apheresis therapies for nmosd attacks · article open access class of evidence apheresis therapies...

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ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter, MD, Anna Gahlen, MD, Nadja Borisow, MD, Katrin Fischer, MD, Klaus-Dieter Wernecke, PhD, Kerstin Hellwig, MD, Florence Pache, MD, Klemens Ruprecht, MD, Joachim Havla, MD, Tania K¨ umpfel, MD, Orhan Aktas, MD, Hans-Peter Hartung, MD, Marius Ringelstein, MD, Christian Geis, MD, Christoph Kleinschnitz, MD, Achim Berthele, MD, Bernhard Hemmer, MD, Klemens Angstwurm, MD, Jan-Patrick Stellmann, MD, Simon Schuster, MD, Martin Stangel, MD, Florian Lauda, MD, Hayrettin Tumani, MD, Christoph Mayer, MD, Markus Krumbholz, MD, Lena Zeltner, MD, Ulf Ziemann, MD, Ralf Linker, MD, Matthias Schwab, MD, Martin Marziniak, MD, Florian Then Bergh, MD, Ulrich Hofstadt-van Oy, MD, Oliver Neuhaus, MD, Uwe K. Zettl, MD, urgen Faiss, MD, Brigitte Wildemann, MD, Friedemann Paul, MD, Sven Jarius, MD, and Corinna Trebst, MD, on behalf of NEMOS (Neuromyelitis Optica Study Group) Neurol Neuroimmunol Neuroinamm 2018;5:e504. doi:10.1212/NXI.0000000000000504 Correspondence Dr. Kleiter [email protected] Abstract Objective To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). Methods This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibodyseropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the eectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. Results Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as rst-line therapy (OR 12.27, 95% CI: 1.04144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.890.99, p = 0.014), the presence of AQP4-ab- antibodies (OR 33.34, 95% CI: 1.76631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.0321.62, p = 0.046). Conclusions Our ndings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. Classification of evidence This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks. RELATED ARTICLE Editorial Plasmapheresis for acute attacks in neuromyelitis optica spectrum disorders Page e510 MORE ONLINE Class of Evidence Criteria for rating therapeutic and diagnostic studies NPub.org/coe From the Department of Neurology (I.K., A.G., K.H.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen f¨ ur Multiple Sklerose Kranke, Berg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (N.B., F. Pache), Charit´ e Universit¨ atsmedizin Berlin, and Max Delbrueck Center for Molecular Medicine, Berlin; Department of Neurology (K.F., J.F.), Asklepios Fachklinikum Teupitz; CRO Sostana GmbH and Charit´ e Universit¨ atsmedizin Berlin (K.-D.W.); Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center (F.Pache, K.R.), Charit´ e Universit¨ atsmedizin Berlin; Institute of Clinical Neuroimmunology (J.H., T.K.), Ludwig Maximilians University, Munich; Department of Neurology (O.A., H.-P.H., M.R.), Medical Faculty, Heinrich Heine University D¨ usseldorf; Department of Neurology (C.G., M. Schwab), Jena University Hospital; Department of Neurology (C.K.), University Hospital Essen; Department of Neurology (A.B.), Klinikum rechts der Isar, Technische Universit¨ at M¨ unchen, Munich; Department of Neurology (B.H.), Klinikum rechts der Isar, Technische Universit¨ at M¨ unchen and Munich Cluster for Systems Neurology (SyNergy); Department of Neurology (K.A.), University Hospital Regensburg; Institute of Neuroimmunology and MS (INIMS) and Department of Neurology (J.-P.S.), University Medical Centre Hamburg-Eppendorf, HamburgKlinik und Poliklinik f¨ ur Neurologie (S.S.), Universit¨ atsklinikum Hamburg-Eppendorf; Clinical Neuroimmunology and Neurochemistry (M. Stangel), Department of Neurology, Hannover Medical School; Department of Neurology (F.L., H.T.), University of Ulm; Fachklinik f¨ ur Neurologie Dietenbronn (H.T.), Akademisches Krankenhaus der Universit¨ at Ulm, Schwendi; Department of Neurology (C.M.), Goethe University Frankfurt; Department of Neurology & Stroke (M.K., L.Z., U. Ziemann), and Hertie-Institute for Clinical Brain Research, University of T¨ ubingen; Department of Neurology (R.L.), Friedrich- Alexander University Erlangen-Nuremberg; Department of Neurology and Neurological Intensive Care (M.M.), Isar-Amper-Clinic, Munich-East, Haar; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (U. Hofstadt-van Oy), Klinikum Westfalen, Dortmund; Department of Neurology (O.N.), SRH Krankenhaus Sigmaringen; Neuroimmunological Section (U. Zettl), Department of Neurology, University of Rostock; Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg; NeuroCure Clinical Research Center (F. Paul), Charit´ e Universit¨ atsmedizin Berlin, corporate member of Freie Universit¨ at Berlin, Humboldt-Universit¨ at zu Berlin, and Berlin Institute of Health, and Experimental and Clinical Research Center, Max Delbr¨ uck Center for Molecular Medicine and Charit´ eUniversit¨ atsmedizin Berlin; and Department of Neurology (C.T.), Hannover Medical School, Germany. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN. NEMOS (Neuromyelitis Optica Study Group) coinvestigators are listed in the appendix at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1

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Page 1: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Apheresis therapies for NMOSD attacksA retrospective study of 207 therapeutic interventions

Ingo Kleiter MD Anna Gahlen MD Nadja Borisow MD Katrin Fischer MD Klaus-Dieter Wernecke PhD

Kerstin Hellwig MD Florence Pache MD Klemens Ruprecht MD Joachim Havla MD Tania Kumpfel MD

Orhan Aktas MD Hans-Peter Hartung MDMarius Ringelstein MD Christian Geis MD Christoph Kleinschnitz MD

Achim Berthele MD Bernhard Hemmer MD Klemens Angstwurm MD Jan-Patrick Stellmann MD

Simon Schuster MD Martin Stangel MD Florian Lauda MD Hayrettin Tumani MD Christoph Mayer MD

Markus Krumbholz MD Lena Zeltner MD Ulf Ziemann MD Ralf Linker MD Matthias Schwab MD

Martin Marziniak MD Florian Then Bergh MD Ulrich Hofstadt-van Oy MD Oliver Neuhaus MD Uwe K Zettl MD

Jurgen FaissMDBrigitteWildemannMD FriedemannPaulMD Sven JariusMD andCorinnaTrebstMD onbehalf

of NEMOS (Neuromyelitis Optica Study Group)

Neurol Neuroimmunol Neuroinflamm 20185e504 doi101212NXI0000000000000504

Correspondence

Dr Kleiter

ingokleiterrubde

AbstractObjectiveTo analyze whether 1 of the 2 apheresis techniques therapeutic plasma exchange (PE) or immunoadsorption (IA) is superiorin treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for completeremission (CR)

MethodsThis retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group a nationwide networkestablished in 2008 It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or withaquaporin-4 (AQP4-ab)-antibodyndashseropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March2013 Besides descriptive data analysis of patient and attack characteristics generalized estimation equation (GEE) analyses wereapplied to compare the effectiveness of the 2 apheresis techniques A GEE model was generated to assess predictors of outcome

ResultsTwo hundred and seven attacks in 105 patients (87 AQP4-ab-antibody seropositive) were treated with at least 1 apheresistherapy Neither PE nor IA was proven superior in the therapy of NMOSD attacks CR was only achieved with early apheresistherapy Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 1227 95 CI 104ndash14491 p =0047) time from onset of attack to start of therapy in days (OR 094 95 CI 089ndash099 p = 0014) the presence of AQP4-ab-antibodies (OR 3334 95 CI 176ndash63117 p = 0019) and monofocal attack manifestation (OR 471 95 CI 103ndash2162 p =0046)

ConclusionsOur findings suggest early use of an apheresis therapy in NMOSD attacks particularly in AQP4-ab-seropositive patients Nosuperiority was shown for one of the 2 apheresis techniques

Classification of evidenceThis study provides Class IV evidence that for patients with NMOSD neither PE nor IA is superior in the treatment ofattacks

RELATED ARTICLE

EditorialPlasmapheresis for acuteattacks in neuromyelitisoptica spectrum disorders

Page e510

MORE ONLINE

Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

NPuborgcoe

From the Department of Neurology (IK AG KH) St Josef Hospital Ruhr University Bochum Marianne-Strauszlig-Klinik (IK) Behandlungszentrum Kempfenhausen fur Multiple SkleroseKranke Berg NeuroCureClinical ResearchCenter andExperimental andClinical ResearchCenter (NB F Pache) Charite UniversitatsmedizinBerlin andMaxDelbrueck Center forMolecularMedicine Berlin Department of Neurology (KF JF) Asklepios Fachklinikum Teupitz CRO Sostana GmbH and Charite Universitatsmedizin Berlin (K-DW) Department of Neurology andClinical and Experimental Multiple Sclerosis Research Center (FPache KR) Charite Universitatsmedizin Berlin Institute of Clinical Neuroimmunology (JH TK) Ludwig MaximiliansUniversityMunich DepartmentofNeurology (OA H-PHMR)Medical Faculty HeinrichHeineUniversity Dusseldorf DepartmentofNeurology (CGM Schwab) JenaUniversity HospitalDepartment of Neurology (CK) University Hospital Essen Department of Neurology (AB) Klinikum rechts der Isar Technische Universitat Munchen Munich Department of Neurology(BH) Klinikum rechts der Isar Technische Universitat Munchen and Munich Cluster for Systems Neurology (SyNergy) Department of Neurology (KA) University Hospital RegensburgInstitute of Neuroimmunology and MS (INIMS) and Department of Neurology (J-PS) University Medical Centre Hamburg-Eppendorf HamburgKlinik und Poliklinik fur Neurologie (SS)UniversitatsklinikumHamburg-Eppendorf Clinical Neuroimmunology andNeurochemistry (M Stangel) Department ofNeurology HannoverMedical School Department of Neurology (FLHT) University of Ulm Fachklinik fur Neurologie Dietenbronn (HT) Akademisches Krankenhaus der Universitat Ulm Schwendi Department of Neurology (CM) Goethe UniversityFrankfurt Department of Neurology amp Stroke (MK LZ U Ziemann) and Hertie-Institute for Clinical Brain Research University of Tubingen Department of Neurology (RL) Friedrich-Alexander University Erlangen-Nuremberg Department of Neurology and Neurological Intensive Care (MM) Isar-Amper-Clinic Munich-East Haar Department of Neurology (FTB)University of Leipzig Department of Neurology (U Hofstadt-vanOy) KlinikumWestfalen Dortmund Department of Neurology (ON) SRHKrankenhaus Sigmaringen NeuroimmunologicalSection (U Zettl) Department of Neurology University of Rostock Molecular Neuroimmunology Group (BW SJ) Department of Neurology University of Heidelberg NeuroCure ClinicalResearch Center (F Paul) Charite Universitatsmedizin Berlin corporate member of Freie Universitat Berlin Humboldt-Universitat zu Berlin and Berlin Institute of Health and ExperimentalandClinical Research CenterMax Delbruck Center forMolecularMedicine andCharitendashUniversitatsmedizin Berlin andDepartment ofNeurology (CT) HannoverMedical School Germany

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgNN

NEMOS (Neuromyelitis Optica Study Group) coinvestigators are listed in the appendix at the end of the article

The Article Processing Charge was funded by the authors

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

Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Adequate treatment of attacks in neuromyelitis optica spec-trum disorders (NMOSDs) is crucial as long-term disability inthese patients is accumulated by poor recovery fromattacks12 We have previously shown in a retrospective ana-lysis that aggressive treatment of attacks particularly escala-tion of attack therapy can improve the attack outcome withthe sequence of treatments being crucial3 In particular ourstudy suggested that first-line therapy with apheresis therapiesmay be superior to high-dose steroid pulse therapy in attacksinvolving the spinal cord

Apheresis therapies aim to eliminate pathogenic antibodiesand other proinflammatory factors from the patientrsquos circu-lation Two major techniques are used Therapeutic plasmaexchange (PE) separates patientrsquos plasma from the wholeblood4 Centrifugation devices or highly permeable filters areused to separate the plasma filtrate with molecules up to 1000kD including immunoglobulins complement factors andalbumin from blood cells The plasma filtrate is discarded andeither 5 albumin solution or fresh-frozen plasma is added tothe filtered blood before reinfusion For immunoadsorption(IA) plasma separation is equally needed as the first step5

The plasma fraction is then passed through an IA deviceSingle-pass devices use tryptophan as an adsorber whereasreusable devices use in most cases the Staphylococcus aureuscell wallndashderived protein A Several plasma constituentsincluding immunoglobulins and complement are removedfrom the plasma whereas albumin and clotting factors aremostly spared and reinfused Besides the immediate intra-vasal reduction of autoantibodies eg those targetingaquaporin-4 (AQP4-ab)6 PE and IA also show effects onimmunoglobulin redistribution and subsequent immuno-modulatory changes7ndash10

It remains to be elucidated whether one of the apheresistherapies might be superior in the treatment of NMOSDattacks We therefore conducted a retrospective analysis of207 NMOSD attacks in 105 patients who were treated eitherwith PE or IA and aimed to identify predictive factors fora favorable therapeutic response

MethodsStudy designThis retrospective cohort study is based on data of the registryof the German Neuromyelitis Optica Study Group (NEMOSnemos-netde) Final data entry varied across centers and wasperformed between January 2012 and March 2013 At thistime the registry contained 215 patients with both NMO

diagnosed according to the 2006 Wingerchuk criteria11 andAQP4-ab-seropositive NMOSD12

Previously we identified and characterized 1124 attacks in186 patients with NMO and NMOSD treated at 6 regionalhospitals and 16 tertiary referral centres3 Of these all attackstreated with an apheresis therapy PE or IA were included inthis subgroup analysis Twelve centers used both PE and IA 9centers used only PE and 1 center used only IA Furtherdetails on data collection quality and processing can be foundin the original characterization of the cohort3

For each patient demographic and diagnostic data as well asthe number and dates of acute attacks from disease onset tolast follow-up were included in the analysis Moreover attack-related clinical features (Expanded Disability Status Scale[EDSS] and visual acuity were available) and information onattack treatment and outcome were assessed from the patientrecords The definition of an attack followed the definitionused for MS relapses an objective neurologic worseninglasting for at least 24 hours in the absence of fever or infec-tions and occurring more than 30 days after the previousattack All attacks were confirmed by neurologic examination

PE and IA were conducted according to local standard pro-cedures IA was performed using tryptophan (TR-350Diamed Medizintechnik GmbH) or protein A (Immuno-sorba Fresenius Medical Care) as an adsorber One apheresistreatment course was defined as at least 3 therapeutic PEs orat least 3 IAs

Short-term remission status of attack-related neurologic def-icits was chosen as the primary outcome parameter and ratedas complete remission (CR) when there was full recoverypartial remission (PR) when there was incomplete recoveryand no remission (NR) when there was no improvement at allof the attack-related neurologic deficits in relation to thetherapy cycle The remission status was evaluated immedi-ately after the end of the apheresis therapy

The primary research question was to evaluate whether PE orIA was more beneficial for NMOSD attack therapy Given itsretrospective nature this study was expected to provide ClassIV evidence

Standard protocol approvals registrationsand patient consentsEthics approval was obtained from the Institutional ReviewBoard of the Ruhr University Bochum (4573-13) and of theparticipating centers Patients provided written informed

GlossaryAQP4-ab = aquaporin-4 CR = complete remission EDSS = Expanded Disability Status Scale GEE = generalized estimatingequation IA = immunoadsorption IQR = interquartile range NEMOS = Neuromyelitis Optica Study Group NMOSD =neuromyelitis optica spectrum disorderNR = no remissionON = optic neuritis PE = plasma exchange PR = partial remission

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

consent The study was performed according to ICHGCPand current German legal requirements it was not registeredbecause registration was neither required nor available forretrospective noninterventional studies at the time of datacollection

Statistical analysisPatient characteristics were descriptively analyzed Com-parison of the use as first-line or consecutive treatment of PEand IA as well as distribution among treatment courses andclinical attack manifestation was performed using the exactχ2 test Generalized estimating equations (GEEs)13 withremission status (CR vs PR or NR) of attacks as the de-pendent variable were used for the analysis of direct com-parisons of the effectiveness of PE vs IA in the first- orsecond-line use ORs with 95 CIs and corresponding pvalues were given GEE analyses with the same dependentvariable were also used to identify predictors of outcomeThe following variables were analyzed sex age at attacktime from onset of disease to attack AQP4-status NMO vsNMOSD clinical manifestation (absence or presence ofmyelitis isolated manifestation of optic neuritis [ON] ormyelitis vs simultaneous) disease-modifying immunother-apy time from onset of attack to initiation of therapyapheresis as first- vs second-line therapy technique oftherapy (PE vs IA) and center (to control for a center ef-fect) We indicated missing data in the figure legends thecorresponding observations were dropped in the multivari-ate statistical analyses as usual p Values lt 005 were con-sidered statistically significant All tests were performed asexploratory data analysis therefore no adjustments formultiple testing were made IBM SPSS Statistics Version 24

STATA (Data Analysis and Statistical Software StataCorpLP) and StatXact 6 (CYTEL Software Corp) were used forcomputations and GraphPad Prism version 60f (GraphPadSoftware) for visualization

Data availabilityAs far as permitted according to data protection requirementsand consent provided by the participants original data areavailable from the corresponding author on request from anyqualified investigator within 5 years after publication

ResultsDemographic and clinical characteristicsAmong the initial 1124 attacks in 186 patients 253 attackswere excluded due to insufficient data 42 were not treatedand 622 attacks did not receive an apheresis therapy(figure 1)

Two hundred and seven attacks in 105 patients were treatedwith apheresis therapies of these 189 with a single apheresistherapy and 18 with multiple apheresis therapies A total of192 PE (in 99 patients) and 38 IA procedures (in 23 patients)each with at least 3 exchanges were examined Patient andattack characteristics are given in table 1

Apheresis therapies were applied as first-line choice in 72attacks as second-line (another attack therapy was given be-fore the start of apheresis therapy) in 98 attacks and as third-line or later (2 or more previous attack therapies were given)in 37 attacks Time from onset of attack to start of therapy was

Figure 1 Study flow chart

HD-S = high-dose IV steroids IA = immunoadsorption PE = plasma exchange

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 3

median 1 day (interquartile range [IQR] 0ndash4 n = 58) in first-line therapy 115 days (IQR 50ndash2275 n = 92) in second-linetherapy and 155 days (IQR 10ndash4575 n = 32) in third-line orlater therapy No difference between PE and IA usage wasfound in terms of distribution among lines of therapy (p =

0303 exact χ2 test) and clinical attack manifestation (p =0055 exact χ2 test figure 2)

PE and IA are both effective in the therapy ofNMOSD attacksBoth PE and IA were effective and induced at least PR in mostattacks when used as first- to fifth-line therapy (figure 3 A andB) Although attacks treated with IA always showed a clinicalresponse as nonresponders were not found in this treatmentgroup we could not show a difference in efficacy between PEand IA (p = 0264 GEE analysis CR as the dependent vari-able) (figure 3C) There was also no difference for the changein EDSS between PE and IA (figure 3D) Because of over-lapping effects of preceding attack therapies we excludedthird- to fifth-line apheresis therapies from this statisticalanalysis Clinical characteristics of first- and second-lineapheresis therapies are given in table 2

The use of apheresis therapies as first-line andearly therapy is associated with the highestremission rateCR was only reached with apheresis therapy initiated early(first- and second-line therapy in IA first- to third-line therapyin PE) Forty percent of patients had CR when apheresistherapy was started without delay ie day 0ndash2 after onset ofsymptoms but improvement declined stepwise with latertreatment start (figure 3E) No patient completely recoveredwhen apheresis therapy was commenced later than 20 daysafter symptom onset CR was reached more often with earlyPE (start after symptom onset day 0ndash6 29 day ge7 37 n =144 attacks) than with early IA treatment (start after symptomonset day 0ndash6 67 day ge7 0 n = 28 attacks)

Table 1 Patient characteristics

Patients (n = 105)

NMOa (n ) 84 (80)

AQP4-ab positive NMOSDb (n ) 21 (20)

Female sex (n ) 82 (78)

Age at onset (y mean SD) 434 (147)

Disease onset to last visit (y median IQR) 59 (30ndash101)

AQP4-ab positivec (n ) 91 (87)

ge1 optic neuritis ever (n ) 87 (83)

ge1 myelitis ever (n ) 102 (97)

Relapsing disease coursed (n ) 99 (94)

Attackspatient (n IQR) 5 (3ndash8)

ARR (n = 97 median IQR)e 091 (063ndash146)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody ARR = annualized re-lapse rate IQR = interquartile range NMO = neuromyelitis optica NMOSD =neuromyelitis optica spectrum disordera According to 2006 Wingerchuk criteria11b According to Wingerchuk et al 200712c AQP4-ab result not available in 1 NMO patientd Two or more attackse Only patients with follow-up gt1 year

Figure 2 Overview of apheresis therapies

Plasma exchange and immunoadsorption were applied at similar frequencies for escalation from first- to fifth-line treatment (A) and for various clinicalmanifestations (B) of NMOSD attacks The chi-square test was used for statistical analysis IA = immunoadsorption MY = myelitis ON = optic neuritis PE =plasma exchange

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

For multivariate GEE analyses of predictors of CR we fur-ther excluded attacks that were treated with an apheresistherapy in both first and second line of treatment (n = 3)attacks where a second-line apheresis therapy was not pre-ceded by high-dose steroids (n = 4) and attacks with missingclinical information (n = 24) Therefore multivariate

analyses were possible in 139 attacks in 79 patients (see flowchart figure 1)

Strong predictors for CR were the use of apheresis therapy asfirst-line therapy (OR 12271 95CI 104ndash14491 p = 0047)time from onset of attack to start of therapy in days (OR 0937

Figure 3 Clinical outcome of apheresis therapies for NMOSD attacks

Remission status of all attacks (total n = 207) treatedwith plasma exchange (A) or immunoadsorption (B)Missing data plasmaexchange 1st line n = 1 2nd linen = 4 3rd line n = 6 and 4th line n = 1 (C) Short-term remission status after first- or second-line therapy with plasma exchange or immunoadsorptionTreatment courses with PEIA as first- and second-line therapy were excluded (n = 2) Missing data plasma exchange 1st line n = 1 and 2nd line n = 4Generalized estimationequationswith complete remission as thedependent variablewereused for statistical analysis (D) Change in EDSSafter first or second-line therapywithplasmaexchange (gray triangles) or immunoadsorption (red triangles)Missing data plasmaexchange 1st line n = 19 2nd line n = 30missingdata immunoadsorption 1st line n = 7 and 2nd line n = 15 One out of range value (immunoadsorption minus60) is not shown Generalized estimation equationswere used for statistical analysis TheMedian is highlighted as black line (E) Short-term remission status after apheresis therapy according to time intervals ofattack onset to start of therapy CR = complete remission IA = immunoadsorption NR = no remission PE = plasma exchange PR = partial remission

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 5

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

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

Page 2: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

Adequate treatment of attacks in neuromyelitis optica spec-trum disorders (NMOSDs) is crucial as long-term disability inthese patients is accumulated by poor recovery fromattacks12 We have previously shown in a retrospective ana-lysis that aggressive treatment of attacks particularly escala-tion of attack therapy can improve the attack outcome withthe sequence of treatments being crucial3 In particular ourstudy suggested that first-line therapy with apheresis therapiesmay be superior to high-dose steroid pulse therapy in attacksinvolving the spinal cord

Apheresis therapies aim to eliminate pathogenic antibodiesand other proinflammatory factors from the patientrsquos circu-lation Two major techniques are used Therapeutic plasmaexchange (PE) separates patientrsquos plasma from the wholeblood4 Centrifugation devices or highly permeable filters areused to separate the plasma filtrate with molecules up to 1000kD including immunoglobulins complement factors andalbumin from blood cells The plasma filtrate is discarded andeither 5 albumin solution or fresh-frozen plasma is added tothe filtered blood before reinfusion For immunoadsorption(IA) plasma separation is equally needed as the first step5

The plasma fraction is then passed through an IA deviceSingle-pass devices use tryptophan as an adsorber whereasreusable devices use in most cases the Staphylococcus aureuscell wallndashderived protein A Several plasma constituentsincluding immunoglobulins and complement are removedfrom the plasma whereas albumin and clotting factors aremostly spared and reinfused Besides the immediate intra-vasal reduction of autoantibodies eg those targetingaquaporin-4 (AQP4-ab)6 PE and IA also show effects onimmunoglobulin redistribution and subsequent immuno-modulatory changes7ndash10

It remains to be elucidated whether one of the apheresistherapies might be superior in the treatment of NMOSDattacks We therefore conducted a retrospective analysis of207 NMOSD attacks in 105 patients who were treated eitherwith PE or IA and aimed to identify predictive factors fora favorable therapeutic response

MethodsStudy designThis retrospective cohort study is based on data of the registryof the German Neuromyelitis Optica Study Group (NEMOSnemos-netde) Final data entry varied across centers and wasperformed between January 2012 and March 2013 At thistime the registry contained 215 patients with both NMO

diagnosed according to the 2006 Wingerchuk criteria11 andAQP4-ab-seropositive NMOSD12

Previously we identified and characterized 1124 attacks in186 patients with NMO and NMOSD treated at 6 regionalhospitals and 16 tertiary referral centres3 Of these all attackstreated with an apheresis therapy PE or IA were included inthis subgroup analysis Twelve centers used both PE and IA 9centers used only PE and 1 center used only IA Furtherdetails on data collection quality and processing can be foundin the original characterization of the cohort3

For each patient demographic and diagnostic data as well asthe number and dates of acute attacks from disease onset tolast follow-up were included in the analysis Moreover attack-related clinical features (Expanded Disability Status Scale[EDSS] and visual acuity were available) and information onattack treatment and outcome were assessed from the patientrecords The definition of an attack followed the definitionused for MS relapses an objective neurologic worseninglasting for at least 24 hours in the absence of fever or infec-tions and occurring more than 30 days after the previousattack All attacks were confirmed by neurologic examination

PE and IA were conducted according to local standard pro-cedures IA was performed using tryptophan (TR-350Diamed Medizintechnik GmbH) or protein A (Immuno-sorba Fresenius Medical Care) as an adsorber One apheresistreatment course was defined as at least 3 therapeutic PEs orat least 3 IAs

Short-term remission status of attack-related neurologic def-icits was chosen as the primary outcome parameter and ratedas complete remission (CR) when there was full recoverypartial remission (PR) when there was incomplete recoveryand no remission (NR) when there was no improvement at allof the attack-related neurologic deficits in relation to thetherapy cycle The remission status was evaluated immedi-ately after the end of the apheresis therapy

The primary research question was to evaluate whether PE orIA was more beneficial for NMOSD attack therapy Given itsretrospective nature this study was expected to provide ClassIV evidence

Standard protocol approvals registrationsand patient consentsEthics approval was obtained from the Institutional ReviewBoard of the Ruhr University Bochum (4573-13) and of theparticipating centers Patients provided written informed

GlossaryAQP4-ab = aquaporin-4 CR = complete remission EDSS = Expanded Disability Status Scale GEE = generalized estimatingequation IA = immunoadsorption IQR = interquartile range NEMOS = Neuromyelitis Optica Study Group NMOSD =neuromyelitis optica spectrum disorderNR = no remissionON = optic neuritis PE = plasma exchange PR = partial remission

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

consent The study was performed according to ICHGCPand current German legal requirements it was not registeredbecause registration was neither required nor available forretrospective noninterventional studies at the time of datacollection

Statistical analysisPatient characteristics were descriptively analyzed Com-parison of the use as first-line or consecutive treatment of PEand IA as well as distribution among treatment courses andclinical attack manifestation was performed using the exactχ2 test Generalized estimating equations (GEEs)13 withremission status (CR vs PR or NR) of attacks as the de-pendent variable were used for the analysis of direct com-parisons of the effectiveness of PE vs IA in the first- orsecond-line use ORs with 95 CIs and corresponding pvalues were given GEE analyses with the same dependentvariable were also used to identify predictors of outcomeThe following variables were analyzed sex age at attacktime from onset of disease to attack AQP4-status NMO vsNMOSD clinical manifestation (absence or presence ofmyelitis isolated manifestation of optic neuritis [ON] ormyelitis vs simultaneous) disease-modifying immunother-apy time from onset of attack to initiation of therapyapheresis as first- vs second-line therapy technique oftherapy (PE vs IA) and center (to control for a center ef-fect) We indicated missing data in the figure legends thecorresponding observations were dropped in the multivari-ate statistical analyses as usual p Values lt 005 were con-sidered statistically significant All tests were performed asexploratory data analysis therefore no adjustments formultiple testing were made IBM SPSS Statistics Version 24

STATA (Data Analysis and Statistical Software StataCorpLP) and StatXact 6 (CYTEL Software Corp) were used forcomputations and GraphPad Prism version 60f (GraphPadSoftware) for visualization

Data availabilityAs far as permitted according to data protection requirementsand consent provided by the participants original data areavailable from the corresponding author on request from anyqualified investigator within 5 years after publication

ResultsDemographic and clinical characteristicsAmong the initial 1124 attacks in 186 patients 253 attackswere excluded due to insufficient data 42 were not treatedand 622 attacks did not receive an apheresis therapy(figure 1)

Two hundred and seven attacks in 105 patients were treatedwith apheresis therapies of these 189 with a single apheresistherapy and 18 with multiple apheresis therapies A total of192 PE (in 99 patients) and 38 IA procedures (in 23 patients)each with at least 3 exchanges were examined Patient andattack characteristics are given in table 1

Apheresis therapies were applied as first-line choice in 72attacks as second-line (another attack therapy was given be-fore the start of apheresis therapy) in 98 attacks and as third-line or later (2 or more previous attack therapies were given)in 37 attacks Time from onset of attack to start of therapy was

Figure 1 Study flow chart

HD-S = high-dose IV steroids IA = immunoadsorption PE = plasma exchange

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 3

median 1 day (interquartile range [IQR] 0ndash4 n = 58) in first-line therapy 115 days (IQR 50ndash2275 n = 92) in second-linetherapy and 155 days (IQR 10ndash4575 n = 32) in third-line orlater therapy No difference between PE and IA usage wasfound in terms of distribution among lines of therapy (p =

0303 exact χ2 test) and clinical attack manifestation (p =0055 exact χ2 test figure 2)

PE and IA are both effective in the therapy ofNMOSD attacksBoth PE and IA were effective and induced at least PR in mostattacks when used as first- to fifth-line therapy (figure 3 A andB) Although attacks treated with IA always showed a clinicalresponse as nonresponders were not found in this treatmentgroup we could not show a difference in efficacy between PEand IA (p = 0264 GEE analysis CR as the dependent vari-able) (figure 3C) There was also no difference for the changein EDSS between PE and IA (figure 3D) Because of over-lapping effects of preceding attack therapies we excludedthird- to fifth-line apheresis therapies from this statisticalanalysis Clinical characteristics of first- and second-lineapheresis therapies are given in table 2

The use of apheresis therapies as first-line andearly therapy is associated with the highestremission rateCR was only reached with apheresis therapy initiated early(first- and second-line therapy in IA first- to third-line therapyin PE) Forty percent of patients had CR when apheresistherapy was started without delay ie day 0ndash2 after onset ofsymptoms but improvement declined stepwise with latertreatment start (figure 3E) No patient completely recoveredwhen apheresis therapy was commenced later than 20 daysafter symptom onset CR was reached more often with earlyPE (start after symptom onset day 0ndash6 29 day ge7 37 n =144 attacks) than with early IA treatment (start after symptomonset day 0ndash6 67 day ge7 0 n = 28 attacks)

Table 1 Patient characteristics

Patients (n = 105)

NMOa (n ) 84 (80)

AQP4-ab positive NMOSDb (n ) 21 (20)

Female sex (n ) 82 (78)

Age at onset (y mean SD) 434 (147)

Disease onset to last visit (y median IQR) 59 (30ndash101)

AQP4-ab positivec (n ) 91 (87)

ge1 optic neuritis ever (n ) 87 (83)

ge1 myelitis ever (n ) 102 (97)

Relapsing disease coursed (n ) 99 (94)

Attackspatient (n IQR) 5 (3ndash8)

ARR (n = 97 median IQR)e 091 (063ndash146)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody ARR = annualized re-lapse rate IQR = interquartile range NMO = neuromyelitis optica NMOSD =neuromyelitis optica spectrum disordera According to 2006 Wingerchuk criteria11b According to Wingerchuk et al 200712c AQP4-ab result not available in 1 NMO patientd Two or more attackse Only patients with follow-up gt1 year

Figure 2 Overview of apheresis therapies

Plasma exchange and immunoadsorption were applied at similar frequencies for escalation from first- to fifth-line treatment (A) and for various clinicalmanifestations (B) of NMOSD attacks The chi-square test was used for statistical analysis IA = immunoadsorption MY = myelitis ON = optic neuritis PE =plasma exchange

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

For multivariate GEE analyses of predictors of CR we fur-ther excluded attacks that were treated with an apheresistherapy in both first and second line of treatment (n = 3)attacks where a second-line apheresis therapy was not pre-ceded by high-dose steroids (n = 4) and attacks with missingclinical information (n = 24) Therefore multivariate

analyses were possible in 139 attacks in 79 patients (see flowchart figure 1)

Strong predictors for CR were the use of apheresis therapy asfirst-line therapy (OR 12271 95CI 104ndash14491 p = 0047)time from onset of attack to start of therapy in days (OR 0937

Figure 3 Clinical outcome of apheresis therapies for NMOSD attacks

Remission status of all attacks (total n = 207) treatedwith plasma exchange (A) or immunoadsorption (B)Missing data plasmaexchange 1st line n = 1 2nd linen = 4 3rd line n = 6 and 4th line n = 1 (C) Short-term remission status after first- or second-line therapy with plasma exchange or immunoadsorptionTreatment courses with PEIA as first- and second-line therapy were excluded (n = 2) Missing data plasma exchange 1st line n = 1 and 2nd line n = 4Generalized estimationequationswith complete remission as thedependent variablewereused for statistical analysis (D) Change in EDSSafter first or second-line therapywithplasmaexchange (gray triangles) or immunoadsorption (red triangles)Missing data plasmaexchange 1st line n = 19 2nd line n = 30missingdata immunoadsorption 1st line n = 7 and 2nd line n = 15 One out of range value (immunoadsorption minus60) is not shown Generalized estimation equationswere used for statistical analysis TheMedian is highlighted as black line (E) Short-term remission status after apheresis therapy according to time intervals ofattack onset to start of therapy CR = complete remission IA = immunoadsorption NR = no remission PE = plasma exchange PR = partial remission

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 5

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 3: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

consent The study was performed according to ICHGCPand current German legal requirements it was not registeredbecause registration was neither required nor available forretrospective noninterventional studies at the time of datacollection

Statistical analysisPatient characteristics were descriptively analyzed Com-parison of the use as first-line or consecutive treatment of PEand IA as well as distribution among treatment courses andclinical attack manifestation was performed using the exactχ2 test Generalized estimating equations (GEEs)13 withremission status (CR vs PR or NR) of attacks as the de-pendent variable were used for the analysis of direct com-parisons of the effectiveness of PE vs IA in the first- orsecond-line use ORs with 95 CIs and corresponding pvalues were given GEE analyses with the same dependentvariable were also used to identify predictors of outcomeThe following variables were analyzed sex age at attacktime from onset of disease to attack AQP4-status NMO vsNMOSD clinical manifestation (absence or presence ofmyelitis isolated manifestation of optic neuritis [ON] ormyelitis vs simultaneous) disease-modifying immunother-apy time from onset of attack to initiation of therapyapheresis as first- vs second-line therapy technique oftherapy (PE vs IA) and center (to control for a center ef-fect) We indicated missing data in the figure legends thecorresponding observations were dropped in the multivari-ate statistical analyses as usual p Values lt 005 were con-sidered statistically significant All tests were performed asexploratory data analysis therefore no adjustments formultiple testing were made IBM SPSS Statistics Version 24

STATA (Data Analysis and Statistical Software StataCorpLP) and StatXact 6 (CYTEL Software Corp) were used forcomputations and GraphPad Prism version 60f (GraphPadSoftware) for visualization

Data availabilityAs far as permitted according to data protection requirementsand consent provided by the participants original data areavailable from the corresponding author on request from anyqualified investigator within 5 years after publication

ResultsDemographic and clinical characteristicsAmong the initial 1124 attacks in 186 patients 253 attackswere excluded due to insufficient data 42 were not treatedand 622 attacks did not receive an apheresis therapy(figure 1)

Two hundred and seven attacks in 105 patients were treatedwith apheresis therapies of these 189 with a single apheresistherapy and 18 with multiple apheresis therapies A total of192 PE (in 99 patients) and 38 IA procedures (in 23 patients)each with at least 3 exchanges were examined Patient andattack characteristics are given in table 1

Apheresis therapies were applied as first-line choice in 72attacks as second-line (another attack therapy was given be-fore the start of apheresis therapy) in 98 attacks and as third-line or later (2 or more previous attack therapies were given)in 37 attacks Time from onset of attack to start of therapy was

Figure 1 Study flow chart

HD-S = high-dose IV steroids IA = immunoadsorption PE = plasma exchange

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 3

median 1 day (interquartile range [IQR] 0ndash4 n = 58) in first-line therapy 115 days (IQR 50ndash2275 n = 92) in second-linetherapy and 155 days (IQR 10ndash4575 n = 32) in third-line orlater therapy No difference between PE and IA usage wasfound in terms of distribution among lines of therapy (p =

0303 exact χ2 test) and clinical attack manifestation (p =0055 exact χ2 test figure 2)

PE and IA are both effective in the therapy ofNMOSD attacksBoth PE and IA were effective and induced at least PR in mostattacks when used as first- to fifth-line therapy (figure 3 A andB) Although attacks treated with IA always showed a clinicalresponse as nonresponders were not found in this treatmentgroup we could not show a difference in efficacy between PEand IA (p = 0264 GEE analysis CR as the dependent vari-able) (figure 3C) There was also no difference for the changein EDSS between PE and IA (figure 3D) Because of over-lapping effects of preceding attack therapies we excludedthird- to fifth-line apheresis therapies from this statisticalanalysis Clinical characteristics of first- and second-lineapheresis therapies are given in table 2

The use of apheresis therapies as first-line andearly therapy is associated with the highestremission rateCR was only reached with apheresis therapy initiated early(first- and second-line therapy in IA first- to third-line therapyin PE) Forty percent of patients had CR when apheresistherapy was started without delay ie day 0ndash2 after onset ofsymptoms but improvement declined stepwise with latertreatment start (figure 3E) No patient completely recoveredwhen apheresis therapy was commenced later than 20 daysafter symptom onset CR was reached more often with earlyPE (start after symptom onset day 0ndash6 29 day ge7 37 n =144 attacks) than with early IA treatment (start after symptomonset day 0ndash6 67 day ge7 0 n = 28 attacks)

Table 1 Patient characteristics

Patients (n = 105)

NMOa (n ) 84 (80)

AQP4-ab positive NMOSDb (n ) 21 (20)

Female sex (n ) 82 (78)

Age at onset (y mean SD) 434 (147)

Disease onset to last visit (y median IQR) 59 (30ndash101)

AQP4-ab positivec (n ) 91 (87)

ge1 optic neuritis ever (n ) 87 (83)

ge1 myelitis ever (n ) 102 (97)

Relapsing disease coursed (n ) 99 (94)

Attackspatient (n IQR) 5 (3ndash8)

ARR (n = 97 median IQR)e 091 (063ndash146)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody ARR = annualized re-lapse rate IQR = interquartile range NMO = neuromyelitis optica NMOSD =neuromyelitis optica spectrum disordera According to 2006 Wingerchuk criteria11b According to Wingerchuk et al 200712c AQP4-ab result not available in 1 NMO patientd Two or more attackse Only patients with follow-up gt1 year

Figure 2 Overview of apheresis therapies

Plasma exchange and immunoadsorption were applied at similar frequencies for escalation from first- to fifth-line treatment (A) and for various clinicalmanifestations (B) of NMOSD attacks The chi-square test was used for statistical analysis IA = immunoadsorption MY = myelitis ON = optic neuritis PE =plasma exchange

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

For multivariate GEE analyses of predictors of CR we fur-ther excluded attacks that were treated with an apheresistherapy in both first and second line of treatment (n = 3)attacks where a second-line apheresis therapy was not pre-ceded by high-dose steroids (n = 4) and attacks with missingclinical information (n = 24) Therefore multivariate

analyses were possible in 139 attacks in 79 patients (see flowchart figure 1)

Strong predictors for CR were the use of apheresis therapy asfirst-line therapy (OR 12271 95CI 104ndash14491 p = 0047)time from onset of attack to start of therapy in days (OR 0937

Figure 3 Clinical outcome of apheresis therapies for NMOSD attacks

Remission status of all attacks (total n = 207) treatedwith plasma exchange (A) or immunoadsorption (B)Missing data plasmaexchange 1st line n = 1 2nd linen = 4 3rd line n = 6 and 4th line n = 1 (C) Short-term remission status after first- or second-line therapy with plasma exchange or immunoadsorptionTreatment courses with PEIA as first- and second-line therapy were excluded (n = 2) Missing data plasma exchange 1st line n = 1 and 2nd line n = 4Generalized estimationequationswith complete remission as thedependent variablewereused for statistical analysis (D) Change in EDSSafter first or second-line therapywithplasmaexchange (gray triangles) or immunoadsorption (red triangles)Missing data plasmaexchange 1st line n = 19 2nd line n = 30missingdata immunoadsorption 1st line n = 7 and 2nd line n = 15 One out of range value (immunoadsorption minus60) is not shown Generalized estimation equationswere used for statistical analysis TheMedian is highlighted as black line (E) Short-term remission status after apheresis therapy according to time intervals ofattack onset to start of therapy CR = complete remission IA = immunoadsorption NR = no remission PE = plasma exchange PR = partial remission

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 5

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 4: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

median 1 day (interquartile range [IQR] 0ndash4 n = 58) in first-line therapy 115 days (IQR 50ndash2275 n = 92) in second-linetherapy and 155 days (IQR 10ndash4575 n = 32) in third-line orlater therapy No difference between PE and IA usage wasfound in terms of distribution among lines of therapy (p =

0303 exact χ2 test) and clinical attack manifestation (p =0055 exact χ2 test figure 2)

PE and IA are both effective in the therapy ofNMOSD attacksBoth PE and IA were effective and induced at least PR in mostattacks when used as first- to fifth-line therapy (figure 3 A andB) Although attacks treated with IA always showed a clinicalresponse as nonresponders were not found in this treatmentgroup we could not show a difference in efficacy between PEand IA (p = 0264 GEE analysis CR as the dependent vari-able) (figure 3C) There was also no difference for the changein EDSS between PE and IA (figure 3D) Because of over-lapping effects of preceding attack therapies we excludedthird- to fifth-line apheresis therapies from this statisticalanalysis Clinical characteristics of first- and second-lineapheresis therapies are given in table 2

The use of apheresis therapies as first-line andearly therapy is associated with the highestremission rateCR was only reached with apheresis therapy initiated early(first- and second-line therapy in IA first- to third-line therapyin PE) Forty percent of patients had CR when apheresistherapy was started without delay ie day 0ndash2 after onset ofsymptoms but improvement declined stepwise with latertreatment start (figure 3E) No patient completely recoveredwhen apheresis therapy was commenced later than 20 daysafter symptom onset CR was reached more often with earlyPE (start after symptom onset day 0ndash6 29 day ge7 37 n =144 attacks) than with early IA treatment (start after symptomonset day 0ndash6 67 day ge7 0 n = 28 attacks)

Table 1 Patient characteristics

Patients (n = 105)

NMOa (n ) 84 (80)

AQP4-ab positive NMOSDb (n ) 21 (20)

Female sex (n ) 82 (78)

Age at onset (y mean SD) 434 (147)

Disease onset to last visit (y median IQR) 59 (30ndash101)

AQP4-ab positivec (n ) 91 (87)

ge1 optic neuritis ever (n ) 87 (83)

ge1 myelitis ever (n ) 102 (97)

Relapsing disease coursed (n ) 99 (94)

Attackspatient (n IQR) 5 (3ndash8)

ARR (n = 97 median IQR)e 091 (063ndash146)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody ARR = annualized re-lapse rate IQR = interquartile range NMO = neuromyelitis optica NMOSD =neuromyelitis optica spectrum disordera According to 2006 Wingerchuk criteria11b According to Wingerchuk et al 200712c AQP4-ab result not available in 1 NMO patientd Two or more attackse Only patients with follow-up gt1 year

Figure 2 Overview of apheresis therapies

Plasma exchange and immunoadsorption were applied at similar frequencies for escalation from first- to fifth-line treatment (A) and for various clinicalmanifestations (B) of NMOSD attacks The chi-square test was used for statistical analysis IA = immunoadsorption MY = myelitis ON = optic neuritis PE =plasma exchange

4 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

For multivariate GEE analyses of predictors of CR we fur-ther excluded attacks that were treated with an apheresistherapy in both first and second line of treatment (n = 3)attacks where a second-line apheresis therapy was not pre-ceded by high-dose steroids (n = 4) and attacks with missingclinical information (n = 24) Therefore multivariate

analyses were possible in 139 attacks in 79 patients (see flowchart figure 1)

Strong predictors for CR were the use of apheresis therapy asfirst-line therapy (OR 12271 95CI 104ndash14491 p = 0047)time from onset of attack to start of therapy in days (OR 0937

Figure 3 Clinical outcome of apheresis therapies for NMOSD attacks

Remission status of all attacks (total n = 207) treatedwith plasma exchange (A) or immunoadsorption (B)Missing data plasmaexchange 1st line n = 1 2nd linen = 4 3rd line n = 6 and 4th line n = 1 (C) Short-term remission status after first- or second-line therapy with plasma exchange or immunoadsorptionTreatment courses with PEIA as first- and second-line therapy were excluded (n = 2) Missing data plasma exchange 1st line n = 1 and 2nd line n = 4Generalized estimationequationswith complete remission as thedependent variablewereused for statistical analysis (D) Change in EDSSafter first or second-line therapywithplasmaexchange (gray triangles) or immunoadsorption (red triangles)Missing data plasmaexchange 1st line n = 19 2nd line n = 30missingdata immunoadsorption 1st line n = 7 and 2nd line n = 15 One out of range value (immunoadsorption minus60) is not shown Generalized estimation equationswere used for statistical analysis TheMedian is highlighted as black line (E) Short-term remission status after apheresis therapy according to time intervals ofattack onset to start of therapy CR = complete remission IA = immunoadsorption NR = no remission PE = plasma exchange PR = partial remission

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 5

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 5: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

For multivariate GEE analyses of predictors of CR we fur-ther excluded attacks that were treated with an apheresistherapy in both first and second line of treatment (n = 3)attacks where a second-line apheresis therapy was not pre-ceded by high-dose steroids (n = 4) and attacks with missingclinical information (n = 24) Therefore multivariate

analyses were possible in 139 attacks in 79 patients (see flowchart figure 1)

Strong predictors for CR were the use of apheresis therapy asfirst-line therapy (OR 12271 95CI 104ndash14491 p = 0047)time from onset of attack to start of therapy in days (OR 0937

Figure 3 Clinical outcome of apheresis therapies for NMOSD attacks

Remission status of all attacks (total n = 207) treatedwith plasma exchange (A) or immunoadsorption (B)Missing data plasmaexchange 1st line n = 1 2nd linen = 4 3rd line n = 6 and 4th line n = 1 (C) Short-term remission status after first- or second-line therapy with plasma exchange or immunoadsorptionTreatment courses with PEIA as first- and second-line therapy were excluded (n = 2) Missing data plasma exchange 1st line n = 1 and 2nd line n = 4Generalized estimationequationswith complete remission as thedependent variablewereused for statistical analysis (D) Change in EDSSafter first or second-line therapywithplasmaexchange (gray triangles) or immunoadsorption (red triangles)Missing data plasmaexchange 1st line n = 19 2nd line n = 30missingdata immunoadsorption 1st line n = 7 and 2nd line n = 15 One out of range value (immunoadsorption minus60) is not shown Generalized estimation equationswere used for statistical analysis TheMedian is highlighted as black line (E) Short-term remission status after apheresis therapy according to time intervals ofattack onset to start of therapy CR = complete remission IA = immunoadsorption NR = no remission PE = plasma exchange PR = partial remission

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 5

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

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

Page 6: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

95 CI 089ndash099 p = 0014) and the presence of AQP4-abs(OR 33338 95 CI 176ndash63117 p = 0019) (table 3)Monofocal attack manifestations were more likely to show CRthan multifocal attacks (OR 4709 95 CI 103ndash2162 p =0046) Age (per year) was an intermediate predictor (OR0925 95 CI 085ndash101 p = 0081) the chance to have a CRof attack symptoms decreasedwith age by approximately 8 peryear Other factors such as apheresis technique sex centerdiagnosis of NMO vsNMOSD disease duration or presence ofdisease-modifying immunotherapy did not predict CR

DiscussionTwo hundred and seven NMOSD attacks in 105 patientswere identified in the NEMOS registry which were all treatedwith an apheresis therapy (PE or IA) Confirming previous

reports from smaller patient cohorts14ndash22 both PE and IAwere effective in the therapy of NMOSD attacks We couldnot detect differences between the 2 apheresis techniqueswith regard to clinical outcome Although techniques aredifferent both therapies aim at eliminating circulating anti-bodies from the patientrsquos circulation This is of particularimportance in patients with NMOSD Accordingly ouranalysis revealed that the presence of serum AQP4-abs wasa strong predictor for CR after apheresis therapies This is incontrast to observations from other case series where effec-tiveness of apheresis therapy was independent of the AQP4-ab serostatus161723 and supports the notion that AQP4-abshave direct pathogenic effects Nevertheless these differenceshave to be interpreted with caution as endpoints in these caseseries were different Moreover the analyzed number of se-ropositive patients in our GEE analysis was more than 10

Table 2 First- and second-line use of apheresis therapies for NMOSD attacks

First line (n = 72) Second line (n = 101)

PE (n = 63) IA (n = 9)pValue PE (n = 83) IA (n = 18)

pValue

Characteristics of attacks andtherapies

Isolated optic neuritis (n ) 10 (159) 2 (222) 0879a 14 (169) 6 (333) 0167a

Isolated myelitis (n ) 44 (698) 6 (667) 55 (663) 12 (667)

MY + ON (n ) 9 (143) 1 (111) 13 (157) 0

Age at attack (y mean SD) 449 (163) 382 (77) 0192b 496 (144) 390 (94) 0002b

Disease duration (y median IQR) 33 (08ndash90) 46 (28ndash88) 0216b 27 (02ndash61) 25 (08ndash48) 0845b

Attack number (median IQR) 6 (3ndash12) 4 (3ndash8) 0411b 4 (2ndash7) 4 (3ndash7) 0524b

EDSS at start of therapy (medianIQR)

60 (35ndash75) (n = 50) 85 (45ndash95) (n = 3) 0116b 70 (41ndash80) (n = 56) 58 (39ndash71) (n = 6) 0281b

HD-S as first-line therapy (n ) NA NA NA 77 (928) 17 (944) 0800a

Time from attack onset to start oftherapy (d median IQR)

1 (0ndash4) (n = 52) 15 (0ndash18) (n = 6) 0548b 13 (6ndash23) (n = 74) 6 (5ndash24) (n = 18) 0321b

No of exchanges (median IQR) 5 (5ndash8) (n = 55) 8 (575ndash9) (n = 6) 0020b 5 (5ndash7) (n = 75) 5 (5ndash6) (n = 17) 0552b

Plasma exchange volume persession (l median IQR)

3 (25ndash35) (n = 15) 2 (n = 1) NA 25 (235ndash35) (n = 28) 2 (15ndash255) (n = 9) 0063b

Characteristics of patients

Treated patients (n) 28 7 70 15

NMO (n ) 22 (786) 6 (857) 0673a 55 (786) 12 (80) 0902a

AQP4-ab positive NMOSD (n ) 6 (214) 1 (143) 15 (214) 3 (20)

Female sex (n ) 23 (821) 6 (857) 0823a 54 (771) 13 (867) 0413a

AQP4-ab positive (n ) 26 (929) 5 (714) 0111a 60 (87) 15 (100) 0139a

Abbreviations AQP4-ab = anti-aquaporin-4 antibody EDSS = Expanded Disability Status Scale HD-S = high-dose IV steroids IA = immunoadsorption IQR =interquartile range MY = myelitis NA = not applicable NMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritisPE = plasma exchangeCharacteristics of attacks and therapies andbelow characteristics of treated patients (total n = 90)Missing data second lineMY+ON (n = 1) AQP4-ab status (n = 1)Significant values (p lt 005) are shown in bolda χ2 testb Mann-Whitney test was used for statistical analysis

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

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

Page 7: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

times as high as the seronegatives resulting in considerablestatistical uncertainty Therefore apheresis therapies shouldalso be considered in antibody-negative NMOSD patients

In NMOSD attacks escalation and sequence of therapy isdecisive and we have previously observed an advantage forpatients treated with apheresis therapies as a first choice whenthe spinal cord was affected3 Here we could not show a su-periority for one of the 2 different apheresis techniques in theuse as first-line therapy Because of the small numbers ofpatients with IA therapy included in our study our data couldbe biased A definite comparison between the 2 techniquesshould be conducted in a prospective randomized clinical trialwith appropriate patient numbers In the absence of furtherevidence the decision to use one of both techniques should bemade taking availability side effects economic factors andpatient preferences into account24

The time between attack onset and start of therapy is decisiveand early initiation of PE was shown to be a predictor of goodoutcome in studies of CNS demyelination2526 In a recentstudy early initiation of PE within 5 days was identified asa strong predictor for CR of severe attacks in patients withNMOSD27 Most of our patients received apheresis after

a remarkably short period usually because they had experi-enced insufficient remission of earlier relapses on steroidtreatment and were being treated at tertiary care centers withimmediate availability of apheresis therapies Indeed timefrom onset of attack to start of therapy was also a strongpredictor in our current study and an immediate start (within2 days of symptom onset) was associated with a 40 rate ofCR as compared to 32 when started later as 6 days aftersymptom onset Whether high-dose steroids should be givenshortly before or concomitant with apheresis therapy ishowever an open question In our previous study first-lineexclusive apheresis therapy without high-dose steroid pulsetherapy was superior to first-line high-dose steroids in cases ofisolated myelitis but not in ON3 The concomitant applica-tion of high-dose steroids started on the day of admission andPE initiated ldquoas early as possiblerdquo is a procedure reported to behighly efficient in patients with severe NMOSD attacks1627

Monofocal vs multifocal attack manifestation was also a pre-dictor of CR with apheresis therapies However it has to benoted that monofocal attacks principally have a better chanceto recover completely compared with multiregional in-volvement independent of the chosen attack therapy3

Because of its retrospective nature our study has limitationsNevertheless the analysis comprises one of the largest datasets assembled so far for the analysis of apheresis therapies inNMOSD attacks Data quality was highly ensured by theldquoflying doctorrdquo approach as previously described briefly 2neurologists visited the contributing centers and used a pre-defined standardized evaluation form to assess clinical data3

However bias cannot be excluded Particularly the decisionon therapy modality IA or PE and on the time point whenapheresis therapy was started was an individual decision of thetreating physician A center effect could be excluded in ourdata set reflecting a high standard and good availability ofapheresis therapies in the participating centers Unfortunatelydata of attack severity or tolerability of therapy were notsystematically registered and could therefore not be includedin our analysis In addition delayed improvement may havebeen missed because remission status was assessed at theconclusion of apheresis and no prespecified follow-up visitswere performed because this applied to both PE and IAgroups however it is unlikely to have compromised our mainfinding Of interest concomitant long-term immunotherapyhad influence neither on the use of apheresis therapy nor onits effectiveness

This study has immediate implications for clinical manage-ment of NMOSD attacks The early start of apheresis thera-pies is strongly recommended Whether IA or PE is used canbe decided individually

Author contributionsI Kleiter and C Trebst designed the study analyzed the datacreated the figures conducted literature research and wrotethe manuscript K-D Wernecke performed statistical analysis

Table 3 Factors associatedwith complete remission fromNMOSD attacks after apheresis therapy

Multivariate analysis

p Value OR (95 CI)

Female sex (vs male) 0456 3447 (013ndash8940)

Age at attack (per 1 y) 0081 0925 (085ndash101)

Time from onset of disease toattack (per 1 y)

0247 0926 (081ndash106)

AQP4-ab positive (vs negative) 0019 33338 (176ndash63117)

NMO (vs NMOSD) 0316 2951 (036ndash2441)

MY present (vs absent) 0726 1350 (025ndash72)

Isolated ON or MY (vssimultaneous ON + MY)

0046 4709 (103ndash2162)

Prophylactic immunotherapypresent (vs absent)

0532 1683 (033ndash863)

Time from onset of attack tostart of therapy (per 1 d)

0014 0937 (089ndash099)

First-line apheresis therapy (vssecond-line)

0047 12271 (104ndash14491)

PE (vs IA) 0107 4946 (071ndash3459)

Center number 0247 1080 (095ndash123)

Abbreviations AQP4-ab = anti-aquaporin-4 antibody IA = immu-noadsorption MY = myelitis NMO = neuromyelitis optica NMOSD = NMOspectrum disorder ON = optic neuritis PE = plasma exchangeMultivariate generalized estimating equation (GEE) analyses with remissionstatus (complete remission vs partial remission and no remission) of attacksas the dependent variable (working correlationmatrix autoregressive of the1st order n = 79 patients)Significant values (p lt 005) are shown in bold

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 7

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 8: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

A Gahlen N Borisow and K Fischer collected (ldquoflying doctorapproachrdquo) and analyzed the data K Hellwig F Pache KRuprecht J Havla T Kumpfel O Aktas H-P Hartung MRingelstein C Geis C Kleinschnitz A Berthele B HemmerK Angstwurm J-P Stellmann S Schuster M Stangel FLauda H Tumani C Mayer M Krumbholz L Zeltner UZiemann R Linker M SchwabMMarziniak F Then BerghU Hofstadt-van Oy O Neuhaus U Zettl J Faiss B Wild-emann F Paul and S Jarius collected and analyzed the dataAll authors critically revised the manuscript for importantintellectual content and approved the final version of themanuscript

AcknowledgmentIK and CT had full access to all of the data in the study andtake responsibility for the integrity of the data and theaccuracy of the data analysis The authors thank all thepatients for participating in the study The NEMOScohortNationNMO is supported by the German Ministryfor Education and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMS forNEMOS NationNMO-DAB FKZ 01GI1602C to JSNationNMO-PAT FKZ 01GI1602B to OA andNationNMO-LAB FKZ 01GI1602A to BW)

Study fundingThere was no specific funding for the study

DisclosureI Kleiter received travel funding andor speaker honorariafrom BiogenMerck Novartis Sanofi and Roche served as anassociate editor for BMC Neurology consulted for BayerHealthCare Chugai Roche and Shire and received researchsupport from Chugai and DiaMed A Gahlen received travelfunding from Sanofi Genzyme N Borisow K Fischer andK-D Wernecke report no disclosures K Hellwig served onthe scientific advisory boards of Novartis Genzyme TevaMerck and Roche received travel funding andor speakerhonoraria from Bayer Biogen Merck Serono Novartis TevaSanofiGenzyme and Roche received speaker honoraria fromBiogen Bayer Teva Sanofi Merck and Novartis and re-ceived research support from Biogen Bayer Teva Merck andNovartis F Pache received travel funding from GenzymeBayer Biogen ECTRIMS and received research support fromCharite-Universitatsmedizin Berlin Berlin Institute of HealthKKNMS-Bundesministerium fur Bildung und ForschungMinistry in Germany andNovartis K Ruprecht served on thescientific advisory boards of Sanofi-AventisGenzymeNovartis and Roche received travel funding andorspeaker honoraria from Bayer Biogen Merck SeronoSanofi-AventisGenzyme Teva Novartis and the GuthyJackson Charitable Foundation served as an academic editorfor PLoS One received publishing royalties from Elsevier andreceived research support from Novartis Merck Serono andGerman Ministry of Education and Research J Havla servedon the scientific advisory boards of and received speakerhonoraria fromNovartis Merck Roche SanofiGenzyme and

Santhera Pharmaceuticals received travel funding andorpersonal compensation fromNovartis andMerck Serono andreceived research support from Friedrich-Baur StiftungT Kumpfel received travel funding andor speaker honorariafrom Bayer Teva Merck Novartis Sanofi-AventisGenzymeCLB Behring Roche and Biogen and received grant supportfrom Bayer-Schering AG Novartis and Chugai PharmaO Aktas served on the scientific advisory board of MedI-mmune and received travel funding andor speaker honorariafrom Bayer Novartis Biogen Merck Serono Teva Sanofi-Genzyme Roche and Almirall H-P Hartung served on thescientific advisory boards of Novartis Merck Serono TevaBiogen Roche Genzyme Bayer Sanofi MedImmuneGeNeuro Opexa Octapharma Receptos Celgene andRoche received speaker honoraria from Biogen GenzymeMerck Novartis and Roche and served on the editorialboards of Frontiers NeurologyImmunology the EuropeanJournal of Neurology Current Opinion in Neurology andNatureReviews Neurology M Ringelstein received travel fundingandor speaker honoraria from Novartis Bayer BiogenGenzyme Teva Merz Ipsen and Merck C Geis receivedtravel funding fromMerck Serono served as a guest editor forFrontiers Neurology and received research support from theGerman Research Council and German Ministry of Educa-tion C Kleinschnitz reports no disclosures A Berthele re-ceived travel funding and speaker honoraria from BayerBiogen Genzyme Merck Serono Mylan Novartis Rocheand Teva B Hemmer served on the scientific advisory boardsof F Hoffmann-La Roche Novartis Bayer GenentechAllergyCare and TG Therapeutics received travel fundingandor speaker honoraria from Excemed served on the edi-torial boards of JAMA Neurology and the MS Journal holdsa patent for detection of antibodies and T cells against KIR4 ina subpopulation of MS patients and genetic determinants ofneutralizing antibodies to interferon B received researchsupport from Chugai the German Research FoundationGerman Ministry of Education and Research and EU Hori-zon 2020 and he or his institution received speaker honorariafrom Biogen Teva Merck Serono MedImmune NovartisDestin and Hoffmann-La Roche K Angstwurm receivedtravel funding from Alexion Bayer Biogen Idec MerckSerono Novartis and Teva and received research supportfrom Alexion Chugai Bayer Biogen Merck Serono Novar-tis and Roche J-P Stellmann served on the scientific advisoryboard of Genzyme received speaker honoraria from Gen-zyme and Biogen received a travel grant from Novartis andreceived research support from Biogen Genzyme and DFGResearch Fellowship S Schuster reports no disclosures MStangel served on the scientific advisory boards of BiogenBaxaltaShire CSL Behring Grifols MedDay Merck SeronoNovartis Roche Sanofi-Genzyme and Teva received travelfunding and speaker honoraria from Bayer Biogen CSLBehring Merck Serono Novartis Roche Sanofi-Genzymeand Teva served as an academic editor for PLoS One servedon the editorial board of Multiple Sclerosis International re-ceived research support from Biogen Merck Serono Novar-tis Sanofi-Genzyme Teva Deutsche Forschungsgemeinschaft

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

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httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 9: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

Bundesministerium fur Bildung und Forschung Volkswagen-stiftung F Lauda reports no disclosures H Tumani served onthe scientific advisory boards of Biogen Siemens Health TevaRoche and Merck received travel funding andor speakerhonoraria from Merck Serono Eva Biogen Teva NovartisMerck Serono and Novartis served as section editor forNeurology Psychiatry and Brain Research has provided educa-tional presentations for Merck Serono Bayer Teva and Bio-gen and received research support from Merck TevaNovartis Sanofi Genzyme Siemens Health Biogen RocheBMBF and DMSG C Mayer reports no disclosures MKrumbholz served on the scientific advisory boards of NovartisGenzyme and Roche received travel funding from NovartisBiogen and Celgene consulted for Genzyme and receivedresearch support from Novartis L Zentner reports no dis-closures U Ziemann served on the scientific advisory board ofCorTec received speaker honoraria from Bayer Vital BiogenBristol-Myers Squibb Medtronic and Pfizer served as editor-in-chief for Clinical Neurophysiology associate editor for theJournal of Neuroscience deputy editor for Brain Stimulation andeditorial advisory board member for Experimental Brain Re-search received publishing royalties from Elsevier Springerand Oxford University Press and received research supportfrom Biogen Janssen and Servier RA Linker served on thescientific advisory boards of Biogen Genzyme MerckNovartis Roche and Teva received travel funding andorspeaker honoraria from Biogen Genzyme Merck NovartisRoche and Teva consulted for Biogen Novartis and Rocheand received research support from Biogen and Novartis MSchwab served on the scientific advisory boards of MerckSanofi Biogen Novartis and Roche received travel fundingandor speaker honoraria from Merck Sanofi BiogenNovartis and Teva received academic research support fromNovartis and received research support from the EuropeanCommunity M Marziniak received travel funding from theGerman Migraine Society and the German Multiple SclerosisSociety and received research support from Biogen NovartisBayer Vital GenzymeSanofi-Aventis Merck Serono Rocheand Teva F Then Bergh received speaker honoraria andconsultancy fees as a speaker and advisory from ActelionBayer Biogen Merck Serono Novartis Roche Sanofi

Genzyme and Teva received research support from ActelionNovartis German Federal Ministry of Research and DeutscheForschungsgmeinschaft and received travel funding throughthe employing institution from Bayer Schering Biogen andSanofi Genzyme U hofstadt-van Oy served on the scientificadvisory boards of Merck and Alexion received honoraria fromAlexion Bayer Hormosan and Zambon travel funding fromAbbVie Merck and Sanofi-Genzyme and received researchsupport from Bayer Schering Novartis and Merck O Neu-haus reports no disclosures UK Zettl received speaker hon-oraria and travel funding from Bayer Pharma Aventis TevaMerck Serono and Biogen Idec JH Faiss received travelfunding andor speaker honoraria from Bayer Novartis Bio-gen Genzyme Bohringer Merck Serono and Teva and servedon the editorial board of Fortschritte Neurologie und PsychiatrieBT Wildemann served on the scientific advisory boards ofNovartis Sanofi Genzyme and Roche received personal feesfrom Biogen Merck Serono Novartis Teva and Sanofi Gen-zyme and received research support from Nundesministeriumfur Forschung und Technologie Dietmar Hopp Stiftung KlausTschira Stiftung Merck Serono Novartis and Sanofi Gen-zyme F Paul served on the scientific advisory boards ofNovartis and MedImmune received speaker honoraria andtravel funding from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedI-mmune and Shire served as an academic editor for PLoS Oneand an associate editor for Neurology Neuroimmunology ampNeuroinflammation consulted for Sanofi-Genzyme BiogenMedImmune Shire and Alexion and received research sup-port from Bayer Novartis Biogen Teva Sanofi-AventisGenzyme Alexion Merck Serono the German ResearchCouncil Werth Stiftung of the City of Cologne GermanMinistry of Education and Research Arthur Arnstein StiftungBerlin the Arthur Arnstein Foundation Berlin the GuthyJackson Charitable Foundation andNMSS S Jarius reports nodisclosures C Trebst received speaker honoraria from SanofiGenzyme Novartis and Biogen Full disclosure form in-formation provided by the authors is available with the full textof this article at NeurologyorgNN

Received May 3 2018 Accepted in final form July 23 2018

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated

Name Affiliation Role Contribution

Albrecht P University of Dusseldorf Site investigator Collected data

Ayzenberg I Ruhr-University Bochum Site investigator Collected data

Bayas A Klinikum Augsburg Site investigator Collected data

Bellmann-Strobl J Charite University Medicine Berlin Site investigator Collected data

Bischof F University of Tubingen Site investigator Collected data

Bittner S Johannes Gutenberg University Mainz Site investigator Collected data

Continued

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 9

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 10: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Bottcher T Bonhoeffer Klinikum Neubrandenburg Site investigator Collected data

Brettschneider J University of Ulm Site investigator Collected data

Buttmann M Caritas Hospital Bad Mergentheim Site investigator Collected data

DSouza M Charite University Medicine Berlin Site investigator Collected data

Ettrich B University of Leipzig Site investigator Collected data

Frank B University of Essen Site investigator Collected data

Gass A University hospital Mannheim Site investigator Collected data

Grothe M University of Greifswald Site investigator Collected data

Guthke K Klinikum Gorlitz Site investigator Collected data

Haarmann A University of Wurzburg Site investigator Collected data

Habedank E University of Gottingen Site investigator Collected data

Hoffmann F Krankenhaus Martha-Maria Halle Site investigator Collected data

Hoffmann O St Josefs-Krankenhaus Potsdam Site investigator Collected data

Hummert MW Hannover Medical School Site investigator Collected data

Junghans J Krankenhaus Martha-Maria Halle Site investigator Collected data

Kaste M Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kaulen B University of Hamburg Site investigator Collected data

Kermer P Nordwest-Krankenhaus Sanderbusch Site investigator Collected data

Kern P Asklepios Klinik Teupitz Site investigator Collected data

Klotz L University of Munster Site investigator Collected data

Kohler W Universitatsklinikum Leipzig Site investigator Collected data

Kolesilova E Asklepios Klinik Teupitz Site investigator Collected data

Korsen M University of Munster Site investigator Collected data

Kowarik M University of Tubingen Site investigator Collected data

Langel S Landeskrankenhaus Rheinhessen Site investigator Collected data

Lee DH University of Erlangen Site investigator Collected data

Liebetrau M St Josefs-Hospital Wiesbaden GmbH Site investigator Collected data

Luessi F Johannes Gutenberg University Mainz Site investigator Collected data

Marouf W University Hospital Bonn Site investigator Collected data

Meister S University of Rostock Site investigator Collected data

Melms A University of Erlangen Site investigator Collected data

Metz I University of Gottingen Site investigator Collected data

Munch C Charite University Medicine Berlin Site investigator Collected data

Niehaus S Klinikum Dortmund Site investigator Collected data

Pawlitzki M University of Magdeburg Site investigator Collected data

Pellkofer H Ludwig-Maximilians University Munich Site investigator Collected data

Puhlmann HU Schlosspark-Klinik Berlin Site investigator Collected data

Continued

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 11: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

References1 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patients J Neuro-inflammation 2012914

2 Trebst C Jarius S Berthele A et al Update on the diagnosis and treatment ofneuromyelitis optica recommendations of the Neuromyelitis Optica Study Group(NEMOS) J Neurol 20142611ndash16

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

4 Bronzlik P Toto S Kielstein J Schmidt B Stangel M Trebst C Therapeutic plasmaexchange and immunoadsorption therapy in neurological diseases Eur Neu J 2011356ndash61

5 Braun N Bosch T Immunoadsorption current status and future developmentsExpert Opin Investig Drugs 200092017ndash2038

6 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol NeuroimmunolNeuroinflamm 20152e110 doi 101212NXI0000000000000110

7 Matic G Bosch T Ramlow W Background and indications for protein A-basedextracorporeal immunoadsorption Ther Apher 20015394ndash403

Appendix 1 Coinvestigators of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order All institutions arein Germany unless otherwise indicated (continued)

Name Affiliation Role Contribution

Pul R University of Essen Site investigator Collected data

Retzlaf N University of Rostock Site investigator Collected data

Riedlinger A Asklepios Klinik Teupitz Site investigator Collected data

Rommer P Medical University of Vienna Austria Site investigator Collected data

Ropke L University of Jena Site investigator Collected data

Rostasy K Vestische Caritas-Kliniken GmbH Site investigator Collected data

Ruckriem L MediClin Hedon-Klinik Lingen (Ems) Site investigator Collected data

Ruschil C University of Tubingen Site investigator Collected data

Schippling S University of Zurich Switzerland Site investigator Collected data

Senel M University of Ulm Site investigator Collected data

Sieb JP Helios Hanseklinikum Stralsund Site investigator Collected data

Sommer C University of Wurzburg Site investigator Collected data

Spreer A Johannes Gutenberg University Mainz Site investigator Collected data

Steinbrecher A Helios Klinikum Erfurt Site investigator Collected data

Stephanik H University of Magdeburg Site investigator Collected data

Stoppe M University of Leipzig Site investigator Collected data

Suszlige M University of Greifswald Site investigator Collected data

Tackenberg B University of Marburg Site investigator Collected data

Tunnerhoff J University of Tubingen Site investigator Collected data

Veauthier C Charite University Medicine Berlin Site investigator Collected data

Walter A Klinikum Herford Site investigator Collected data

Wandinger KP University Medical center Schleswig-Holstein Campus Lubeck Site investigator Collected data

Warnke C University of Koln Site investigator Collected data

Weber MS University of Gottingen Site investigator Collected data

Weissert R University of Regensburg Site investigator Collected data

Wiendl H University of Munster Site investigator Collected data

Wilke C Nervenzentrum Potsdam Site investigator Collected data

Winkelmann A University of Rostock Site investigator Collected data

Yalachkov Y University of Frankfurt Site investigator Collected data

Young K University of Hamburg Site investigator Collected data

Zentner C Krankenhaus Martha-Maria Halle Site investigator Collected data

Zipp F Johannes Gutenberg University Mainz Site investigator Collected data

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 11

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 12: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

8 Staudt A Dorr M Staudt Y et al Role of immunoglobulin G3 subclass in dilatedcardiomyopathy results from protein A immunoadsorption Am Heart J 2005150729ndash736

9 Baggi F Ubiali F Nava S et al Effect of IgG immunoadsorption on serum cytokines inMG and LEMS patients J Neuroimmunol 2008201-202104ndash110

10 Bulut D Creutzenberg G Mugge A The number of regulatory T cells correlateswith hemodynamic improvement in patients with inflammatory dilated car-diomyopathy after immunoadsorption therapy Scand J Immunol 20137754ndash61

11 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

12 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

13 Dahmen G Ziegler A Generalized estimating equation on controlled clinical trialshypotheses testing Biomed J 200446214ndash232

14 Weinshenker BG OrsquoBrien PC Petterson TM et al A randomized trial of plasmaexchange in acute central nervous system inflammatory demyelinating disease AnnNeurol 199946878ndash886

15 Watanabe S Nakashima I Misu T et al Therapeutic efficacy of plasma exchangein NMO-IgG-positive patients with neuromyelitis optica Mult Scler 200713128ndash132

16 BonnanM Valentino R Olindo S Mehdaoui H Smadja D Cabre P Plasma exchangein severe spinal attacks associated with neuromyelitis optica spectrum disorder MultScler 200915487ndash492

17 Merle H Olindo S Jeannin S et al Treatment of optic neuritis by plasma exchange(add-on) in neuromyelitis optica Arch Ophthalmol 2012130858ndash862

18 Kim SH KimW Huh SY Lee KY Jung IJ KimHJ Clinical efficacy of plasmapheresisin patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels J Clin Neurol 2013936ndash42

19 Koziolek M Muhlhausen J Friede T et al Therapeutic apheresis in pediatric patientswith acute CNS inflammatory demyelinating disease Blood Purif 20133692ndash97

20 Lim YM Pyun SY Kang BH Kim J Kim KK Factors associated with the effectivenessof plasma exchange for the treatment of NMO-IgG-positive neuromyelitis opticaspectrum disorders Mult Scler 2013191216ndash1218

21 Yasuda T Mikami T Kawase Y Efficacy of tryptophan immunoadsorption plasma-pheresis for neuromyelitis optica in two cases Ther Apher Dial 201519411ndash412

22 Abboud H Petrak A Mealy M Sasidharan S Siddique L Levy M Treatment of acuterelapses in neuromyelitis optica steroids alone versus steroids plus plasma exchangeMult Scler 201622185ndash192

23 Magana SM Keegan BM Weinshenker BG et al Beneficial plasma exchange re-sponse in central nervous system inflammatory demyelination Arch Neurol 201168870ndash878

24 Kleiter I Gold R Present and future therapies in neuromyelitis optica spectrumdisorders Neurotherapeutics 20161370ndash83

25 Keegan M Pineda AA McClelland RL Darby CH Rodriguez M Weinshenker BGPlasma exchange for severe attacks of CNS demyelination predictors of responseNeurology 200258143ndash146

26 Llufriu S Castillo J Blanco Y et al Plasma exchange for acute attacks of CNSdemyelination predictors of improvement at 6 months Neurology 200973949ndash953

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

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 5 Number 6 | November 2018 NeurologyorgNN

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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

Page 13: Apheresis therapies for NMOSD attacks · ARTICLE OPEN ACCESS CLASS OF EVIDENCE Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic interventions Ingo Kleiter,

DOI 101212NXI000000000000050420185 Neurol Neuroimmunol Neuroinflamm

Ingo Kleiter Anna Gahlen Nadja Borisow et al interventions

Apheresis therapies for NMOSD attacks A retrospective study of 207 therapeutic

This information is current as of September 26 2018

ServicesUpdated Information amp

httpnnneurologyorgcontent56e504fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent56e504fullhtmlref-list-1

This article cites 27 articles 2 of which you can access for free at

Citations httpnnneurologyorgcontent56e504fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectiondevics_syndromeDevics syndromefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

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

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

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