lesionpatterns considered typical of MS are rarely seen inNMOSD including perpendicular orientation of

periventricular lesions (Dawson fingers) periven-tricular lesions located in the inferior temporal lobeand cortical lesions333843e64 Recent 7T MRI stud-ies revealed differences between NMOSD and MSspecifically regarding cortical lesions (frequent inMS but absent in NMOSD) and white matterlesions (MS plaques are periventricular and tra-versed by a central venule whereas NMOSD lesionsare subcortical and lack a central venule)e84e85

However this technology is not widely availableand further validation is needed

The Panel considered evidence for use of otherimaging modalities such as nonconventional MRItechniques and optical coherence tomography andneurophysiologic tests such as visual evoked poten-tials None of these modalities were included in therevised diagnostic criteria because of concerns regard-ing lack of evidence specificity or reliability

Considerations for AQP4-IgG serologic and other

laboratory testing Technological advances in AQP4-IgG assays have improved diagnostic sensitivitywithout compromising specificity44 The Panelrecommended testing with cell-based serum assays(microscopy or flow cytometry-based detection)whenever possible because they optimize autoantibodydetection (mean sensitivity 767 in a pooled analysis01 false-positive rate in a MS clinic cohort)12ndash144445

However cell-based assays are not yet widely availableIndirect immunofluorescence assays and ELISAs

have lower sensitivity (mean sensitivity 63ndash64 each)and occasionally yield false-positive results (05ndash13for ELISA) often at low titer12ndash144445e86 The Panelstrongly recommended interpretative caution if such as-says are used and when low-titer positive ELISA resultsare detected in individuals who present with NMOSDclinical symptoms less commonly associated with AQP4-IgG (eg presentations other than recurrent optic neu-ritis myelitis with LETM or area postrema syndrome)or in situations where clinical evidence suggests a viablealternate diagnosis Confirmatory testing is recom-mended ideally using 1 or more different AQP4-IgG assay techniques Cell-based assay has the bestcurrent sensitivity and specificity and samples mayneed to be referred to a specialized laboratory

Patients who fulfill NMOSD criteria but do nothave detectable AQP4-IgG despite use of the bestavailable assays or for whom serologic testing isunavailable sometimes represent a diagnostic chal-lenge46 A greater proportion of patients with NMOwho have monophasic disease appear to be AQ-P4-IgG-seronegative compared to those with estab-lished relapsing disease37 A minority of patients withclinical characteristics of NMO almost all AQP4-IgG-seronegative have been reported to have detect-able serum myelin oligodendrocyte glycoprotein

Table 3 Neuroimaging characteristics of NMOSD

Spinal cord MRI acute

LETM lesion associated with acute TM

Increased signal on sagittal T2-weighted (standard T2-weighted proton density or STIRsequences) extending over 3 or more complete vertebral segments (figure 1 A and D)

Central cord predominance (more than 70 of the lesion residing within the central graymatter) (figure 1 AndashD)

Gadolinium enhancement of the lesion on T1-weighted sequences (no specific distribution orpattern of enhancement is required) (figure 1 C E and F)

Other characteristic features that may be detected

Rostral extension of the lesion into the brainstem (figure 1 D and E)

Cord expansionswelling

Decreased signal on T1-weighted sequences corresponding to region of increasedT2-weighted signal (figure 1F)

Spinal cord MRI chronic

Longitudinally extensive cord atrophy (sharply demarcated atrophy extending over $3complete contiguous vertebral segments and caudal to a particular segment of the spinalcord) with or without focal or diffuse T2 signal change involving the atrophic segment (figure 1G and H)

Optic nerve MRI

Unilateral or bilateral increased T2 signal or T1 gadolinium enhancement within optic nerve oroptic chiasm (figure 1 IndashK) relatively long lesions (eg those extending more than half thedistance from orbit to chiasm) and those involving the posterior aspects of the optic nerves orthe chiasm are associated with NMO

Cerebral MRI NMOSD-typical brain lesion patterns (increased signal on T2-weighted MRIsequences unless otherwise noted)

Lesions involving the dorsal medulla (especially the area postrema) either small and localizedoften bilateral or contiguous with an upper cervical spinal cord lesion (figure 2 AndashE)

Periependymal surfaces of the fourth ventricle in the brainstemcerebellum (figure 2 FndashH)

Lesions involving the hypothalamus thalamus or periependymal surfaces of the third ventricle(figure 3 A and B)

Large confluent unilateral or bilateral subcortical or deepwhite matter lesions (figure 3 C and D)

Long (12 of the length of the corpus callosum or greater) diffuse heterogeneous oredematous corpus callosum lesions (figure 3E)

Long corticospinal tract lesions unilateral or bilateral contiguously involving internal capsuleand cerebral peduncle (figure 3F)

Extensive periependymal brain lesions often with gadolinium enhancement (figure 3 GndashI)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions NMOSD 5 neu-romyelitis optica spectrum disorders STIR 5 short tau inversion recovery

Neurology 85 July 14 2015 5

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

(MOG) antibodies and might have different charac-teristics (younger age less frequently female and lesslikely to relapse) from those with AQP4-IgG47ndash49e87

These findings might suggest that some AQP4-IgG-seronegative patients with clinical and neuroimagingfeatures of NMOSD have a different underlying

pathogenesis46 the role of MOG or other antibodiesin disease pathogenesis remains undeterminede88 TheIPND nomenclature is designed to allow incorpora-tion of cases of NMOSD associated with other vali-dated biomarkers (eg NMOSD with a specificautoantibody)

Figure 1 Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder

Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals alongitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments Sagittal T2-weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord(arrows) LETM lesions have a predilection for the central cord as shown by axial T2-weighted (B arrowhead) and T1-weighted MRI with gadolinium (C arrowhead) Cervical LETMmay extend into the medulla a characteristic NMOSD patterndemonstrated in D (arrows sagittal T2-weighted MRI) and E (arrows sagittal T1-weighted MRI with gadolinium) AcuteLETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F arrow) in thisexample a rim of gadolinium enhancement surrounds the hypointense region Chronic sequelae of LETM may include lon-gitudinally extensive segments of spinal cord atrophy as shown by T2-weightedMRI using sagittal (G the 2 arrowheads indi-cate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axialplanes (H arrowhead shows an atrophic spinal cord) Fast spin echo fat-suppressed T2-weighted MRI in the axial (I) and cor-onal (J) planes shows increased signal throughout most the length of the left optic nerve especially its posterior portion(arrows) Axial T1-weightedMRI with gadolinium shows enhancement of the optic chiasm (K arrows) These images are from2 different patients experiencing acute optic neuritis in the setting of NMOSD

6 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Occasionally patients without detectable serumAQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasmaexchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases ofclinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89ndashe91 Routine CSF testing ofAQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confoundingserum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the timeof an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric WorkingGroup members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude (31femalemale ratio compared with up to 91 foradults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acute CSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of aLETMMRI lesion associated with acute myelitis may beless specific for NMOSD Approximately 15 ofchildren with MS may have LETM during relapseLETM can accompany monophasic ADEM andAQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed withADEM according to international consensus criteriawhich require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence ofAQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In onestudy of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstrate an acute lesion (arrows) associated with area postrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)

Neurology 85 July 14 2015 7

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

thorough investigation for potential competing disor-ders the weight of evidence may justify NMOSDdiagnosis despite presence of 1 or more red flagsThe presence of systemic autoimmune diseases andcertain CSF data and pathologic findings (see below)may also influence NMOSD likelihood Regardlessof AQP4-IgG serologic status NMOSD should bediagnosed when criteria are fulfilled and alternativediagnoses for the clinical syndrome have beenexcluded

Neuroimaging and neurophysiologic testing MRI lesionpatterns are a major arbiter of CNS demyelinatingdisease differential diagnosis Several brain opticnerve and spinal cord patterns are characteristic orhighly suggestive of NMOSD (table 3 figures 1ndash3)Detection of a LETM spinal cord lesion (figure 1)

associated with acute myelitis is the most specificneuroimaging characteristic of NMOSD and is veryuncommon in adult MS2 Such lesions typicallyinvolve the central gray matter and may be associatedwith cord swelling central hypointensity on T1-weighted sequences and enhancement followingIV gadolinium administration extension of acervical lesion into the brainstem is characteris-tic43233e35e64ndashe67 In contrast MS cord lesions areusually about 1 vertebral segment long or less occupyperipheral white matter tracts such as the dorsal col-umns and may be asymptomatic (see table 3 forneuroimaging red flags relevant to MS and other dis-eases)34ndash36e68ndashe70 Although the LETM pattern is char-acteristic of NMOSD 7ndash14 of initial and 8 ofsubsequent myelitis attacks in AQP4-IgG-seroposi-tive patients do not meet the LETM definition3237

Therefore NMOSD must be considered in the dif-ferential diagnosis in patients presenting with shortmyelitis lesions The timing of an individual MRIscan must be correlated with clinical status Occasion-ally lesions of less than 3 segments are detected inNMOSD because the MRI was performed early inthe evolution of acute myelitis or in clinical remissionduring which a LETM lesion may fragment into dis-continuous lesions37e71 Some patients with progress-ive MS have coalescent cord lesions that cansuperficially suggest a LETM patterne72 both axialand sagittal plane images should be used to judgelesion extent A LETM MRI pattern may also occurin patients with infectious granulomatous neoplas-tic and paraneoplastic diseases acute disseminatedencephalomyelitis (ADEM) spinal cord infarctionand dural arteriovenous fistulae63

During optic neuritis attacks increased signalwithin the optic nerve may be detected with fat-suppressed T2-weighted orbital MRI sequencestypically with gadolinium enhancement seen on T1-weighted sequences (figure 1) Bilateral optic nerveinvolvement posterior nerve predominance (especiallywith extension into the optic chiasm) or extensivelesions of the optic nerve (more than half of its length)are all suggestive of NMOSD (table 3)e51e73e74

According to the 2006 diagnostic scheme a nor-mal brain MRI or detection of only nonspecific whitematter lesions was a key supportive criterion2 Sixtypercent of patients with NMOSD accumulate asymp-tomatic white matter lesions on longitudinal studyand as many as 16 fulfill Barkhof MS MRI crite-ria333839e75ndashe76 Detection of brain MRI white matterlesions compatible with MS does not exclude thediagnosis of NMOSD but is considered a red flagindicating that additional evidence may be requiredto confidently distinguish NMOSD fromMS in indi-vidual cases3338e64e76e77 Analysis of qualitative fea-tures of lesions assists in distinguishing NMOSD

Table 2 Red flags Findings atypical for NMOSD

Red flags (clinicallaboratory)

1 Clinical features and laboratory findings

Progressive overall clinical course (neurologic deterioration unrelated to attacks consider MS)

Atypical time to attack nadir less than 4 hours (consider cord ischemiainfarction) continualworsening for more than 4 weeks from attack onset (consider sarcoidosis or neoplasm)

Partial transverse myelitis especially when not associated with LETMMRI lesion (consider MS)

Presence of CSF oligoclonal bands (oligoclonal bands occur in 20 of cases of NMO vs80 of MS)

2 Comorbidities associated with neurologic syndromes that mimic NMOSD

Sarcoidosis established or suggestive clinical radiologic or laboratory findings thereof (egmediastinal adenopathy fever and night sweats elevated serum angiotensin convertingenzyme or interleukin-2 receptor levels)

Cancer established or with suggestive clinical radiologic or laboratory findings thereofconsider lymphoma or paraneoplastic disease (eg collapsin response mediator protein-5associated optic neuropathy and myelopathy or anti-Ma-associated diencephalic syndrome)

Chronic infection established or with suggestive clinical radiologic or laboratory findingsthereof (eg HIV syphilis)

Red flags (conventional neuroimaging)

1 Brain

a Imaging features (T2-weighted MRI) suggestive of MS (MS-typical)

Lesions with orientation perpendicular to a lateral ventricular surface (Dawson fingers)

Lesions adjacent to lateral ventricle in the inferior temporal lobe

Juxtacortical lesions involving subcortical U-fibers

Cortical lesions

b Imaging characteristics suggestive of diseases other than MS and NMOSD

Lesions with persistent (3 mo) gadolinium enhancement

2 Spinal cord

Characteristics more suggestive of MS than NMOSD

Lesions 3 complete vertebral segments on sagittal T2-weighted sequences

Lesions located predominantly (70) in the peripheral cord on axial T2-weightedsequences

Diffuse indistinct signal change on T2-weighted sequences (as sometimes seen withlongstanding or progressive MS)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions MS 5 multiplesclerosis NMO 5 neuromyelitis optica NMOSD 5 neuromyelitis optica spectrum disordersThese are some common or key findings that should prompt thorough investigation forcompeting differential diagnoses before making a diagnosis of NMOSD

4 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

from MS First at least 7 of patients haveNMOSD-typical patterns that although not pathog-nomonic for NMOSD are considered exceptional forMS (table 3)39 including lesions of the dorsalmedullaarea postrema (figure 2)223340e36e73e78

and periependymal regions in the brainstem(figure 2)3340e36e73 and diencephalic struc-tures3940e79 or cerebral hemispherese80 (figure 3)or long lesions spanning much of the length of thecorpus callosum3941 or corticospinal tracts(figure 3)3334 Large confluent or tumefactivecerebral lesions may suggest NMOSD but in isola-tion may not be discernable from atypical MSlesions especially in AQP4-IgG-seronegative pa-tients27333942e46e812e83 Second some MRI lesionpatterns considered typical of MS are rarely seen inNMOSD including perpendicular orientation of

periventricular lesions (Dawson fingers) periven-tricular lesions located in the inferior temporal lobeand cortical lesions333843e64 Recent 7T MRI stud-ies revealed differences between NMOSD and MSspecifically regarding cortical lesions (frequent inMS but absent in NMOSD) and white matterlesions (MS plaques are periventricular and tra-versed by a central venule whereas NMOSD lesionsare subcortical and lack a central venule)e84e85

However this technology is not widely availableand further validation is needed

The Panel considered evidence for use of otherimaging modalities such as nonconventional MRItechniques and optical coherence tomography andneurophysiologic tests such as visual evoked poten-tials None of these modalities were included in therevised diagnostic criteria because of concerns regard-ing lack of evidence specificity or reliability

Considerations for AQP4-IgG serologic and other

laboratory testing Technological advances in AQP4-IgG assays have improved diagnostic sensitivitywithout compromising specificity44 The Panelrecommended testing with cell-based serum assays(microscopy or flow cytometry-based detection)whenever possible because they optimize autoantibodydetection (mean sensitivity 767 in a pooled analysis01 false-positive rate in a MS clinic cohort)12ndash144445

However cell-based assays are not yet widely availableIndirect immunofluorescence assays and ELISAs

have lower sensitivity (mean sensitivity 63ndash64 each)and occasionally yield false-positive results (05ndash13for ELISA) often at low titer12ndash144445e86 The Panelstrongly recommended interpretative caution if such as-says are used and when low-titer positive ELISA resultsare detected in individuals who present with NMOSDclinical symptoms less commonly associated with AQP4-IgG (eg presentations other than recurrent optic neu-ritis myelitis with LETM or area postrema syndrome)or in situations where clinical evidence suggests a viablealternate diagnosis Confirmatory testing is recom-mended ideally using 1 or more different AQP4-IgG assay techniques Cell-based assay has the bestcurrent sensitivity and specificity and samples mayneed to be referred to a specialized laboratory

Patients who fulfill NMOSD criteria but do nothave detectable AQP4-IgG despite use of the bestavailable assays or for whom serologic testing isunavailable sometimes represent a diagnostic chal-lenge46 A greater proportion of patients with NMOwho have monophasic disease appear to be AQ-P4-IgG-seronegative compared to those with estab-lished relapsing disease37 A minority of patients withclinical characteristics of NMO almost all AQP4-IgG-seronegative have been reported to have detect-able serum myelin oligodendrocyte glycoprotein

Table 3 Neuroimaging characteristics of NMOSD

Spinal cord MRI acute

LETM lesion associated with acute TM

Increased signal on sagittal T2-weighted (standard T2-weighted proton density or STIRsequences) extending over 3 or more complete vertebral segments (figure 1 A and D)

Central cord predominance (more than 70 of the lesion residing within the central graymatter) (figure 1 AndashD)

Gadolinium enhancement of the lesion on T1-weighted sequences (no specific distribution orpattern of enhancement is required) (figure 1 C E and F)

Other characteristic features that may be detected

Rostral extension of the lesion into the brainstem (figure 1 D and E)

Cord expansionswelling

Decreased signal on T1-weighted sequences corresponding to region of increasedT2-weighted signal (figure 1F)

Spinal cord MRI chronic

Longitudinally extensive cord atrophy (sharply demarcated atrophy extending over $3complete contiguous vertebral segments and caudal to a particular segment of the spinalcord) with or without focal or diffuse T2 signal change involving the atrophic segment (figure 1G and H)

Optic nerve MRI

Unilateral or bilateral increased T2 signal or T1 gadolinium enhancement within optic nerve oroptic chiasm (figure 1 IndashK) relatively long lesions (eg those extending more than half thedistance from orbit to chiasm) and those involving the posterior aspects of the optic nerves orthe chiasm are associated with NMO

Cerebral MRI NMOSD-typical brain lesion patterns (increased signal on T2-weighted MRIsequences unless otherwise noted)

Lesions involving the dorsal medulla (especially the area postrema) either small and localizedoften bilateral or contiguous with an upper cervical spinal cord lesion (figure 2 AndashE)

Periependymal surfaces of the fourth ventricle in the brainstemcerebellum (figure 2 FndashH)

Lesions involving the hypothalamus thalamus or periependymal surfaces of the third ventricle(figure 3 A and B)

Large confluent unilateral or bilateral subcortical or deepwhite matter lesions (figure 3 C and D)

Long (12 of the length of the corpus callosum or greater) diffuse heterogeneous oredematous corpus callosum lesions (figure 3E)

Long corticospinal tract lesions unilateral or bilateral contiguously involving internal capsuleand cerebral peduncle (figure 3F)

Extensive periependymal brain lesions often with gadolinium enhancement (figure 3 GndashI)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions NMOSD 5 neu-romyelitis optica spectrum disorders STIR 5 short tau inversion recovery

Neurology 85 July 14 2015 5

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

(MOG) antibodies and might have different charac-teristics (younger age less frequently female and lesslikely to relapse) from those with AQP4-IgG47ndash49e87

These findings might suggest that some AQP4-IgG-seronegative patients with clinical and neuroimagingfeatures of NMOSD have a different underlying

pathogenesis46 the role of MOG or other antibodiesin disease pathogenesis remains undeterminede88 TheIPND nomenclature is designed to allow incorpora-tion of cases of NMOSD associated with other vali-dated biomarkers (eg NMOSD with a specificautoantibody)

Figure 1 Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder

Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals alongitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments Sagittal T2-weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord(arrows) LETM lesions have a predilection for the central cord as shown by axial T2-weighted (B arrowhead) and T1-weighted MRI with gadolinium (C arrowhead) Cervical LETMmay extend into the medulla a characteristic NMOSD patterndemonstrated in D (arrows sagittal T2-weighted MRI) and E (arrows sagittal T1-weighted MRI with gadolinium) AcuteLETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F arrow) in thisexample a rim of gadolinium enhancement surrounds the hypointense region Chronic sequelae of LETM may include lon-gitudinally extensive segments of spinal cord atrophy as shown by T2-weightedMRI using sagittal (G the 2 arrowheads indi-cate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axialplanes (H arrowhead shows an atrophic spinal cord) Fast spin echo fat-suppressed T2-weighted MRI in the axial (I) and cor-onal (J) planes shows increased signal throughout most the length of the left optic nerve especially its posterior portion(arrows) Axial T1-weightedMRI with gadolinium shows enhancement of the optic chiasm (K arrows) These images are from2 different patients experiencing acute optic neuritis in the setting of NMOSD

6 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Occasionally patients without detectable serumAQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasmaexchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases ofclinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89ndashe91 Routine CSF testing ofAQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confoundingserum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the timeof an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric WorkingGroup members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude (31femalemale ratio compared with up to 91 foradults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acute CSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of aLETMMRI lesion associated with acute myelitis may beless specific for NMOSD Approximately 15 ofchildren with MS may have LETM during relapseLETM can accompany monophasic ADEM andAQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed withADEM according to international consensus criteriawhich require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence ofAQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In onestudy of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstrate an acute lesion (arrows) associated with area postrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)

Neurology 85 July 14 2015 7

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

from MS First at least 7 of patients haveNMOSD-typical patterns that although not pathog-nomonic for NMOSD are considered exceptional forMS (table 3)39 including lesions of the dorsalmedullaarea postrema (figure 2)223340e36e73e78

and periependymal regions in the brainstem(figure 2)3340e36e73 and diencephalic struc-tures3940e79 or cerebral hemispherese80 (figure 3)or long lesions spanning much of the length of thecorpus callosum3941 or corticospinal tracts(figure 3)3334 Large confluent or tumefactivecerebral lesions may suggest NMOSD but in isola-tion may not be discernable from atypical MSlesions especially in AQP4-IgG-seronegative pa-tients27333942e46e812e83 Second some MRI lesionpatterns considered typical of MS are rarely seen inNMOSD including perpendicular orientation of

periventricular lesions (Dawson fingers) periven-tricular lesions located in the inferior temporal lobeand cortical lesions333843e64 Recent 7T MRI stud-ies revealed differences between NMOSD and MSspecifically regarding cortical lesions (frequent inMS but absent in NMOSD) and white matterlesions (MS plaques are periventricular and tra-versed by a central venule whereas NMOSD lesionsare subcortical and lack a central venule)e84e85

However this technology is not widely availableand further validation is needed

The Panel considered evidence for use of otherimaging modalities such as nonconventional MRItechniques and optical coherence tomography andneurophysiologic tests such as visual evoked poten-tials None of these modalities were included in therevised diagnostic criteria because of concerns regard-ing lack of evidence specificity or reliability

Considerations for AQP4-IgG serologic and other

laboratory testing Technological advances in AQP4-IgG assays have improved diagnostic sensitivitywithout compromising specificity44 The Panelrecommended testing with cell-based serum assays(microscopy or flow cytometry-based detection)whenever possible because they optimize autoantibodydetection (mean sensitivity 767 in a pooled analysis01 false-positive rate in a MS clinic cohort)12ndash144445

However cell-based assays are not yet widely availableIndirect immunofluorescence assays and ELISAs

have lower sensitivity (mean sensitivity 63ndash64 each)and occasionally yield false-positive results (05ndash13for ELISA) often at low titer12ndash144445e86 The Panelstrongly recommended interpretative caution if such as-says are used and when low-titer positive ELISA resultsare detected in individuals who present with NMOSDclinical symptoms less commonly associated with AQP4-IgG (eg presentations other than recurrent optic neu-ritis myelitis with LETM or area postrema syndrome)or in situations where clinical evidence suggests a viablealternate diagnosis Confirmatory testing is recom-mended ideally using 1 or more different AQP4-IgG assay techniques Cell-based assay has the bestcurrent sensitivity and specificity and samples mayneed to be referred to a specialized laboratory

Patients who fulfill NMOSD criteria but do nothave detectable AQP4-IgG despite use of the bestavailable assays or for whom serologic testing isunavailable sometimes represent a diagnostic chal-lenge46 A greater proportion of patients with NMOwho have monophasic disease appear to be AQ-P4-IgG-seronegative compared to those with estab-lished relapsing disease37 A minority of patients withclinical characteristics of NMO almost all AQP4-IgG-seronegative have been reported to have detect-able serum myelin oligodendrocyte glycoprotein

Table 3 Neuroimaging characteristics of NMOSD

Spinal cord MRI acute

LETM lesion associated with acute TM

Increased signal on sagittal T2-weighted (standard T2-weighted proton density or STIRsequences) extending over 3 or more complete vertebral segments (figure 1 A and D)

Central cord predominance (more than 70 of the lesion residing within the central graymatter) (figure 1 AndashD)

Gadolinium enhancement of the lesion on T1-weighted sequences (no specific distribution orpattern of enhancement is required) (figure 1 C E and F)

Other characteristic features that may be detected

Rostral extension of the lesion into the brainstem (figure 1 D and E)

Cord expansionswelling

Decreased signal on T1-weighted sequences corresponding to region of increasedT2-weighted signal (figure 1F)

Spinal cord MRI chronic

Longitudinally extensive cord atrophy (sharply demarcated atrophy extending over $3complete contiguous vertebral segments and caudal to a particular segment of the spinalcord) with or without focal or diffuse T2 signal change involving the atrophic segment (figure 1G and H)

Optic nerve MRI

Unilateral or bilateral increased T2 signal or T1 gadolinium enhancement within optic nerve oroptic chiasm (figure 1 IndashK) relatively long lesions (eg those extending more than half thedistance from orbit to chiasm) and those involving the posterior aspects of the optic nerves orthe chiasm are associated with NMO

Cerebral MRI NMOSD-typical brain lesion patterns (increased signal on T2-weighted MRIsequences unless otherwise noted)

Lesions involving the dorsal medulla (especially the area postrema) either small and localizedoften bilateral or contiguous with an upper cervical spinal cord lesion (figure 2 AndashE)

Periependymal surfaces of the fourth ventricle in the brainstemcerebellum (figure 2 FndashH)

Lesions involving the hypothalamus thalamus or periependymal surfaces of the third ventricle(figure 3 A and B)

Large confluent unilateral or bilateral subcortical or deepwhite matter lesions (figure 3 C and D)

Long (12 of the length of the corpus callosum or greater) diffuse heterogeneous oredematous corpus callosum lesions (figure 3E)

Long corticospinal tract lesions unilateral or bilateral contiguously involving internal capsuleand cerebral peduncle (figure 3F)

Extensive periependymal brain lesions often with gadolinium enhancement (figure 3 GndashI)

Abbreviations LETM 5 longitudinally extensive transverse myelitis lesions NMOSD 5 neu-romyelitis optica spectrum disorders STIR 5 short tau inversion recovery

Neurology 85 July 14 2015 5

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

(MOG) antibodies and might have different charac-teristics (younger age less frequently female and lesslikely to relapse) from those with AQP4-IgG47ndash49e87

These findings might suggest that some AQP4-IgG-seronegative patients with clinical and neuroimagingfeatures of NMOSD have a different underlying

pathogenesis46 the role of MOG or other antibodiesin disease pathogenesis remains undeterminede88 TheIPND nomenclature is designed to allow incorpora-tion of cases of NMOSD associated with other vali-dated biomarkers (eg NMOSD with a specificautoantibody)

Figure 1 Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder

Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals alongitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments Sagittal T2-weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord(arrows) LETM lesions have a predilection for the central cord as shown by axial T2-weighted (B arrowhead) and T1-weighted MRI with gadolinium (C arrowhead) Cervical LETMmay extend into the medulla a characteristic NMOSD patterndemonstrated in D (arrows sagittal T2-weighted MRI) and E (arrows sagittal T1-weighted MRI with gadolinium) AcuteLETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F arrow) in thisexample a rim of gadolinium enhancement surrounds the hypointense region Chronic sequelae of LETM may include lon-gitudinally extensive segments of spinal cord atrophy as shown by T2-weightedMRI using sagittal (G the 2 arrowheads indi-cate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axialplanes (H arrowhead shows an atrophic spinal cord) Fast spin echo fat-suppressed T2-weighted MRI in the axial (I) and cor-onal (J) planes shows increased signal throughout most the length of the left optic nerve especially its posterior portion(arrows) Axial T1-weightedMRI with gadolinium shows enhancement of the optic chiasm (K arrows) These images are from2 different patients experiencing acute optic neuritis in the setting of NMOSD

6 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Occasionally patients without detectable serumAQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasmaexchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases ofclinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89ndashe91 Routine CSF testing ofAQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confoundingserum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the timeof an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric WorkingGroup members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude (31femalemale ratio compared with up to 91 foradults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acute CSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of aLETMMRI lesion associated with acute myelitis may beless specific for NMOSD Approximately 15 ofchildren with MS may have LETM during relapseLETM can accompany monophasic ADEM andAQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed withADEM according to international consensus criteriawhich require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence ofAQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In onestudy of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstrate an acute lesion (arrows) associated with area postrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)

Neurology 85 July 14 2015 7

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

(MOG) antibodies and might have different charac-teristics (younger age less frequently female and lesslikely to relapse) from those with AQP4-IgG47ndash49e87

These findings might suggest that some AQP4-IgG-seronegative patients with clinical and neuroimagingfeatures of NMOSD have a different underlying

pathogenesis46 the role of MOG or other antibodiesin disease pathogenesis remains undeterminede88 TheIPND nomenclature is designed to allow incorpora-tion of cases of NMOSD associated with other vali-dated biomarkers (eg NMOSD with a specificautoantibody)

Figure 1 Spinal cord and optic nerve MRI patterns in neuromyelitis optica spectrum disorder

Spinal cord imaging in the context of acute myelitis in neuromyelitis optica spectrum disorders (NMOSD) usually reveals alongitudinally extensive transverse myelitis (LETM) lesion extending over 3 or more vertebral segments Sagittal T2-weighted MRI of the thoracic spinal cord (A) demonstrates a typical LETM lesion involving most of the thoracic spinal cord(arrows) LETM lesions have a predilection for the central cord as shown by axial T2-weighted (B arrowhead) and T1-weighted MRI with gadolinium (C arrowhead) Cervical LETMmay extend into the medulla a characteristic NMOSD patterndemonstrated in D (arrows sagittal T2-weighted MRI) and E (arrows sagittal T1-weighted MRI with gadolinium) AcuteLETM lesions can be associated with intralesional hypointensity as shown by sagittal T1-weighted MRI (F arrow) in thisexample a rim of gadolinium enhancement surrounds the hypointense region Chronic sequelae of LETM may include lon-gitudinally extensive segments of spinal cord atrophy as shown by T2-weightedMRI using sagittal (G the 2 arrowheads indi-cate the atrophic segment and the top arrow indicates the normal diameter of unaffected cervical spinal cord) and axialplanes (H arrowhead shows an atrophic spinal cord) Fast spin echo fat-suppressed T2-weighted MRI in the axial (I) and cor-onal (J) planes shows increased signal throughout most the length of the left optic nerve especially its posterior portion(arrows) Axial T1-weightedMRI with gadolinium shows enhancement of the optic chiasm (K arrows) These images are from2 different patients experiencing acute optic neuritis in the setting of NMOSD

6 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Occasionally patients without detectable serumAQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasmaexchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases ofclinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89ndashe91 Routine CSF testing ofAQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confoundingserum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the timeof an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric WorkingGroup members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude (31femalemale ratio compared with up to 91 foradults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acute CSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of aLETMMRI lesion associated with acute myelitis may beless specific for NMOSD Approximately 15 ofchildren with MS may have LETM during relapseLETM can accompany monophasic ADEM andAQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed withADEM according to international consensus criteriawhich require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence ofAQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In onestudy of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstrate an acute lesion (arrows) associated with area postrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)

Neurology 85 July 14 2015 7

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Occasionally patients without detectable serumAQP4-IgG are later found to be seropositive Theremay be technical explanations in some cases but anti-body levels also increase with clinical relapses anddecrease with immunosuppressive therapy in somepatients50 Therefore retesting should be consideredbefore B-cell or antibody-targeted therapies (plasmaexchange immunosuppressive drugs) are institutedand in seronegative patients who relapse51 Cases ofclinical NMO in which AQP4-IgG was detected inCSF but not serum have been reported but thisappears to be rare52e89ndashe91 Routine CSF testing ofAQP4-IgG-seronegative patients is not recommen-ded but might be considered in selected seronegativecases especially those with additional confoundingserum autoantibodies that may lead to uninterpret-able or false-positive assay results

The Panel considered absence of CSF oligoclonalbands as supportive evidence for NMOSD (althoughthey are sometimes transiently detectable at the timeof an attack) and presence of bands a red flag but sen-sitivity and specificity are modest453 CSF pleocytosis50 leukocytesmL (incidence approximately 35 inNMOSD) or the presence of neutrophils or eosino-phils (either 5mL incidence 44 and 10respectively in attack-associated samples) are partic-ularly useful in distinguishing NMOSD from MS453

CSF glial fibrillary acidic protein also shows promiseas a diagnostic and prognostic biomarker but is ele-vated only for days to weeks following an attacke92e93

Pediatric NMOSD criteria The Pediatric WorkingGroup members noted that most clinical neuroimag-ing and laboratory characteristics of pediatric NMOSDare similar to those of adult-onset disease The femalepreponderance may be of lower magnitude (31femalemale ratio compared with up to 91 foradults)54e94 a greater proportion of children may havemonophasic disease5455e95 and acute CSF abnormalitiesin pediatric MS may mimic those ordinarily consideredsuggestive of NMOSD54ndash56 The Working Groupidentified caveats to application of the adult NMOSDcriteria in children noting especially that detection of aLETMMRI lesion associated with acute myelitis may beless specific for NMOSD Approximately 15 ofchildren with MS may have LETM during relapseLETM can accompany monophasic ADEM andAQP4-IgG is rarely detected in children withmonophasic LETM55 In children diagnosed withADEM according to international consensus criteriawhich require a polyfocal demyelinating clinicalpresentation with encephalopathy57 the presence ofAQP4-IgG favors a diagnosis of NMOSD althoughprospective validation studies are required todetermine risk of recurrent NMOSD events In onestudy of AQP4-IgG-seropositive children 45

Figure 2 Dorsal medulla area postrema and other brainstem lesions inneuromyelitis optica spectrum disorder

Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI shows a lesion in thedorsal medulla (A arrow) Sagittal T2-weighted (B) and T1-weighted MRI with gadolinium (C)each demonstrate an acute lesion (arrows) associated with area postrema clinical syndromeAxial T2-weighted FLAIR (D arrows) and T1-weighted MRI with gadolinium (E arrowheads)show dorsal medulla involvement in a patient with acute area postrema clinical syndromeAxial T2-weighted FLAIR MRI shows periependymal lesions involving the pons (F arrows)and dorsal midbrain (G arrow) Sagittal T2-weighted FLAIR MRI shows increased signal sur-rounding the fourth ventricle (H arrows)

Neurology 85 July 14 2015 7

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Figure 3 Diencephalic and cerebral lesions in neuromyelitis optica spectrum disorder

A variety of brain lesion patterns are associated with neuromyelitis optica spectrum disorder Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI from 2 patients demonstrates lesions involving the right thalamus (A arrow)and the hypothalamus (B arrows) Axial T2-weighted FLAIR MRI shows an extensive subcortical white matter lesion(C arrow) that enhances after gadolinium administration on T1-weighted sequences (D arrow) Chronic longitudinallyextensive and linear corpus callosum lesions are depicted on sagittal T2-weighted FLAIR MRI (E arrows) CoronalT2-weighted FLAIR MRI shows longitudinal involvement of the corticospinal tract extending to the cerebral peduncleand pons (F arrows) Acute periependymal cerebral lesions from one patient are depicted using sagittal (G arrow) andaxial (H arrows) T2-weighted FLAIR MRI and axial T1-weighted MRI with gadolinium (I arrows)

8 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

experienced recurrent cerebral manifestations includingencephalopathy56 Aside from these caveats thecurrently proposed diagnostic criteria for NMOSDare appropriate for pediatric patients Longitudinalobservation of the clinical course for dissemination intime and retesting the AQP4-IgG status of somechildren especially AQP4-IgG-seronegative individualspresenting with an ADEM-like event that includesoptic neuritis and LETM may be required to achieveconfident diagnosis

Monophasic NMOSD The occurrence of a second clin-ical attack which defines a relapsing disorder wasoften considered sufficient to revise the diagnosis toMS in otherwise typical NMO cases Approximately5ndash10 of contemporary cases are described as mon-ophasic although the optimal definition for monopha-sic NMOSD remains elusive It is unclear whether theoccurrence of bilateral optic neuritis and myelitis atinitial presentation are helpful or essential to distin-guish such cases from relapsing NMOSD Similarlythe interval between index clinical events that is com-patible with monophasic NMO has not been consis-tently defined or adequately examined as a predictor offuture clinical course Although early risk of relapse ishigh in AQP4-IgG-seropositive cases (eg about 60within 1 year after LETM)20 cases have beendocumented in whom more than a decade elapsedbetween the index events and relapsee34

Several studies show a pattern of apparently mon-ophasic NMO being associated with a more equitablesex distribution relatively younger age at diseaseonset tendency to present with simultaneous myelitisand bilateral optic neuritis (rather than unilateraloptic nerve involvement) lower frequency of otherautoimmune diseases and lower prevalence of serumAQP4-IgG compared to relapsing NMO437e96 Afraction of these patients may have other serum anti-bodies such as MOG-IgG47

The Panel concluded that monophasic NMOSDis a recognizable clinical entity but that criteria thataccurately predict long-term adherence to a mono-phasic course cannot currently be defined An intervallonger than 4 weeks between index attacks indicatesrelapsing disease The Panel also recommended thatat least 5 years (preferably longer) of relapse-free clin-ical observation after the index events be requiredbefore a monophasic course is assumed with anydegree of confidence Patients who are AQP4-IgG-seropositive should be assumed to be at risk forrelapse indefinitely and preventive treatment shouldbe considered even in the setting of a prolonged clin-ical remission

Systemic autoimmunity associated with NMOSD Basedon evidence from several observational studies the

Panel concluded that clinical diagnoses of SLE SSor myasthenia gravis may coexist with NMOSD clin-ical syndromes in AQP4-IgG-seropositive patientsand in fact their presence strengthens confidenceabout a NMOSD diagnosis58e97e98 The underlyingcause of CNS symptoms and signs is more likely to beco-associated NMOSD than a direct complication(eg associated vasculitis) of SLE or SS In apatient suspected of having NMOSD the presenceof clinical myasthenia gravis or detectable serumacetylcholine receptor antibodies is consideredsupportive of NMOSD diagnosise99ndashe101

Pathology Pathologic findings in biopsy or autopsy tissueobtained from patients with AQP4-IgG-seropositiveNMOSD demonstrate loss of AQP4 immunoreactivityand evidence of perivascular complement activation inactively demyelinating lesionse20e21 Additionallyfindings supportive of astrocytopathy such as truncatedastrocyte processes or cell loss may be detected byimmunostaining for glial fibrillary acidic protein59e20

These findings in active lesions distinguish AQP4-IgG-positive NMOSD from MS data from seronegativeindividuals are not yet available59 Necrosis and lesioninfiltration with neutrophils and eosinophils aresupportive characteristicse102 but may not be presentSpinal cord lesions may differ from supraspinal lesionsin this respecte103 Serum AQP4-IgG testing usuallyobviates the need for biopsy in severe myelitis andleukoencephalopathy syndromese19e104e105 Aquaporin-4immunostaining is not a routine procedure in CNSbiopsy processing and is available only in select centersThe Panel does not recommend CNS biopsy butrecognizes that in atypical cases expert pathologicreview of biopsy tissue of brain or spinal cord mighthelp establish NMOSD and exclude competingdiagnoses60

Opticospinal MS The term opticospinal MS wasintroduced in Japan to refer to a pattern of MS thatis relatively more common in Asian countries11e106

It was defined by recurrent optic neuritis and myelitisattacks with no brain involvement although someinvestigators allow occurrence of certain brainstemsyndromese107 The description of opticospinal MSrepresented an important milestone because it recog-nized that there was a relapsing illness distinct fromconventional MS that selectively targeted the opticnerve and spinal cord at a time when relapses weredeemed to be incompatible with a diagnosis of NMOin both Western countries and Japan

Contemporary NMO criteria that include MRIcriteria for length of spinal cord lesions and detectionof AQP4-IgG are more specific than historical optico-spinal MS criteria Clinicians and investigators inmany Asian countries now use the term NMO rather

Neurology 85 July 14 2015 9

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

than opticospinal MS in research and practice Whensimilarly defined in Asia NMO clinical syndromesand brain MRI lesions are both analogous to thoseencountered in Western countries22233339e108 ThePanel concluded that opticospinal MS is a historicallyimportant but now superseded term especially inlight of the need to distinguish NMO from MS toguide treatment decisions15ndash18e24ndashe26

DISCUSSION The high specificity of AQP4-IgG hasbeen exploited to expand the clinical andneuroimaging spectrum of NMO The consensusdefinition of NMOSD unifies traditional NMO andmodern NMOSD definitions It allows for NMOSDdiagnosis in AQP4-IgG-seropositive patients withinvolvement of almost any CNS region as well as inthose with restricted involvement of a single region(eg recurrent transverse myelitis) For the first timecriteria allow for NMOSD diagnosis in patients whohave not experienced clinical involvement of eitheroptic nerves or spinal cord The Panel reached theseconclusions for the following reasons (1) there areno established biological differences between patientsdiagnosed with NMO compared with NMOSD(using 2006 and 2007 definitions respectively)in AQP4-IgG-seropositive patients (2) limitedNMOSD syndromes affecting CNS regions otherthan the optic nerve and spinal cord often heraldsubsequent clinical attacks consistent withconventional NMO in AQP4-IgG-positive patientsand (3) current immunotherapeutic strategies are thesame for relapsing NMO and NMOSD regardlessof AQP4-IgG serologic status To enhance criteriaspecificity AQP4-IgG-seronegative patients musthave experienced at least one of the 3 most commonclinical characteristics of seropositive NMOSDnamely optic neuritis transverse myelitis withLETM or area postrema syndrome with associatedMRI lesions These criteria are appropriate for adultsand with minor caveats children Finally the Panelcautions against making a diagnosis of monophasicNMOSD especially in AQP4-IgG-seropositivepatients and recommends abandonment of the termopticospinal MS for cases that meet NMOSD criteria

The IPND criteria are expected to facilitate earlierand more accurate diagnosis by identifying individu-als who would have been diagnosed with idiopathictransverse myelitis idiopathic optic neuritis or atyp-ical MS This will be particularly true for AQP4-IgG-seropositive patients experiencing their first CNSattack (such patients will now meet NMOSD crite-ria) leading to a specific treatment path with immu-notherapy for attack prevention The criteria shouldalso provide greater specificity for distinguishing bothAQP4-IgG-seropositive and AQP4-IgG-seronegativeNMOSD from MS Early-stage diagnostic specificity

is critical because recent observational data suggestthat interferon-b natalizumab and fingolimod mayworsen NMO15ndash18e24ndashe26

The IPND criteria are expected to facilitate morecomprehensive and comparable epidemiologic studiesby supplying a uniform case definition and a glossaryof defined terms For AQP4-IgG-seronegative casesdiagnosed using the new NMOSD scheme detailedclinical neuroimaging and laboratory descriptionsof patients will be necessary to better characterize thisheterogeneous population This is particularly impor-tant to identify the frequencies with which serocon-version to AQP4-IgG positivity or detection ofother autoantibodies of interest occur and to identifyphenocopies later diagnosed as other conditions

Many observations used to construct the IPNDcriteria were derived from relatively small case seriesThe Panel recommends several large-scale prospectivevalidation and assessment strategies These includebut are not limited to studies that (1) systematicallyapply the criteria to consecutive cases of NMOSDwith and without AQP4-IgG to determine whetherthe diagnosis is confirmed or another alternative diag-nosis emerges in follow-up (2) validate the associa-tion and potential immunopathogenesis of serumMOG-IgG (and other future potential laboratoryand neuroimaging biomarkers) with clinically diag-nosed NMOSD (3) identify clinical settings in whichfalse-negative and false-positive AQP4-IgG results aremore likely (4) validate different definitions predic-tive of clinical course (monophasic vs relapsing) anddetermine the distinguishing characteristics of thesesubtypes and (5) further examine the immunopa-thology of NMOSD to determine whether there isunrecognized heterogeneity to inform its classifica-tion especially of AQP4-IgG-seronegative casesThese and other approaches to criteria validation willallow future refinement of NMOSD diagnostic crite-ria commensurate with the next era of scientificadvances

AUTHOR CONTRIBUTIONSD Wingerchuk participated in study concept and design obtaining

funding acquisition and analysis of data drafting and revising the man-

uscript and coordinating the study B Banwell participated in the acqui-

sition and analysis of data and writing and critical review of the

manuscript for important intellectual content J Bennett participated

in the acquisition and analysis of data and writing and critical review

of the manuscript for important intellectual content P Cabre partici-

pated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content W Carroll

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content T Chitnis

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content J de Seze

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content K Fujihara

participated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content B Greenberg

participated in the acquisition and analysis of data and writing and critical

10 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

REFERENCES1 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

review of the manuscript for important intellectual content A Jacob par-

ticipated in the acquisition and analysis of data and writing and critical

review of the manuscript for important intellectual content S Jarius

participated in the acquisition and analysis of data and writing and

critical review of the manuscript for important intellectual content M

Lana-Peixoto participated in the acquisition and analysis of data and writ-

ing and critical review of the manuscript for important intellectual con-

tent M Levy participated in the acquisition and analysis of data and

writing and critical review of the manuscript for important intellectual

content J Simon participated in the acquisition and analysis of data

and writing and critical review of the manuscript for important intellec-

tual content S Tenembaum participated in the acquisition and analysis

of data and writing and critical review of the manuscript for important

intellectual content A Traboulsee participated in the acquisition and

analysis of data and writing and critical review of the manuscript for

important intellectual content P Waters participated in the acquisition

and analysis of data and writing and critical review of the manuscript

for important intellectual content K Wellik participated in the acquisi-

tion and analysis of data and writing and critical review of the manuscript

for important intellectual content B Weinshenker participated in study

concept and design obtaining funding acquisition and analysis of data

drafting and revising the manuscript and coordinating the study

ACKNOWLEDGMENTThe authors thank the Guthy-Jackson Charitable Foundation for organi-

zational and financial support Dr Katja van Herle Dr Valerie Pasquetto

Dr Michael Yeaman and Jacinta Behne for assistance Prof Jun-ichi Kira

Kyushu University for initial IPND discussions and Amy Clayton and

Katrina Rivera for administrative assistance and Cory Poetzl and Bonnie

Schimek for media support services (Mayo Clinic Scottsdale AZ)

STUDY FUNDINGThe International Panel for Neuromyelitis Optica Diagnosis was sup-

ported by the Guthy Jackson Charitable Foundation

DISCLOSURED Wingerchuk has received research support from Alexion TerumoBCT

and the Guthy Jackson Charitable Foundation receives financial compensa-

tion for participation on a relapse adjudication panel for MedImmune has

served as a consultant to Alexion MedImmune and Chugai Pharmaceuti-

cals and has served as co-Editor-in-Chief of The Neurologist B Banwell

serves as an advisor on clinical trial design for Biogen Idec Sanofi Teva

Neuroscience and Novartis Dr Banwell provides consultant services for

Novartis Dr Banwell is an Editor-in-Chief for Multiple Sclerosis and Related

Disorders J Bennett serves as a consultant for Novartis Pharmaceuticals

Alnaylam Pharmaceuticals MedImmune Chugai Pharmaceuticals EMD

Serono Abbott Pharmaceuticals Genentech Genzyme and Questcor Phar-

maceuticals receives license royalties for a patent re Compositions and

Methods for the Treatment of Neuromyelitis Optica and serves on

the editorial boards of the Multiple Sclerosis Journal and Journal of Neuro-

ophthalmology P Cabre reports no disclosures relevant to the manuscript

W Carroll has received travel assistance andor honoraria from and provided

advice to Bayer Schering Pharma Biogen Idec Novartis Genzyme Sanofi-

Aventis CSL and Merck-Serono T Chitnis has performed consulting for

Biogen Idec and Novartis Has received support for research activities from

Novartis and Merck-Serono J de Seze has performed consulting for Alexion

Chugai and Novartis K Fujihara serves on scientific advisory boards for

Bayer Schering Pharma Biogen Idec Mitsubishi Tanabe Pharma Corpora-

tion Novartis Pharma Chugai Pharmaceutical Ono Pharmaceutical Nihon

Pharmaceutical Merck Serono Alexion Pharmaceuticals Medimmune and

Medical Review has received funding for travel and speaker honoraria from

Bayer Schering Pharma Biogen Idec Eisai Inc Mitsubishi Tanabe Pharma

Corporation Novartis Pharma Astellas Pharma Inc Takeda Pharmaceutical

Company Limited Asahi Kasei Medical Co Daiichi Sankyo and Nihon

Pharmaceutical serves as an editorial board member of Clinical and Exper-

imental Neuroimmunology (2009ndashpresent) and an advisory board member of

Sri Lanka Journal of Neurology has received research support from Bayer

Schering Pharma Biogen Idec Japan Asahi Kasei Medical The Chemo-

Sero-Therapeutic Research Institute Teva Pharmaceutical Mitsubishi Ta-

nabe Pharma Teijin Pharma Chugai Pharmaceutical Ono Pharmaceutical

Nihon Pharmaceutical and Genzyme Japan and is funded as the secondary

investigator (22229008 2010ndash2015) by the Grants-in-Aid for Scientific

Research from the Ministry of Education Science and Technology of Japan

and as the secondary investigator by the Grants-in-Aid for Scientific Research

from the Ministry of Health Welfare and Labor of Japan (2010ndashpresent) B

Greenberg has received compensation for consulting services from Chugai

GSK Biogen Novartis DioGenix and Amplimmune and receives research

support from the Guthy Jackson Charitable Foundation A Jacob has

received honoraria for clinical trial advisory boards and speakerrsquos fees from

Chugai Alexion and Biogen S Jarius has been supported by a research

grant from the European Committee for Treatment and Research in Mul-

tiple Sclerosis (ECTRIMS) S Jariusrsquo department has been supported by

research grants from Merck Serono and from the Dietmar Hopp Foundation

and by a travel grant from the Guthy-Jackson Charitable Foundation M

Lana-Peixoto has served on a scientific advisory board for Novartis M Levy

is supported by research funds from the NIH Guthy Jackson Charitable

Foundation Viropharma Acorda ApoPharma and Sanofi He has received

advisory compensation from GlaxoSmithKline and Asterias J Simon has

served as a consultant and received research support from Biogen Idec S

Tenembaum has received honoraria for speaking from Biogen Idec and

Merck Serono and for participation in an advisory group for Biogen Idec

Merck Serono and Teva Pharmaceutical Ind A Traboulsee has received

grant funding from the MS Society of Canada the Canadian Institute for

Health Research the Lotte and John Hecht Foundation the Vancouver

Hospital Foundation Bayer Roche and Biogen He has served on the data

safety monitoring board for Merck Serono and a clinical trial steering com-

mittee for Roche He has received honoraria or travel grants from Biogen

Teva Canada Innovation Roche MerckEMD Serono and Chugai Phar-

maceuticals P Waters is a named inventor on patents for antibody assays

(no 20120114666 application no 13108550) and has received royalties

He has received a speaker honorarium from Biogen Idec and Euroimmun

AG K Wellik reports no disclosures relevant to the manuscript B Wein-

shenker has received a research grant from the Guthy Jackson Foundation

He receives royalties from RSR Ltd for a technology license related to a test

for aquaporin-4 autoantibodies for diagnosis of neuromyelitis optica He

receives financial compensation for service on data safety monitoring com-

mittees for Novartis Biogen Idec and Mitsubishi pharmaceutical companies

for MS clinical trials and on a relapse adjudication panel for MedImmune

Pharmaceuticals for NMO clinical trials He served as a consultant for

GlaxoSmithKline Elan Ono Chugai Chord and Alexion pharmaceutical

companies and for Asahi Kasei Medical Company all for activities related to

design of clinical trials for neuromyelitis optica He serves on editorial boards

for Neurologyreg the Canadian Journal of Neurological Sciences and the Turkish

Journal of Neurology Go to Neurologyorg for full disclosures

Received September 30 2014 Accepted in final form January 28 2015

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Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

2 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

3 Jarius S Wildemann B The history of neuromyelitis op-

tica J Neuroinflammation 2013108

4 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

5 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

6 Lennon VA Kryzer TJ Pittock SJ Verkman AS

Hinson SR IgG marker of optic-spinal multiple sclerosis

binds to the aquaporin-4 water channel J Exp Med 2005

202473ndash477

7 Papadopoulos MC Verkman AS Aquaporin 4 and neu-

romyelitis optica Lancet Neurol 201211535ndash544

Neurology 85 July 14 2015 11

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

8 Asgari N Lillevang ST Skejoe HP Falah M Stenager E

Kyvik KO A population-based study of neuromyelitis

optica in Caucasians Neurology 2011761589ndash1595

9 Cabre P Migration and multiple sclerosis the French

West Indies experience J Neurol Sci 2007262117ndash121

10 Cabrera-Gomez JA Kurtzke JF Gonzalez-Quevedo A

Lara-Rodriguez R An epidemiological study of neuromy-

elitis optica in Cuba J Neurol 200925635ndash44

11 Kuroiwa Y Shibasaki H Epidemiologic and clinical studies

of multiple sclerosis in Japan Neurology 1976268ndash10

12 Jarius S Wildemann B Aquaporin-4 antibodies (NMO-

IgG) as a serological marker of neuromyelitis optica a crit-

ical review of the literature Brain Pathol 201323661ndash683

13 Waters PJ McKeon A Leite MI et al Serologic diagnosis

of NMO a multicenter comparison of aquaporin-4-IgG

assays Neurology 201278665ndash671

14 Sato DK Nakashima I Takahashi T et al Aquaporin-4

antibody-positive cases beyond current diagnostic criteria for

NMO spectrum disorders Neurology 2013802210ndash2216

15 Kimbrough DJ Fujihara K Jacob A et al Treatment of

neuromyelitis optica review and recommendations Mult

Scler Relat Disord 20121180ndash187

16 Kleiter I Hellwig K Berthele A et al Failure of natalizu-

mab to prevent relapses in neuromyelitis optica Arch

Neurol 201269239ndash245

17 Min JH Kim BJ Lee KH Development of extensive

brain lesions following fingolimod (FTY720) treatment

in a patient with neuromyelitis optica spectrum disorder

Mult Scler 201218113ndash115

18 Papeix C Vidal JS de Seze J et al Immunosuppressive

therapy is more effective than interferon in neuromyelitis

optica Mult Scler 200713256ndash259

19 Matiello M Lennon VA Jacob A et al NMO-IgG pre-

dicts the outcome of recurrent optic neuritis Neurology

2008702197ndash2200

20 Weinshenker BG Wingerchuk DM Vukusic S et al

Neuromyelitis optica IgG predicts relapse after longitudi-

nally extensive transverse myelitis Ann Neurol 200659

566ndash569

21 Nagaishi A Takagi M Umemura A et al Clinical features

of neuromyelitis optica in a large Japanese cohort com-

parison between phenotypes J Neurol Neurosurg Psychi-

atry 2011821360ndash1364

22 Misu T Fujihara K Nakashima I Sato S Itoyama Y

Intractable hiccup and nausea with periaqueductal lesions

in neuromyelitis optica Neurology 2005651479ndash1482

23 Apiwattanakul M Popescu BF Matiello M et al Intrac-

table vomiting as the initial presentation of neuromyelitis

optica Ann Neurol 201068757ndash761

24 Kremer L Mealy M Jacob A et al Brainstem manifes-

tations in neuromyelitis optica a multicenter study of 258

patients Mult Scler 201420843ndash847

25 Poppe AY Lapierre Y Melancon D et al Neuromyelitis

optica with hypothalamic involvement Mult Scler 2005

11617ndash621

26 Vernant JC Cabre P Smadja D et al Recurrent optic

neuromyelitis with endocrinopathies a new syndrome

Neurology 19974858ndash64

27 Kim W Kim SH Lee SH Li XF Kim HJ Brain abnor-

malities as an initial manifestation of neuromyelitis optica

spectrum disorder Mult Scler 2011171107ndash1112

28 Magana SM Matiello M Pittock SJ et al Posterior

reversible encephalopathy syndrome in neuromyelitis op-

tica spectrum disorders Neurology 200972712ndash717

29 Kim SM Go MJ Sung JJ Park KS Lee KW Painful

tonic spasm in neuromyelitis optica incidence diagnostic

utility and clinical characteristics Arch Neurol 201269

1026ndash1031

30 Popescu BF Lennon VA Parisi JE et al Neuromyelitis

optica unique area postrema lesions nausea vomiting and

pathogenic implications Neurology 2011761229ndash1237

31 Wingerchuk DM Pittock SJ Lucchinetti CF Lennon VA

Weinshenker BG A secondary progressive clinical course is

uncommon in neuromyelitis optica Neurology 200768

603ndash605

32 Flanagan EP Weinshenker BG Krecke KN et al Short

myelitis lesions in aquaporin-4-IgGndashpositive neuromyelitis

optica spectrum disorders JAMA Neurol 20157281ndash87

33 Kim W Park MS Lee SH et al Characteristic brain

magnetic resonance imaging abnormalities in central ner-

vous system aquaporin-4 autoimmunity Mult Scler 2010

161229ndash1236

34 Huh SY Min JH Kim W et al The usefulness of brain

MRI at onset in the differentiation of multiple sclerosis

and seropositive neuromyelitis optica spectrum disorders

Mult Scler 201420695ndash704

35 Bourre B Zephir H Ongagna JC et al Long-term follow-

up of acute partial transverse myelitis Arch Neurol 2012

69357ndash362

36 Scott TF Kassab SL Pittock SJ Neuromyelitis optica IgG

status in acute partial transverse myelitis Arch Neurol

2006631398ndash1400

37 Jarius S Ruprecht K Wildemann B et al Contrasting

disease patterns in seropositive and seronegative neuromy-

elitis optica a multicentre study of 175 patients

J Neuroinflammation 2012914

38 Matthews L Marasco R Jenkinson M et al Distinction

of seropositive NMO spectrum disorder and MS brain

lesion distribution Neurology 2013801330ndash1337

39 Pittock SJ Lennon VA Krecke K Wingerchuk DM

Lucchinetti CF Weinshenker BG Brain abnormalities

in neuromyelitis optica Arch Neurol 200663390ndash396

40 Pittock SJ Weinshenker BG Lucchinetti CF

Wingerchuk DM Corboy JR Lennon VA Neuromyelitis

optica brain lesions localized at sites of high aquaporin 4

expression Arch Neurol 200663964ndash968

41 Nakamura M Misu T Fujihara K et al Occurrence of

acute large and edematous callosal lesions in neuromyelitis

optica Mult Scler 200915695ndash700

42 Magana SM Pittock SJ Lennon VA Keegan BM

Weinshenker BG Lucchinetti CF Neuromyelitis

optica IgG serostatus in fulminant central nervous system

inflammatory demyelinating disease Arch Neurol 2009

66964ndash966

43 Kim JE Kim SM Ahn SW et al Brain abnormalities in

neuromyelitis optica J Neurol Sci 201130243ndash48

44 Waters P Pittock SJ Bennett JL Jarius S

Weinshenker BG Wingerchuk DM Evaluation of

aquaporin-4 antibody assays Clin Exp Neuroimmunol

20145290ndash303

45 Pittock SJ Lennon VA Bakshi N et al Seroprevalence of

aquaporin-4ndashIgG in a northern California population rep-

resentative cohort of multiple sclerosis JAMA Neurol

2014711433ndash1436

46 Marignier R Bernard-Valnet R Giraudon P et al

Aquaporin-4 antibody-negative neuromyelitis optica dis-

tinct assay sensitivity-dependent entity Neurology 2013

802194ndash2200

12 Neurology 85 July 14 2015

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

47 Kitley J Woodhall M Waters P et al Myelin-oligodendrocyte

glycoprotein antibodies in adults with a neuromyelitis

optica phenotype Neurology 2012791273ndash1277

48 Kitley J Waters P Woodhall M et al Neuromyelitis

optica spectrum disorders with aquaporin-4 and myelin-

oligodendrocyte glycoprotein antibodies a comparative

study JAMA Neurol 201471276ndash283

49 Sato DK Callegaro D Lana-Peixoto MA et al Distinction

between MOG antibody-positive and AQP4 antibody-positive

NMO spectrum disorders Neurology 201482474ndash481

50 Jarius S Aboul-Enein F Waters P et al Antibody to

aquaporin-4 in the long-term course of neuromyelitis op-

tica Brain 20081313072ndash3080

51 Jiao Y Fryer JP Lennon VA et al Updated estimate of

AQP4-IgG serostatus and disability outcome in neuromy-

elitis optica Neurology 2013811197ndash1204

52 McKeon A Pittock SJ Lennon VA CSF complements

serum for evaluating paraneoplastic antibodies and

NMO-IgG Neurology 2011761108ndash1110

53 Jarius S Paul F Franciotta D et al Cerebrospinal fluid

findings in aquaporin-4 antibody positive neuromyelitis

optica results from 211 lumbar punctures J Neurol Sci

201130682ndash90

54 Collongues N Marignier R Zephir H et al Long-term

follow-up of neuromyelitis optica with a pediatric onset

Neurology 2010751084ndash1088

55 Banwell B Tenembaum S Lennon VA et al Neuromy-

elitis opticandashIgG in childhood inflammatory demyelinat-

ing CNS disorders Neurology 200870344ndash352

56 McKeon A Lennon VA Lotze T et al CNS aquaporin-4

autoimmunity in children Neurology 20087193ndash100

57 Krupp LB Tardieu M Amato MP et al International

Pediatric Multiple Sclerosis Study Group criteria for pedi-

atric multiple sclerosis and immune-mediated central ner-

vous system demyelinating disorders revisions to the 2007

definitions Mult Scler 2013191261ndash1267

58 Wingerchuk DM Weinshenker BG The emerging rela-

tionship between neuromyelitis optica and systemic rheu-

matologic autoimmune disease Mult Scler 2012185ndash10

59 Lucchinetti CF Guo Y Popescu BF Fujihara K

Itoyama Y Misu T The pathology of an autoimmune

astrocytopathy lessons learned from neuromyelitis optica

Brain Pathol 20142483ndash97

60 Popescu BFG Guo Y Jentoft ME et al Diagnostic utility

of aquaporin-4 in the analysis of active demyelinating le-

sions Neurology 201584148ndash158

Neurology 85 July 14 2015 13

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

DOI 101212WNL0000000000001729 published online June 19 2015Neurology

Dean M Wingerchuk Brenda Banwell Jeffrey L Bennett et al International consensus diagnostic criteria for neuromyelitis optica spectrum disorders

This information is current as of June 19 2015

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

729fullhttpnneurologyorgcontentearly20150619WNL0000000000001including high resolution figures can be found at

Supplementary Material

729DC3httpnneurologyorgcontentsuppl20160410WNL0000000000001

729DC2httpnneurologyorgcontentsuppl20150619WNL0000000000001

729DC1httpnneurologyorgcontentsuppl20150619WNL0000000000001Supplementary material can be found at

Citations

729fullotherarticleshttpnneurologyorgcontentearly20150619WNL0000000000001This article has been cited by 34 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosis

httpnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnneurologyorgcgicollectionall_demyelinating_disease_cnsAll Demyelinating disease (CNS)following collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

47 Kitley J Woodhall M Waters P et al Myelin-oligodendrocyte

glycoprotein antibodies in adults with a neuromyelitis

optica phenotype Neurology 2012791273ndash1277

48 Kitley J Waters P Woodhall M et al Neuromyelitis

optica spectrum disorders with aquaporin-4 and myelin-

oligodendrocyte glycoprotein antibodies a comparative

study JAMA Neurol 201471276ndash283

49 Sato DK Callegaro D Lana-Peixoto MA et al Distinction

between MOG antibody-positive and AQP4 antibody-positive

NMO spectrum disorders Neurology 201482474ndash481

50 Jarius S Aboul-Enein F Waters P et al Antibody to

aquaporin-4 in the long-term course of neuromyelitis op-

tica Brain 20081313072ndash3080

51 Jiao Y Fryer JP Lennon VA et al Updated estimate of

AQP4-IgG serostatus and disability outcome in neuromy-

elitis optica Neurology 2013811197ndash1204

52 McKeon A Pittock SJ Lennon VA CSF complements

serum for evaluating paraneoplastic antibodies and

NMO-IgG Neurology 2011761108ndash1110

53 Jarius S Paul F Franciotta D et al Cerebrospinal fluid

findings in aquaporin-4 antibody positive neuromyelitis

optica results from 211 lumbar punctures J Neurol Sci

201130682ndash90

54 Collongues N Marignier R Zephir H et al Long-term

follow-up of neuromyelitis optica with a pediatric onset

Neurology 2010751084ndash1088

55 Banwell B Tenembaum S Lennon VA et al Neuromy-

elitis opticandashIgG in childhood inflammatory demyelinat-

ing CNS disorders Neurology 200870344ndash352

56 McKeon A Lennon VA Lotze T et al CNS aquaporin-4

autoimmunity in children Neurology 20087193ndash100

57 Krupp LB Tardieu M Amato MP et al International

Pediatric Multiple Sclerosis Study Group criteria for pedi-

atric multiple sclerosis and immune-mediated central ner-

vous system demyelinating disorders revisions to the 2007

definitions Mult Scler 2013191261ndash1267

58 Wingerchuk DM Weinshenker BG The emerging rela-

tionship between neuromyelitis optica and systemic rheu-

matologic autoimmune disease Mult Scler 2012185ndash10

59 Lucchinetti CF Guo Y Popescu BF Fujihara K

Itoyama Y Misu T The pathology of an autoimmune

astrocytopathy lessons learned from neuromyelitis optica

Brain Pathol 20142483ndash97

60 Popescu BFG Guo Y Jentoft ME et al Diagnostic utility

of aquaporin-4 in the analysis of active demyelinating le-

sions Neurology 201584148ndash158

Neurology 85 July 14 2015 13

ordf 2015 American Academy of Neurology Unauthorized reproduction of this article is prohibited

DOI 101212WNL0000000000001729 published online June 19 2015Neurology

Dean M Wingerchuk Brenda Banwell Jeffrey L Bennett et al International consensus diagnostic criteria for neuromyelitis optica spectrum disorders

This information is current as of June 19 2015

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

729fullhttpnneurologyorgcontentearly20150619WNL0000000000001including high resolution figures can be found at

Supplementary Material

729DC3httpnneurologyorgcontentsuppl20160410WNL0000000000001

729DC2httpnneurologyorgcontentsuppl20150619WNL0000000000001

729DC1httpnneurologyorgcontentsuppl20150619WNL0000000000001Supplementary material can be found at

Citations

729fullotherarticleshttpnneurologyorgcontentearly20150619WNL0000000000001This article has been cited by 34 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosis

httpnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnneurologyorgcgicollectionall_demyelinating_disease_cnsAll Demyelinating disease (CNS)following collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

DOI 101212WNL0000000000001729 published online June 19 2015Neurology

Dean M Wingerchuk Brenda Banwell Jeffrey L Bennett et al International consensus diagnostic criteria for neuromyelitis optica spectrum disorders

This information is current as of June 19 2015

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

729fullhttpnneurologyorgcontentearly20150619WNL0000000000001including high resolution figures can be found at

Supplementary Material

729DC3httpnneurologyorgcontentsuppl20160410WNL0000000000001

729DC2httpnneurologyorgcontentsuppl20150619WNL0000000000001

729DC1httpnneurologyorgcontentsuppl20150619WNL0000000000001Supplementary material can be found at

Citations

729fullotherarticleshttpnneurologyorgcontentearly20150619WNL0000000000001This article has been cited by 34 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosis

httpnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnneurologyorgcgicollectionall_demyelinating_disease_cnsAll Demyelinating disease (CNS)following collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

729fullhttpnneurologyorgcontentearly20150619WNL0000000000001including high resolution figures can be found at

Supplementary Material

729DC3httpnneurologyorgcontentsuppl20160410WNL0000000000001

729DC2httpnneurologyorgcontentsuppl20150619WNL0000000000001

729DC1httpnneurologyorgcontentsuppl20150619WNL0000000000001Supplementary material can be found at

Citations

729fullotherarticleshttpnneurologyorgcontentearly20150619WNL0000000000001This article has been cited by 34 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectiontransverse_myelitisTransverse myelitis

httpnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

httpnneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosis

httpnneurologyorgcgicollectiondevics_syndromeDevics syndrome

httpnneurologyorgcgicollectionall_demyelinating_disease_cnsAll Demyelinating disease (CNS)following collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2015 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology