aquaporin-4 autoimmunitynn.neurology.org/content/nnn/2/4/e110.full.pdfaquaporin-4 autoimmunity...

VIEWS amp REVIEWS

Anastasia Zekeridou MDVanda A Lennon MD

PhD

Correspondence toDr Lennonlennonvandamayoedu

Supplemental dataat Neurologyorgnn

Aquaporin-4 autoimmunity

ABSTRACT

Neuromyelitis optica (NMO) and a related spectrum of inflammatory CNS disorders are unified bydetection of a serum autoantibody specific for the aquaporin-4 (AQP4) water channel which isabundant in astrocytic foot processes The classic clinical manifestations of NMO are optic neu-ritis and longitudinally extensive transverse myelitis Newly recognized manifestations of AQP4autoimmunity include lesions of circumventricular organs and skeletal muscle NMO is commonlyrelapsing is frequently accompanied by other autoimmune disorders and sometimes occurs in aparaneoplastic context The goals of treatment are to minimize neurologic disability in the acuteattack and thereafter to prevent relapses and cumulative disability The disease specificity ofAQP4 immunoglobulin (Ig) G approaches 100 using optimized molecular-based detection as-says Clinical immunohistopathologic and in vitro evidence support this antibody being centralto NMO pathogenesis Current animal models yield limited histopathologic characteristics ofNMO with no clinical deficits to date Recent descriptions of a myelin oligodendrocyte glycopro-tein autoantibody in a minority of patients with NMO spectrum phenotype who lack AQP4-IgGpredict serologic delineation of additional distinctive disease entities Neurol Neuroimmunol

Neuroinflamm 20152e110 doi 101212NXI0000000000000110

GLOSSARYAChR5 acetylcholine receptor ADEM 5 acute disseminated encephalomyelitis AQP4 5 aquaporin-4 EAAT2 5 excitatoryamino acid transporter 2 EAE 5 experimental autoimmune encephalomyelitis EDSS 5 Expanded Disability Status ScaleGFAP 5 glial fibrillary acidic protein Ig 5 immunoglobulin IVMP 5 IV methylprednisolone MBP 5 myelin basic proteinMOG 5 myelin oligodendrocyte glycoprotein MS 5 multiple sclerosis NK 5 natural killer NMO 5 neuromyelitis opticaNMOSD 5 NMO spectrum disorder PLEX 5 plasma exchange

Neuromyelitis optica (NMO) is an inflammatory autoimmune neurologic disease that typicallypresents as recurrent longitudinally extensive transverse myelitis and optic neuritis1 The dis-covery of a serum immunoglobulin (Ig) G autoantibody specific for the aquaporin-4 (AQP4)water channel unified a spectrum of NMO-related disorders NMO spectrum disorders(NMOSDs) and distinguished them from multiple sclerosis (MS)2ndash4 Appreciation of AQP4distribution both within and beyond the CNS (where it is largely concentrated on astrocyticfoot processes) has enabled recognition of the broadening clinical NMOSD phenotype that weaddress in this review An arising controversy concerns the relationship of idiopathic opticneuritis and transverse myelitis to NMO in AQP4-IgGndashseronegative patients with alternativeautoantibody markers for which CNS lesions are as yet undefined immunohistopathologically56

CLINICAL CHARACTERISTICS Epidemiology NMOSD prevalence has not been evaluated formally accord-ing to raceethnicity in different populations but in Western countries non-Caucasian patients are affecteddisproportionately7ndash9 In Asia NMOSD diagnosis may be more frequent than MS diagnosis1011 Womenare affected disproportionately by 361 to 1041911ndash13 Initial symptoms begin around age 35ndash45 yearsbut 18 of cases occur in children or the elderly111314 Although most cases are sporadic rare reports offamilial AQP4-IgGndashseropositive NMO with classic phenotype support a genetic component to NMOsusceptibility15

From the Departments of Laboratory Medicine and Pathology (AZ VAL) Neurology (VAL) and Immunology (VAL) NeuroimmunologyLaboratory Mayo Clinic College of Medicine Rochester MN

Funding information and disclosures are provided at the end of the article Go to Neurologyorgnn for full disclosure forms The Article ProcessingCharge was waived at the discretion of the Editor

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 40 License whichpermits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or used commercially

Neurologyorgnn copy 2015 American Academy of Neurology 1

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

Neurologic manifestations Table 1 summarizes 2006criteria for definite NMO diagnosis12 The patientdescribed by Devic in 1894 was a woman with uri-nary retention paraplegia bilateral blindness andpapilledema Autopsy revealed acute myelitis andbilateral optic neuritis16 Simultaneous bilateraloptic neuritis and transverse myelitis is a rare con-temporary presentation for NMO These casesgenerally follow a monophasic course affect bothsexes equally and are AQP4-IgG seronegativeThey may not be synonymous with an autoimmuneAQP4 channelopathy14 A longer interval betweeninitial clinical events older age at disease onset andfemale sex predict a relapsing NMO course17

Unlike MS a secondary progressive course israre1418

Unilateral or bilateral optic neuritis is generallymore severe and recovery poorer in NMOSD thanin MS with complete remission in only 3214

Transverse myelitis in NMOSD is usually longitudi-nally extensive with complete clinical remission inonly 17 of attacks14 (figure 1) MRI lesions areshort in 14 of first myelitis episodes (92 long atrelapse)19 Conus medullaris lesions and lumbosacralmyeloradiculitis are rare20

Neuromyelitis optica spectrum disorders AQP4-IgGseropositivity unifies partial and inaugural forms ofNMO that do not fulfill all NMO diagnosticcriteria Clinical manifestations may include opticneuritis transverse myelitis circumventricular organinvolvement and autoimmune AQP4 myopathy(table 2)221 NMO and NMOSD can occur in aparaneoplastic context however detection ofAQP4-IgG in a patient with cancer does notsupport NMOSD diagnosis unless neurologicfindings are consistent22

Brain involvement Brain lesions are detectable byMRI at first relapse in 60 of patients withNMO In 10 the brain lesions resemble thosecommonly seen in MS Another 10 haveldquoNMO-typicalrdquo lesions in regions of high AQP4content (periventricular hypothalamic)2324 (figure 2)

Brain lesions may be asymptomatic or a manifestationof circumventricular organ involvement intractablenausea and vomiting (area postrema and medullaryfloor of the fourth ventricle) hiccups inappropriateantidiuresis narcolepsy or anorexia (hypothalamus)or posterior pituitary endocrinopathies25ndash29 Brainstemsigns occur in 31 of patients and are more commonin non-Caucasians These include vomiting (33)hiccups (22) oculomotor dysfunction (20) andpruritus (12) 33 have hearing loss facial palsyvestibulopathy trigeminal neuralgia or cranial neu-ropathies29 Posterior reversible encephalopathy syn-drome with MRI evidence of vasogenic edema wasreported in 5 women30 Clinical manifestations andlesions in children may resemble acute disseminatedencephalomyelitis (ADEM)31

Coexisting autoimmune disorders Organ-specific andnon-organ-specific autoimmune manifestations (iecoexisting disease or autoantibody markers) are fre-quent with NMOSD3233 However AQP4-IgG isrestricted to NMOSD Sjoumlgren syndrome and sys-temic lupus erythematosus are common NMOSDaccompaniments32 Transverse myelitis in either con-text is a manifestation of NMOSD and not a vascu-litic complication of connective tissue disease32

Autoimmune myasthenia gravis is 100 times morecommon in patients with NMOSD (2) than inthe general population (002)34 Celiac diseaseautoimmune gastritis autoimmune thyroiditis ulcer-ative colitis and sclerosing cholangitis have also beenreported32333536

Skeletal muscle involvement HyperCKemia may pre-cede or accompany NMOSD An illustrative patientexperienced corticosteroid-responsive episodes ofproximal myalgia (serum creatine kinase exceeding10000 UL) and attacks of optic neuritis and trans-verse myelitis Biopsy of affected muscle revealed sar-colemmal AQP4 loss with linear deposits of IgG andcomplement products21 As is characteristic of CNSNMO lesions the lymphohistiocytic infiltrates inmuscle contained scattered eosinophils In contrasthealthy control muscle had abundant surface AQP4immunoreactivity Control biopsies of necrotizingautoimmune myopathy and dermatomyositis hadpatchy AQP4 loss without sarcolemmal immunecomplex deposition

Paraneoplastic NMOSD The cancer frequency re-ported in large NMOSD cohorts is 4ndash5 and15 in older patients (mean age 487 years)142237

Reported neoplasms include thymoma carcinomas(breast lung nasopharynx cervix bladder gastrointes-tinal tract thyroid prostate and skin) pituitary ade-noma carcinoids and hematologic malignancies142237

Demonstration of AQP4 protein in thymoma tis-sue from patients with NMOSD but not in normalthymus suggests an etiologic association38 AQP4

Table 1 Criteria for definite NMO diagnosis Wingerchuk 200612

Both major criteria

Optic neuritis

Acute myelitis

At least 2 of 3 supportive criteria

Spinal cord MRI lesion extending 3 vertebral segments or more

Brain MRI not meeting diagnostic criteria for MS

AQP4-IgG seropositive status

Abbreviations AQP4-IgG 5 aquaporin-4 immunoglobulin G MS 5 multiple sclerosisNMO 5 neuromyelitis optica

2 Neurology Neuroimmunology amp Neuroinflammation


immunoreactivity was also demonstrated in breastcarcinoma intestinal carcinoid and ovarian tera-toma tissues from patients with and withoutNMOSD39ndash41

Myelin oligodendrocyte glycoprotein autoimmunityMye-lin oligodendrocyte glycoprotein (MOG)-IgG onceconsidered a candidate autoantibody for pediatricMS is reproducibly found in pediatric cases of ADEMusing a substrate of MOG-transfected cells42 It is alsofound in some adult and pediatric cases of relapsingoptic neuritis and transverse myelitis and in occasionalAQP4-IgGndashseronegative and AQP4-IgGndashseropositivepatients with NMO phenotype542ndash44 MOG-IgGndashpos-itive cases tend to be monophasic occur more fre-quently in men have a younger age at onset resultin better outcome and have more frequent MRIinvolvement of conus and brain deep gray matter455

It is important to note that no MOG-IgGndashpositivecase has been evaluated neuropathologically A re-ported patient with clinically definite NMO MOG-IgG positivity and AQP4-IgG negativity had a highlevel of myelin basic protein (MBP) in CSF but unde-tectable glial fibrillary acidic protein (GFAP)46 Thissuggests demyelinating pathology rather than astrocyt-opathy47 Until immunohistopathologic data are docu-mented for MOG-IgGndashpositive cases we advocatetheir classification as ldquoautoimmune MOG optic neu-ritis transverse myelitis or encephalomyelitisrdquo ratherthan ldquoNMOSDrdquo48

Ancillary testing MRI findings Imaging of the acutemyelitis of NMO typically reveals lesions longer than

3 vertebral segments12 but lesions are short in 14 ofinitial attacks19 Long lesions are edematous at onsetwith nonhomogenous gadolinium enhancement andsometimes with central necrosis and cavitation1214

Late images show focal cord atrophy Involvementof central gray matter aids in distinguishing NMOfrom other demyelinating diseases49 Diffusion tensorimaging performed a year after the last NMO relapserevealed higher radial diffusivity within spinal whitematter tracts than in MS consistent with greater tis-sue destruction50

Orbital MRI findings in the optic neuritis ofNMO unilateral or bilateral are common to all opticneuritis Optic nerve lesions more characteristic ofNMO are bilateral and long and involve chiasmand posterior segments51 Optical coherence tomog-raphy and visual evoked potentials complete the diag-nostic evaluation52 Brain lesions are typicallyperiventricular and hypothalamic but 10 are MS-like and sometimes fulfill Barkhof criteria2324

CSF findings The CSF findings in NMO and MSdiffer Only 16 of AQP4-IgGndashseropositive NMOpatients have oligoclonal Ig bands 50 have pleocy-tosis (median leukocyte number 19mL) which issevere in 62 (100 leukocytesmL)53 Lympho-cytes and monocytes are generally most frequentneutrophils eosinophils and basophils may be ad-mixed or predominate153

Levels of GFAP a marker of astrocytic damagehave been reported to be significantly higher in acuteNMO than in MS and other neurologic diseases47

Figure 1 Representative spinal cord MRIs from patients with neuromyelitis optica

Longitudinally extensive transversemyelitis of the cervical (A) and cervicothoracic (B) region (T2-weighted images) with non-homogeneous gadolinium enhancement in multiple levels of the spinal cord (C) (T1-weighted imagewith gadolinium injection)in aquaporin-4 immunoglobulin Gndashseropositive patients

Neurology Neuroimmunology amp Neuroinflammation 3


with S100b cytoplasmic protein elevated more mod-estly MBP and neurofilament H chain levels weresimilar for the 3 diagnoses GFAP levels normalizedrapidly following immunotherapy but MBP

remained high presumably reflecting demyelinationHigher acute attack levels of GFAP S100b andMBP correlated with longer spinal lesion length andworse Expanded Disability Status Scale (EDSS)score47 The EDSS outcome at 6 months correlatedonly with acute-phase GFAP level

Autoantibody profile Multiple autoantibodies(organ-specific and non-organ-specific) are a serologiccharacteristic that aids in differentiating NMO fromMS54 Titers are generally relatively low There mayor may not be evidence of coexisting autoimmunedisease13233 (table 3)

Muscle acetylcholine receptor (AChR) autoantibod-ies are detectable in 11 of patients with NMO34

Other neural autoantibody specificities include gangli-onic AChR collapsin response-mediator protein 5 glu-tamic acid decarboxylase 65 NMDA receptor andKv1 voltage-gated potassium channel complex3455

Aquaporin-1-IgG has been reported inNMO but clin-ical utility has not been established656

Figure 2 Representative brain MRIs from patients with neuromyelitis optica

Lesions are localized at sites of high aquaporin-4 expression (white dots) Patient 1 around the 3rd ventricle and hypothal-amus patient 2 around the 4th ventricle patient 3 around the 4th ventricle and aqueduct patient 4 periependymalaround lateral ventricles cervical lesion extends into the brainstem patient 5 thalamus hypothalamus optic chiasmaround the 4th ventricle subpial in cerebellar hemispheres patient 6 around the 4th ventricle and cerebellar pedunclesModified with permission from Pittock et al Arch Neurol 2006 Copyright copy 2006 American Medical Association All rightsreserved

Table 2 NMO spectrum disorders unified by AQP4-IgG positivity 2015

Neuromyelitis optica2

Limited forms of neuromyelitis optica219

Single or recurrent transverse myelitisa

Optic neuritis (recurrent or simultaneous bilateral)

Optic neuritis or transverse myelitisa associated with systemic autoimmune disease2

Optic neuritis or transverse myelitisa associated with NMO-typical brain lesions(circumventricular periaqueductal hypothalamic corpus callosal brainstem)2

Myopathy with or without optic neuritis or transverse myelitisa21

Optic neuritis or transverse myelitisa associated with cancer22

Abbreviations AQP4-IgG 5 aquaporin-4 immunoglobulin G NMO 5 neuromyelitis opticaaMedullary lesions are generally longitudinally extensive but short lesions have also beendescribed



The first-generation tissue-based immunofluorescenceassay for detecting the AQP4-IgG marker of NMO is91 specific but only 48 sensitive57 Contemporaryclinical practice uses molecular-based techniques themost sensitive and specific being immunofluorescenceapplied to indicator cells expressing recombinantAQP4 (M1 or M23 isoform) either fixed or live5859

Fluorescence-activated sorting of live M1 isoformndash

transfected cells has proven to be the most sensitiveand specific technique in Mayo Clinic experience58

An ELISA based on bridging of soluble biotinylatedAQP4 and plate-bound AQP4 by patient IgG is lesssensitive and more prone to yield false-positive re-sults58 Immunoprecipitation of green fluorescenceproteinndashtagged AQP4 is least sensitive (50)57

Prognosis NMO prognosis was very poor in reportspredating the era of AQP4-IgG testing Appropriatetherapeutic options were uncertain In a 1999 caseseries Wingerchuk et al1 reported that sequential

index events of monophasic NMO occurred rapidly(median 5 days) with moderate recovery With arelapsing course the interval between initial myelitisand optic neuritis events was long (median 166 days)severe relapses clustered within 3 years and severedisability developed in a stepwise manner one-thirdof patients died of respiratory failure1

In a 2012 study of AQP4-IgGndashpositive patientsfrom the UK and Japan permanent bilateral visualdisability had developed in 18 of patients (mediandisease duration 75 months) permanent motor disa-bility in 34 (inability to walk farther than 100 munaided) and wheelchair dependency in 2360 Atmedian disease duration of 99 months 9 of pa-tients had died after a mean of 45 attacks60 In theUK cohort Afro-Caribbean patients were younger atdisease onset and had a higher likelihood of visualdisability than Caucasian patients60

In a 2013 report of AQP4-IgGndashseropositive andAQP4-IgGndashseronegative patients 65 were blind amedian of 83 years after disease onset (50 unilat-eral and 15 bilateral) and more than one-thirdcould not walk without unilateral assistancee1 Thesereports suggest a better outcome in the postndashAQP4-IgG era presumably because of earlier diagnosis andtherapies that lower Ig levels or intercept complementactivation or interleukin 6 action

Treatment options NMO treatment has dual goals(1) to stop the acute attack thus minimizing neuro-logic disability and maximizing reversibility and (2)to prevent relapses with cumulative disability Thera-peutic decisions should be individualized for eachpatient depending on the clinical situation and out-come and should not be based on AQP4-IgG levelsgiven the current state of knowledge No publishedprospective controlled trials have evaluated NMOtreatments Promising open-label pilot studies havespawned continuing randomized trialse2 Table 4summarizes current treatment options

For acute attacks As in other IgG-mediated autoim-mune diseases IV methylprednisolone (IVMP) andplasma exchange (PLEX) are generally consideredoptimal first-line therapy Experts recommend 1 gIVMP for 3 to 5 days A course of oral prednisonewith a slow taper is usually undertaken to preventearly relapse and to serve as a bridge to immune sup-pression with a steroid-sparing druge2 For severe at-tacks the IVMP response may not be satisfactoryPLEX (5ndash7 exchanges) is more efficacious in combi-nation with IVMPe3 In some severe cases cyclophos-phamide has been reported to be efficacious as IVpulse therapy (750ndash1000 mgm2)e4

IVIg (with or without PLEX) was effective in astudy of 10 patients (11 episodes) who did notrespond to IVMP 45 of attacks improved and no

Table 3 Autoantibody profile in neuromyelitisoptica32ndash34585955

Frequency

IgG specificity

Aquaporin-4 78ndash83

Non-organ-specific

Antinuclear 53

Extractable nuclear antibody 17

Sjoumlgren syndrome A 8

Sjoumlgren syndrome B 4

U1 ribonucleoprotein 13

Scleroderma-70 13

Jo (histidyl transfer RNA) 13

Neural

Acetylcholine receptor

Muscle-type 11

Ganglionic-type 6

Glutamic acid decarboxylase 65 15

Collapsin response-mediatorprotein 5

1

Kv1 voltage-gated potassiumchannel complex

5

Voltage-gated calcium channel

PQ-type 2

N-type 4

Myelin oligodendrocyteglycoprotein

Reported in rare cases

NMDA receptor Reported in rare cases

Thyroid

Thyroglobulin 40

Thyroid peroxidase 50



patient worsenede5 Formal trials focusing on attacksare needed in order to determine optimal therapeuticoptions taking into account the patientrsquos age comor-bidities and attack severity

For relapse rate reduction Practical considerationsinclude the patientrsquos age access to care cost adverseevents previous treatments and existing disabilityImmunomodulatory treatments used for MS are gen-erally not effective for NMO and some are deleteri-ouse6ndashe8 Retrospective data are available for largenumbers of patients treated with azathioprine myco-phenolate mofetil or rituximab which are the usualoptions considered for relapse prevention

Azathioprine (2 mgkgday rather than lowerdose) reduced the annual relapse rate in a study of99 patientse9 Hemogram and liver and renal functionmust be monitored during treatment and it is desir-able to ascertain thiopurine methyltransferase activitybefore initiating treatmente10 Because azathioprinersquosefficacy is delayed oral corticosteroids are usuallycontinued for the first few months Azathioprinereduced the relapse rate by 72 in a study of 32patients but was ineffective for half the patientsdespite continuing prednisonee11

Mycophenolate mofetil is another option for long-term immunosuppression In a study of 28 patients

relapse rate was reduced up to 87 and failure ratewas 36e11

Rituximab an anti-CD20 monoclonal antibodythat depletes B cells has excellent efficacy forNMOSD Open-label studies using different proto-cols for dosing and monitoring CD19-positive bloodlymphocytes suggest that infusion should be repeatedwhen B cells reappear Annual relapse rates werereduced by 87 and 60ndash70 of patients becamerelapse-free for as long as 3 years following treatmentStudies reported improved or stabilized disability(80ndash97 of patients)e11ndashe13

Eculizumab a monoclonal antibody that neutral-izes the C5 complement protein rendered 12 of 14patients relapse-free in a 12-month open-label pilotstudye14 During treatment the median annualizedpretreatment attack rate fell from 3 to 0 and theEDSS score improved from 43 to 35e14

Tocilizumab a monoclonal antibody targeting in-terleukin 6 receptor showed efficacy in an open-labelpilot study of 7 patients After 1 year the annualizedrelapse rate fell from 296 to 04 EDSS score neuro-pathic pain and general fatigue were significantlyreducede15

Oral corticosteroids as monotherapy or adjunctivetherapy have been reported to prevent relapses in asmall retrospective studye16 Addition of a steroid-sparing immunosuppressive agent minimizes theadverse events of extended corticosteroid therapyOsteoporosis prophylaxis and monitoring of plasmaglucose are recommended during long-term treatment

Cyclosporine A has been used with oral corticoste-roids The annual relapse rate for 9 patients receivingthis treatment fell from 27 to 038e17

In a retrospective study of 14 patients methotrex-ate therapy was associated with a significantly reducedmedian annualized relapse rate (018 during therapyvs 139 before) 43 of patients were relapse-freeand disability stabilized or improved in 79e18

In 20 patients with high relapse rate mitoxan-trone (IV monthly or every 3 months) was associatedwith a median annualized relapse rate reduction of75e19 Disability improved or stabilized in all pa-tients and 50 became relapse-freee19 Laboratoryand cardiac monitoring is necessary during treatment

Cyclophosphamide was associated with a medianEDSS improvement from 80 to 575 in 4 patientswith longitudinally extensive transverse myelitise20

Autologous hemopoietic stem cell transplantationarrested progression in 3 of 16 patients who wererefractory to conventional therapy They remainedtreatment-free (median follow-up period 47months)The remaining 13 patients required continuing ther-apy due to disability progression or relapsee21 Alloge-neic hematopoietic stem cell transplantation wasreported to be efficacious in 2 patients with aggressive

Table 4 Treatment of NMO

Acute attackse2ndashe5

Treatment Main mode of actiontarget

IV methylpredisolone Multiple

Plasma exchange AQP4-IgG depletion

IV immune globulin Multiple

Cyclophosphamide Anti-mitotic

Relapse rate reductione9ndashe12e14ndashe21


Azathioprine Guanosine nucleotide biosynthesis inhibition

Mycophenolate mofetil Inosine monophosphate dehydrogenaseinhibition (T and B lymphocytes)

Rituximab B-cell depletion (anti-CD20)

Eculizumab Anti-C5 (complement inhibition)

Tocilizumab Anti-IL-6 receptor

Oral corticosteroids Multiple

Cyclosporine A Calcineurin inhibition (T cells)

Methotrexate Folate-dependent enzyme inhibition

Mitoxantrone Topoisomerase II inhibition anti-mitotic


Autologous stem cell transplantation Immune reconstitution following marrowablation

Allogeneic stem cell transplantation Immune reconstitution following marrowablation

Abbreviations AQP4-IgG 5 aquaporin-4 immunoglobulin G IL 5 interleukin NMO 5

neuromyelitis optica



NMO in whom previous treatments had failedincluding autologous stem cell transplantation Bothpatients remained relapse-free after 36 and 48monthse22

IMMUNOPATHOGENESIS Favorable response toPLEX and B-cellndashdepleting therapies provide clinicalevidence for the pathogenicity of AQP4-IgGe3e11e12

Immunopathology The distinctive immunopathologyof NMO lesions supports a central role for AQP4-IgG in disease pathogenesis Products of complementactivation are prominent around thickened hyalinizedblood vessels and coincide with Ig deposits Thepredominance of polymorphonuclear inflammatorycells is consistent with involvement of IgG andcomplement in lesion genesise23 Loss of AQP4 inastrocytes surviving within sublytic CNS lesionsdistinguishes NMO from MS and may beindicative of potentially reversible histopathologiclesionse24 Some of these lesions exhibit markedinflammation and astrocytic AQP4 loss but GFAPretention Other lesions exhibit reduced astrocyticGFAP immunoreactivity but relative preservationof myelin These findings support AQP4 loss as aprecedent to astrocyte loss with demyelination alater secondary evente25e26 In advanced NMOstages spinal cord gray and white matter showsextensive demyelination cavitation necrosis andaxonal loss (spheroids)e23

Role of AQP4-IgG IgG responses to protein autoanti-gens reflect the interaction of helper and regulatoryT cells with antigen-specific B cells A role forAQP4-specific effector T cells has not beenestablished but they may contribute to initial blood-brain barrier disruptione24 In established NMOlesions CNS tissues contain IgG-producing plasmacellse23 There is increasing evidence for intrathecalproduction of AQP4-IgG High CSF levels correlatesignificantly with attack severitye27ndashe30 Levels ofinterleukin 6 which enhances plasmablast survivalare higher than normal in the plasma of patientswith NMO Plasmablasts are detectable in NMOperipheral blood and are more numerous in attackphase Interleukin 6 promotes in vitro production ofIgG by AQP4-specific plasmablasts derived from bloodand CSF of patients with NMOe28e31ndashe33

Target cellndashspecific pathogenicity requires thebinding of IgG to the extracellular domain ofAQP4e34 AQP4-IgG is predominantly IgG1 class apotent activator of complement In the astrocyticplasma membrane AQP4 exists as tetramers contain-ing one or both of 2 major isoforms full length(M1) and a shorter isoform (M23) M23-AQP4spontaneously forms orthogonal arrays of particlesmost homomeric M1 tetramers remain singlete35e36

On exposure to AQP4-IgG astrocytes rapidly inter-nalize M1 tetramers In contrast AQP4-IgG cross-linking of M23-AQP4 arrays induces their coalescenceinto larger orthogonal arrays that exceed the astrocytersquosendocytic capacitye35 When complement becomesavailable locally large AQP4 arrays displayingdensely packed Fc tails of IgG1 would initiate com-plement activation explosively promoting leukocytechemotaxis vascular permeability and massiveinflux of plasma rich in IgG complement and rheu-matoid factorndashlike IgM which on binding to theantigen-complexed IgG would further enhancecomplement activatione34 A reported positivein vitro correlate of NMO attack severity is thedegree of complement-mediated injury to AQP4-expressing cells following exposure to IgG from pa-tients with NMO (6 with severe attacks comparedwith 6 with mild attacks p5 005)e37 Natural killer(NK) cell degranulation activated as a complement-independent function of IgG binding to AQP4(antibody-dependent cellular cytotoxicity) alsocauses astrocyte killing in vitroe38

Autoantibody blockade of water flux would plau-sibly explain the prominent intramyelinic edemaobserved in early NMO lesions which is a potentialprecursor of demyelinatione35e39 Autoantibodieswith potential to reduce water flux independent ofAQP4 endocytosis (ie temperature independent)were demonstrated functionally in a Xenopus expres-sion system using sera pooled from at least 50 NMOpatients with high levels of AQP4-IgGe35e39 Datadisputing this AQP4-IgG property were based ontesting monoclonal AQP4-IgG and sera from rela-tively few individual patients by quantum dot tech-nologye40e41

Disruption of glutamate homeostasis is anotherpotentially pathogenic property of AQP4-IgG Theexcitatory amino acid transporter 2 (EAAT2) is non-covalently linked to AQP4 on perisynaptic astrocyticmembranes EAAT2 accounts for 90 of CNS gluta-mate uptake and is co-internalized by AQP4-IgGWhen applied to cultured astrocytes AQP4-IgG re-duces the functional uptake of 3H-glutamate Fur-thermore in sublytic lesions of NMO spinal cordthe central gray matter is profoundly deficient inEAAT2e42 The particular vulnerability of oligoden-drocytes to glutamate toxicity is another plausibleexplanation for demyelination in NMOe43e44

Animal models Animal models described to datereproduce some histopathologic characteristics ofNMO but not clinical findings NMO lesions donot ensue when serum IgG from patients withNMO is injected systemically into rats with an intactblood-brain barrier However when NMO-IgG isinjected systemically into rats with incipient



experimental autoimmune encephalomyelitis (EAE)Ig deposition complement activation andgranulocyte influx occure28 Astrocytic damagesimilar to that of NMO was seen in spinal cordregions containing EAE-type lesionse45 Neurologicimpairment was worse in rats injected systemicallywith IgG from patients with NMO and did notoccur in the absence of encephalitogenic T cellsSystemically injected NMO-IgG had no effect onjuvenile rats with leaky CNS endothelial cellse24

On the other hand 2 groups have reportedastrocytic damage and spinal cord AQP4 lossfollowing systemic injection of IgG from patientswith NMO in mice pretreated with completeFreund adjuvant either alone or with pertussistoxine46e47 The authors speculated that themycobacterial adjuvant promoted blood-brainbarrier leakiness

Focal lesions characteristic of NMO developed inmice injected with IgG from patients with NMOdirectly into the cerebral hemisphere but only if freshhuman serum was co-injected as a source of comple-mente48 Similar findings in T-cellndashdeficient miceindicated that AQP4-IgG and locally available com-plement are sufficient for creating NMO-like patho-logic lesionse49 Astrocyte injury defined as loss ofAQP4 and GFAP was produced in brain slice organculture preparations in the absence of complementwhen IgG from patients with NMO was added toNK cells Lesions consistent with antibody-dependent cellular cytotoxicity were also induced byinjecting mice intracerebrally with IgG and NK cellsfrom patients with NMOe50 Optic nerve lesionsresembling those of NMO were induced in mice bycontinuously infusing serum from patients withNMO for 3 days in the region of the optic chiasme51

The animal models described to date are based onthe concept that AQP4-IgG produced in the periph-ery will penetrate the CNS when the blood-brainbarrier is disrupted It is evident however thatAQP4-IgG can be produced intrathecallye27ndashe30 Theideal animal model should reproduce typical clinicalfindings including relapses and the immunohistopa-thologic phenotype of AQP4 autoimmunity

CONCLUSIONS AND FUTURE CHALLENGES Inthe decade since AQP4-IgG was described as abiomarker distinguishing NMO and relateddisorders from MS our understanding of NMOimmunopathogenesis has greatly advanced Clinicaldividends include sensitive molecular-based diagnosticassays and more effective therapies targetingpathogenic antibodies B cells complement and aninterleukin receptor The initial trigger of the AQP4autoimmune response remains an importantquestion Animal models have not yet reproduced

clinical signs or full histopathologic manifestations ofNMO lesions The immunopathogenesis of opticneuritis and transverse myelitis occurring in thecontext of alternative autoantibodies and in theabsence of detectable AQP4-IgG remains speculativeand cannot be resolved without immunopathologicdata Symptoms and signs do not equate withmolecular pathology

AUTHOR CONTRIBUTIONSAnastasia Zekeridou design draftingrevising manuscript Vanda A

Lennon revising and editing manuscript

STUDY FUNDINGNo targeted funding reported

DISCLOSUREA Zekeridou reports no disclosures V Lennon received research support

from NIH V Lennon and Mayo Clinic have a financial interest in the

following intellectual property ldquoMarker for Neuromyelitis Opticardquo A

patent has been issued for this technology and it has been licensed to

commercial entities They have received cumulative royalties of greater

than the federal threshold for significant financial interest from the licens-

ing of these technologies The author receives no royalties from the sale of

these tests by Mayo Medical Laboratories however Mayo Collaborative

Services Inc does receive revenue for conducting these tests The Mayo

Neuroimmunology Laboratory performs service testing for aquaporin-4

autoantibodies on behalf of Mayo Collaborative Services Inc an agency

of Mayo Foundation V Lennon does not benefit financially from this

testing Go to Neurologyorgnn for full disclosure forms

Received December 17 2014 Accepted in final form March 23 2015

REFERENCES1 Wingerchuk DM Hogancamp WF OrsquoBrien PC

Weinshenker BG The clinical course of neuromyelitis op-

tica (Devicrsquos syndrome) Neurology 1999531107ndash1114

2 Wingerchuk DM Lennon VA Lucchinetti CF

Pittock SJ Weinshenker BG The spectrum of neuromy-

elitis optica Lancet Neurol 20076805ndash815

3 Lennon VA Wingerchuk DM Kryzer TJ et al A serum

autoantibody marker of neuromyelitis optica distinction

from multiple sclerosis Lancet 20043642106ndash2112

4 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 2005202473ndash477

5 Mao Z Lu Z Hu X et al Distinction between MOG

antibody-positive and AQP4 antibody-positive NMO

spectrum disorders Neurology 2014831122

6 Tzartos JS Stergiou C Kilidireas K Zisimopoulou P

Thomaidis T Tzartos SJ Anti-aquaporin-1 autoantibodies

in patients with neuromyelitis optica spectrum disorders

PLoS One 20138e74773

7 Mealy MA Wingerchuk DM Greenberg BM Levy M

Epidemiology of neuromyelitis optica in the United States

a multicenter analysis Arch Neurol 2012691176ndash1180

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 Collongues N Marignier R Zeacutephir H et al Neuromye-

litis optica in France a multicenter study of 125 patients

Neurology 201074736ndash742

10 Apiwattanakul M Asawavichienjinda T Pulkes T Diag-

nostic utility of NMOAQP4-IgG in evaluating CNS



inflammatory diseases in Thai patients J Neurol Sci 2012

320118ndash120

11 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

12 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF

Weinshenker BG Revised diagnostic criteria for neuromy-

elitis optica Neurology 2006661485ndash1489

13 Quek AM McKeon A Lennon VA et al Effects of age

and sex on aquaporin-4 autoimmunity Arch Neurol

2012691039ndash1043

14 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

15 Matiello M Schaefer-Klein JL Hebrink DD

Kingsbury DJ Atkinson EJ Weinshenker BG Genetic

analysis of aquaporin-4 in neuromyelitis optica Neurology

2011771149ndash1155

16 Devic E Myeacutelite subaigueuml compliqueacutee de neacutevrite optique

Le Bulletin Meacutedical 189481033ndash1034

17 Wingerchuk DM Weinshenker BG Neuromyelitis opti-

ca clinical predictors of a relapsing course and survival


18 Wingerchuk DM Pittock SJ Lucchinetti CF

Lennon VA Weinshenker BG A secondary progressive

clinical course is uncommon in neuromyelitis optica Neu-

rology 200768603ndash605

19 Flanagan EP Weinshenker BG Krecke KN et al Short

myelitis lesions in aquaporin-4-IgG-positive neuromyelitis

optica spectrum disorders JAMA Neurol 20157281ndash87

20 Takai Y Misu T Nakashima I et al Two cases of lum-

bosacral myeloradiculitis with anti-aquaporin-4 antibody


21 Guo Y Lennon VA Popescu BF et al Autoimmune

aquaporin-4 myopathy in neuromyelitis optica spectrum

JAMA Neurol 2014711025ndash1029

22 Pittock SJ Lennon VA Aquaporin-4 autoantibodies in a

paraneoplastic context Arch Neurol 200865629ndash632

23 Pittock SJ Lennon VA Krecke K Wingerchuk DM

Lucchinetti CF Weinshenker BG Brain abnormalities

in neuromyelitis optica Arch Neurol 200663390ndash396

24 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

25 Baba T Nakashima I Kanbayashi T et al Narcolepsy as

an initial manifestation of neuromyelitis optica with anti-

aquaporin-4 antibody J Neurol 2009256287ndash288

26 Iorio R Plantone D Damato V Paola Batocchi A Ano-

rexia heralding the onset of neuromyelitis optica Intern

Med 201352489ndash491

27 Iorio R Lucchinetti CF Lennon VA et al Syndrome of

inappropriate antidiuresis may herald or accompany neu-

romyelitis optica Neurology 2011771644ndash1646

28 Vernant JC Cabre P Smadja D et al Recurrent optic

neuromyelitis with endocrinopathies a new syndrome


29 Kremer L Mealy M Jacob A et al Brainstem manifes-

tations in neuromyelitis optica a multicenter study of 258

patients Mult Scler Epub 2013 Oct 7

30 Magantildea SM Matiello M Pittock SJ et al Posterior

reversible encephalopathy syndrome in neuromyelitis

optica spectrum disorders Neurology 200972

712ndash717

31 McKeon A Lennon VA Lotze T et al CNS

aquaporin-4 autoimmunity in children Neurology

20087193ndash100

32 Pittock SJ Lennon VA de Seze J et al Neuromyelitis

optica and non organ-specific autoimmunity Arch Neurol

20086578ndash83

33 Long Y Zheng Y Chen M et al Serum thyroid-

stimulating hormone and anti-thyroglobulin antibody are

independently associated with lesions in spinal cord in

central nervous system demyelinating diseases PLoS

One 20149e100672

34 McKeon A Lennon VA Jacob A et al Coexistence of

myasthenia gravis and serological markers of neurological

autoimmunity in neuromyelitis optica Muscle Nerve

20093987ndash90

35 Bergamaschi R Jarius S Robotti M Pichiecchio A

Wildemann B Meola G Two cases of benign neuromy-

elitis optica in patients with celiac disease J Neurol 2009

2562097ndash2099

36 Jarius S Paul F Ruprecht K Wildemann B Low vitamin

B12 levels and gastric parietal cell antibodies in patients

with aquaporin-4 antibody-positive neuromyelitis optica

spectrum disorders J Neurol 20122592743ndash2745

37 Ontaneda D Fox RJ Is neuromyelitis optica with

advanced age of onset a paraneoplastic disorder Int J

Neurosci 2014124509ndash511

38 Chan KH Kwan JS Ho PW et al Aquaporin-4 water

channel expression by thymoma of patients with and with-

out myasthenia gravis J Neuroimmunol 2010227

178ndash184

39 Armagan H Tuumlzuumln E Iccediloumlz S et al Long extensive trans-

verse myelitis associated with aquaporin-4 antibody and

breast cancer favorable response to cancer treatment

J Spinal Cord Med 201235267ndash269

40 Figueroa M Guo Y Tselis A et al Paraneoplastic neuro-

myelitis optica spectrum disorder associated with meta-

static carcinoid expressing aquaporin-4 JAMA Neurol

201471495ndash498

41 Frasquet M Bataller L Torres-Vega E et al Longitudi-

nally extensive transverse myelitis with AQP4 antibodies

revealing ovarian teratoma J Neuroimmunol 2013263

145ndash147

42 Reindl M Di Pauli F Rostaacutesy K Berger T The spectrum

of MOG autoantibody-associated demyelinating diseases

Nat Rev Neurol 20139455ndash461

43 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

44 Houmlftberger R Sepulveda M Armangue T et al Antibod-

ies to MOG and AQP4 in adults with neuromyelitis optica

and suspected limited forms of the disease Mult Scler

Epub 2014 Oct 24 pii 1352458514555785

45 Kitley J Woodhall M Waters P et al Myelin-oligodendrocyte

glycoprotein antibodies in adults with a neuromyelitis optica

phenotype Neurology 2012791273ndash1277

46 Ikeda K Kiyota N Kuroda H et al Severe demyelination

but no astrocytopathy in clinically definite neuromyelitis

optica with anti-myelin-oligodendrocyte glycoprotein anti-

body Mult Scler 201521656ndash659

47 Takano R Misu T Takahashi T Sato S Fujihara K

Itoyama Y Astrocytic damage is far more severe than



demyelination in NMO a clinical CSF biomarker study


48 Zamvil SS Slavin AJ Does MOG Ig-positive AQP4-

seronegative opticospinal inflammatory disease justify a

diagnosis of NMO spectrum disorder Neurol Neuroim-

munol Neuroinflamm 20152e62 doi 101212NXI

0000000000000062

49 Nakamura M Miyazawa I Fujihara K et al Preferential

spinal central gray matter involvement in neuromyelitis

optica An MRI study J Neurol 2008255163ndash170

50 Klawiter EC Xu J Naismith RT et al Increased radial dif-

fusivity in spinal cord lesions in neuromyelitis optica com-

pared with multiple sclerosis Mult Scler 2012181259ndash1268

51 Storoni M Davagnanam I Radon M Siddiqui A

Plant GT Distinguishing optic neuritis in neuromyeli-

tis optica spectrum disease from multiple sclerosis a

novel magnetic resonance imaging scoring system

J Neuroophthalmol 201333123ndash127

52 Petzold A Wattjes MP Costello F et al The investigation

of acute optic neuritis a review and proposed protocol


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 Brickshawana A Hinson SR Romero MF et al Investi-

gation of the KIR41 potassium channel as a putative

antigen in patients with multiple sclerosis a comparative

study Lancet Neurol 201413795ndash806

55 Titulaer MJ Houmlftberger R Iizuka T et al Overlapping

demyelinating syndromes and antindashN-methyl-D-aspar-

tate receptor encephalitis Ann Neurol 201475

411ndash428

56 Long Y Zheng Y Shan F et al Development of a cell-based

assay for the detection of anti-aquaporin 1 antibodies in

neuromyelitis optica spectrum disorders J Neuroimmunol

2014273103ndash110

57 Waters PJ McKeon A Leite MI et al Serologic diagnosis

of NMO a multicenter comparison of aquaporin-4-IgG

assays Neurology 201278665ndash671

58 Fryer JP Lennon VA Pittock SJ et al AQP4 autoanti-

body assay performance in clinical laboratory service

Neurol Neuroimmunol Neuroinflamm 20141e11 doi

101212NXI0000000000000011

59 Jarius S Wildemann B Aquaporin-4 antibodies (NMO-

IgG) as a serological marker of neuromyelitis optica a

critical review of the literature Brain Pathol 201323

661ndash683

60 Kitley J Leite MI Nakashima I et al Prognostic factors

and disease course in aquaporin-4 antibody-positive

patients with neuromyelitis optica spectrum disorder

from the United Kingdom and Japan Brain 2012135

1834ndash1849



DOI 101212NXI000000000000011020152 Neurol Neuroimmunol Neuroinflamm

Anastasia Zekeridou and Vanda A LennonAquaporin-4 autoimmunity

This information is current as of May 21 2015

2015 American Academy of Neurology All rights reserved Online ISSN 2332-7812Published since April 2014 it is an open-access online-only continuous publication journal Copyright copy

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

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httpnnneurologyorgcgicollectionoptic_neuritisOptic neuritis see Neuro-ophthalmologyOptic Nerve

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myelitishttpnnneurologyorgcgicollectionacute_disseminated_encephaloAcute disseminated encephalomyelitisfollowing collection(s) This article along with others on similar topics appears in the

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Neurologic manifestations Table 1 summarizes 2006criteria for definite NMO diagnosis12 The patientdescribed by Devic in 1894 was a woman with uri-nary retention paraplegia bilateral blindness andpapilledema Autopsy revealed acute myelitis andbilateral optic neuritis16 Simultaneous bilateraloptic neuritis and transverse myelitis is a rare con-temporary presentation for NMO These casesgenerally follow a monophasic course affect bothsexes equally and are AQP4-IgG seronegativeThey may not be synonymous with an autoimmuneAQP4 channelopathy14 A longer interval betweeninitial clinical events older age at disease onset andfemale sex predict a relapsing NMO course17

Unlike MS a secondary progressive course israre1418

Unilateral or bilateral optic neuritis is generallymore severe and recovery poorer in NMOSD thanin MS with complete remission in only 3214

Transverse myelitis in NMOSD is usually longitudi-nally extensive with complete clinical remission inonly 17 of attacks14 (figure 1) MRI lesions areshort in 14 of first myelitis episodes (92 long atrelapse)19 Conus medullaris lesions and lumbosacralmyeloradiculitis are rare20

Neuromyelitis optica spectrum disorders AQP4-IgGseropositivity unifies partial and inaugural forms ofNMO that do not fulfill all NMO diagnosticcriteria Clinical manifestations may include opticneuritis transverse myelitis circumventricular organinvolvement and autoimmune AQP4 myopathy(table 2)221 NMO and NMOSD can occur in aparaneoplastic context however detection ofAQP4-IgG in a patient with cancer does notsupport NMOSD diagnosis unless neurologicfindings are consistent22

Brain involvement Brain lesions are detectable byMRI at first relapse in 60 of patients withNMO In 10 the brain lesions resemble thosecommonly seen in MS Another 10 haveldquoNMO-typicalrdquo lesions in regions of high AQP4content (periventricular hypothalamic)2324 (figure 2)

Brain lesions may be asymptomatic or a manifestationof circumventricular organ involvement intractablenausea and vomiting (area postrema and medullaryfloor of the fourth ventricle) hiccups inappropriateantidiuresis narcolepsy or anorexia (hypothalamus)or posterior pituitary endocrinopathies25ndash29 Brainstemsigns occur in 31 of patients and are more commonin non-Caucasians These include vomiting (33)hiccups (22) oculomotor dysfunction (20) andpruritus (12) 33 have hearing loss facial palsyvestibulopathy trigeminal neuralgia or cranial neu-ropathies29 Posterior reversible encephalopathy syn-drome with MRI evidence of vasogenic edema wasreported in 5 women30 Clinical manifestations andlesions in children may resemble acute disseminatedencephalomyelitis (ADEM)31

Coexisting autoimmune disorders Organ-specific andnon-organ-specific autoimmune manifestations (iecoexisting disease or autoantibody markers) are fre-quent with NMOSD3233 However AQP4-IgG isrestricted to NMOSD Sjoumlgren syndrome and sys-temic lupus erythematosus are common NMOSDaccompaniments32 Transverse myelitis in either con-text is a manifestation of NMOSD and not a vascu-litic complication of connective tissue disease32

Autoimmune myasthenia gravis is 100 times morecommon in patients with NMOSD (2) than inthe general population (002)34 Celiac diseaseautoimmune gastritis autoimmune thyroiditis ulcer-ative colitis and sclerosing cholangitis have also beenreported32333536

Skeletal muscle involvement HyperCKemia may pre-cede or accompany NMOSD An illustrative patientexperienced corticosteroid-responsive episodes ofproximal myalgia (serum creatine kinase exceeding10000 UL) and attacks of optic neuritis and trans-verse myelitis Biopsy of affected muscle revealed sar-colemmal AQP4 loss with linear deposits of IgG andcomplement products21 As is characteristic of CNSNMO lesions the lymphohistiocytic infiltrates inmuscle contained scattered eosinophils In contrasthealthy control muscle had abundant surface AQP4immunoreactivity Control biopsies of necrotizingautoimmune myopathy and dermatomyositis hadpatchy AQP4 loss without sarcolemmal immunecomplex deposition

Paraneoplastic NMOSD The cancer frequency re-ported in large NMOSD cohorts is 4ndash5 and15 in older patients (mean age 487 years)142237

Reported neoplasms include thymoma carcinomas(breast lung nasopharynx cervix bladder gastrointes-tinal tract thyroid prostate and skin) pituitary ade-noma carcinoids and hematologic malignancies142237

Demonstration of AQP4 protein in thymoma tis-sue from patients with NMOSD but not in normalthymus suggests an etiologic association38 AQP4

Table 1 Criteria for definite NMO diagnosis Wingerchuk 200612

Both major criteria

Optic neuritis

Acute myelitis

At least 2 of 3 supportive criteria

Spinal cord MRI lesion extending 3 vertebral segments or more

Brain MRI not meeting diagnostic criteria for MS

AQP4-IgG seropositive status

Abbreviations AQP4-IgG 5 aquaporin-4 immunoglobulin G MS 5 multiple sclerosisNMO 5 neuromyelitis optica
















































Frequency

IgG specificity


Non-organ-specific

Antinuclear 53





Scleroderma-70 13


Neural


Muscle-type 11

Ganglionic-type 6



1


5


PQ-type 2

N-type 4




Thyroid

Thyroglobulin 40














































































































320118ndash120




atry 2011821360ndash1364






2012691039ndash1043








2011771149ndash1155

































Med 201352489ndash491













712ndash717



20087193ndash100



20086578ndash83





One 20149e100672




20093987ndash90




2562097ndash2099











178ndash184








201471495ndash498




145ndash147











Epub 2014 Oct 24 pii 1352458514555785


















0000000000000062

























411ndash428




2014273103ndash110







101212NXI0000000000000011




661ndash683





1834ndash1849
























Reprints

















































Frequency

IgG specificity


Non-organ-specific

Antinuclear 53





Scleroderma-70 13


Neural


Muscle-type 11

Ganglionic-type 6



1


5


PQ-type 2

N-type 4




Thyroid

Thyroglobulin 40














































































































320118ndash120




atry 2011821360ndash1364






2012691039ndash1043








2011771149ndash1155

































Med 201352489ndash491













712ndash717



20087193ndash100



20086578ndash83





One 20149e100672




20093987ndash90




2562097ndash2099











178ndash184








201471495ndash498




145ndash147











Epub 2014 Oct 24 pii 1352458514555785


















0000000000000062

























411ndash428




2014273103ndash110







101212NXI0000000000000011




661ndash683





1834ndash1849
























Reprints














































































































320118ndash120




atry 2011821360ndash1364






2012691039ndash1043








2011771149ndash1155

































Med 201352489ndash491













712ndash717



20087193ndash100



20086578ndash83





One 20149e100672




20093987ndash90




2562097ndash2099











178ndash184








201471495ndash498




145ndash147











Epub 2014 Oct 24 pii 1352458514555785


















0000000000000062

























411ndash428




2014273103ndash110







101212NXI0000000000000011




661ndash683





1834ndash1849
























Reprints










0000000000000062

























411ndash428




2014273103ndash110







101212NXI0000000000000011




661ndash683





1834ndash1849
























Reprints

























Reprints




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