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ARTICLE OPEN ACCESS
Pain Depression and Quality of Life inNeuromyelitis Optica Spectrum DisorderA Cross-Sectional Study of 166 AQP4 AntibodyndashSeropositive Patients
Ilya Ayzenberg MD Daniel Richter MD Eugenia Henke MD Susanna Asseyer MD Friedemann Paul MD
Corinna TrebstMDMartinWHummertMD JoachimHavlaMD Tania KumpfelMDMarius RingelsteinMD
Orhan Aktas MD Brigitte Wildemann MD Sven Jarius MD Vivien Hauszligler MD Jan-Patrick Stellmann MD
Makbule Senel MD Luisa Klotz MD Hannah L Pellkofer MD Martin S Weber MD Marc Pawlitzki MD
Paulus S Rommer MD Achim Berthele MD Klaus-Dieter Wernecke MD PhD Kerstin Hellwig MD
Ralf Gold MD and Ingo Kleiter MD on behalf of the NEMOS (Neuromyelitis Optica Study Group)
Neurol Neuroimmunol Neuroinflamm 20218e985 doi101212NXI0000000000000985
Correspondence
Dr Kleiter
ingokleiterrubde
AbstractObjectivesTo evaluate prevalence clinical characteristics and predictors of pain depression and theirimpact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder(NMOSD) cohort
MethodsWe included 166 patients with aquaporin-4ndashseropositive NMOSD from 13 tertiary referralcenters Patients received questionnaires on demographic and clinical characteristics Pain-Detect short form of Brief Pain Inventory Beck Depression InventoryndashII and Short Form 36Health Survey
ResultsOne hundred twenty-five (753) patients suffered from chronic NMOSD-associated pain Ofthese 659 had neuropathic pain 688 reported spasticity-associated pain and 264 painfultonic spasms Number of previous myelitis attacks (OR = 127 p = 0018) and involved upperthoracic segments (OR = 131 p = 0018) were the only predictive factors for chronic pain Thelatter was specifically associated with spasticity-associated pain (OR = 136 p = 0002) Morethan a third (398) suffered from depression which was moderate to severe in 515 Painseverity (OR = 181 p lt 0001) and especially neuropathic character (OR = 344 p lt 0001)were associated with depression Pain severity and walking impairment explained 539 of thephysical QoL variability while depression and walking impairment 397 of the mental QoLvariability No specific medication was given to 706 of patients with moderate or severedepression and 425 of those with neuropathic pain Two-thirds (642) of patients withsymptomatic treatment still reported moderate to severe pain
From the Department of Neurology (IA DR EH KH RG IK) St Josef-Hospital Ruhr-University Bochum Germany Department of Neurology (IA) Sechenov First MoscowState Medical University Russia NeuroCure Clinical Research Center (SA FP) Charite Universitatsmedizin Berlin Berlin Institute of Health Corporate Member of Freie UniversitatBerlin Humboldt-Universitat zu Berlin Germany Department of Neurology (CT MWH) Hannover Medical School Germany Institute of Clinical Neuroimmunology (JH TKHLP) University Hospital and Biomedical Center Ludwig-Maximilians University Munich Germany Department of Neurology (MR OA) Medical Faculty Heinrich Heine UniversityDusseldorf Germany Department of Neurology (MR) Center for Neurology and Neuropsychiatry LVR-Klinikum Dusseldorf Germany Molecular Neuroimmunology Group (BWSJ) Department of Neurology University of Heidelberg Germany Institut fur Neuroimmunologie undMultiple Sklerose (INIMS) (VH J-PS) Zentrum fur Molekulare NeurobiologieHamburg Germany Klinik und Poliklinik fur Neurologie (VH J-PS) Universitatsklinikum Hamburg-Eppendorf Germany APHM (J-PS) Hopital de la Timone CEMEREM MarseilleFrance Aix Marseille Universite (J-PS) CRMBM CNRS UMR 7339 Marseille France Department of Neurology (MS) University of Ulm Germany Munster Department of Neurologywith Institute of Translational Neurology (LK MP) University Hospital Munster Germany Department of Neurology (HLP MSW) UniversityMedical Center Gottingen GermanyDepartment of Neurology (MP) Otto-von-Guericke University Magdeburg Germany Department of Neurology (PSR) Medical University of Vienna Austria NeuroimmunologySection (PSR) Department of Neurology University of Rostock Germany Department of Neurology (AB) School of Medicine Technical University of Munich Germany Charite-Universitatsmedizin Berlin CRO SOSTANA GmbH Berlin (K-DW) Germany and Marianne-Strauszlig-Klinik (IK) Behandlungszentrum Kempfenhausen fur Multiple Sklerose KrankegGmbH Berg Germany
Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article
The Article Processing Charge was funded by the authors
Coinvestigators are listed in Appendix 2
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 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1
ConclusionsMyelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD Although pain intensity was lowerthan in previous studies pain and depression remain undertreated and strongly affect QoL Interventional studies on targetedtreatment strategies for pain are urgently needed in NMOSD
Neuromyelitis optica spectrum disorder (NMOSD) is anautoimmune inflammatory disorder that primarily affects thevisual pathway brain and spinal cord12 Autoantibodies tar-geting aquaporin-4 (AQP4) are present in the majority ofpatients and proved to be pathogenic in animal models34
NMOSD attacks often do not fully recover and residualclinical deficits remain in gt75 of attacks56 Beside severephysical impairments NMOSD can go along with symptomslike chronic pain cognitive deficits and depression78
Spinal pain girdle-like dysesthesia and painful spasms werenoted already in earliest disease descriptions in the 18th century9
Nowadays it has become clear that pain is a frequent and one ofthe most disabling symptoms of NMOSD810-15 ChronicNMOSD-associated pain affects quality of life (QoL) with painseverity being the most important predictive factor10121315
Possible underlying mechanisms include damage of the centralnociceptive and antinociceptive pathways particularly the dorsalhorn of the spinal cord and the dorsal root entry zone auto-nomic thoracolumbar nuclei the periaqueductal gray and hy-pothalamus Excessive levels of extracellular glutamate andincrease of proinflammatory factors such as interleukin (IL)-6IL-17 and C5a can additionally facilitate nociceptive process-ing16 Glutamate excitotoxicity can cause an imbalance betweenexcitation and inhibition in nociceptive system resulting inspontaneous neuropathic pain
Because of the rarity of NMOSD most previous studies ofpain were relatively small101117 Moreover several studiesincluded a mixed population of AQP4-IgGndashseropositive andndashseronegative patients10-1315 whereas recent clinical trialsclearly indicate that pathogenetic mechanisms are different inthese forms18 Accordingly data on clinical and paraclinicalpredictors of pain as well as its association with depressionand effects on QoL remain limited
We sought to investigate clinical characteristics risk factors andimpact of pain syndromes and depression in a Central Europeancohort of patients with AQP4-IgGndashseropositive NMOSD Fur-thermore we wanted to evaluate the efficacy of immunotherapiesand symptomatic treatment for both conditions and search for ashort screening question to detect patients with disabling pain
MethodsPatientsWe performed an exploratory questionnaire-based cross-sectional study in the years 2017ndash2019 Patients with AQP4-IgGndashseropositive NMOSD according to IPND criteria19 wereidentified through the registry of the German NeuromyelitisOptica Study Group (NEMOS nemos-netde) Details on theregistry participating centers and data collection quality andprocessing can be found in previous publications56 Inclusioncriteria were (1) age over 18 years and (2) positive AQP4-IgG confirmed in a cell-based assay Patients with knownrelevant cognitive deficits were excluded All patients were inremission during the study Clinical data including ExpandedDisability Status Scale (EDSS) therapies and localization ofspinal lesions in cervical and thoracic segments on MRI wereretrieved from the NEMOS database or local patient recordsData on current pain depression walking and visual im-pairment and QoL were captured by self-reporting ques-tionnaires Patients were instructed to report on NMOSD-associated pain syndromes only
QuestionnairesCurrent pain was assessed using the PainDetect questionnaire(PDQ)20 the short form of the Brief Pain Inventory (SF-BPI) and the McGill Pain Questionnaire Short Form (MPQ-SF)21 The questions of the SF-BPI consist of 2 categories (1)pain severity (present highest least and average pain) basedon a Numeric Rating Scale (NRS) from 0 (no pain) to 10(worst pain imaginable) within the last week The pain se-verity index score represents the average score of these 4 painintensity scores (2) Seven domains of pain-related in-terference in activity of daily living (ADL) rated from of 0 (nointerference) to 10 (complete interference) general activitymood walking ability working ability relations with otherpeople sleep and enjoyment of life The PDQ was adminis-tered to evaluate pain localization and discriminate betweendefinite neuropathic (PDQ score gt18) probable neuropathic(PDQ score 13ndash18) and nociceptive pain (PDQ score lt13)The MPQ-SF consists of 15 words describing sensory (11words) and affective (4 words) components of pain Patientsrate their intensity as 0 = none 1 = mild 2 = moderate or 3 =
GlossaryADL = activity of daily living BDI = Beck Depression Inventory EDSS = Expanded Disability Status Scale MCS = mentalcomponent summaryMPQ-SF =McGill Pain Questionnaire Short FormNMOSD = neuromyelitis optica spectrum disorderPDQ = PainDetect questionnaire PTS = painful tonic spasm
2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
severe Three pain scores are derived from the sum of the rankvalues (1) sensory (2) affective and (3) total descriptorsPainful tonic spasms (PTSs) were assessed asking the patientwhether they experienced recurrent attacks or short episodes(duration lt1 minute) of localized muscle spasms accompa-nied by severe pain
Depression was evaluated using Beck Depression Inventory II(BDI-II) scored from 0 (best) to 63 (worst) (lt9 no de-pressive affect 9ndash13 minimal mood disturbance 14ndash20 milddepression 21ndash28 moderate depression and ge29 severe de-pression) Clinically relevant depression was defined by a scoreof ge14 Health-related QoL was measured with the SF-36questionnaire consisting of 36 items in 8 subscales A Physical
Component Summary (PCS) and a Mental ComponentSummary (MCS) were calculated using norm-based attainingvalues from 0 (worst) to 100 (best)
Standard Protocol Approvals Registrationsand Patient ConsentsEthics approval was obtained from the Institutional ReviewBoard of the Ruhr-University Bochum (15-5534) Ethicsapproval of the NEMOS registry was obtained in participatingcenters locally Patients provided written informed consentThe study was performed according to International Con-ference on HarmonizationGood Clinical Practice and cur-rent legal requirements
Statistical AnalysisDescriptive statistics were used to describe sample data Com-parisons of interval-scaled variables were performed using the2-sample t test for normally distributed variables the Mann-Whitney-Wilcoxon rank-sum test for nonparametric or ordinal-scaled variables and the χ2 test for categorical variables We usedbinary logistic regression to evaluate factors associated withoverall pain (yes vs no) as well as neuropathic (neuropathic vsnociceptive pain) and spasticity-related pain (spasticity-associatedvs other [nonndashspasticity-associated] pain) as dependent variablesThe following independent variables were included into the lo-gistic model sex age EDSS disease duration AQP4-IgG titeroverall number of previous relapses number of myelitis attacksand number of involved spinal segments Concerning depressivestate sex age disease duration walking and visual impairmentwere included into analysis A multiple robust regression modelwith backward feature selection was used to determine predictorsfor hrQoL with PCS and MCS composites as dependent vari-ables and age sex disease duration walking and visual impair-ment pain severity and Beck depression index as independentvariables22 To check for correlations between pain intensity anddifferent aspects of ADL we performed the Spearman correlationtest This study was an exploratory pilot study with no a priorisample size calculation For the same reason statistical signifi-cance was set at p lt 005 without adjustment for multiple testingNumerical calculations were performed by SPSS Statistics Ver-sion 25 SPSS Inc an IBM Company and The R Project forStatistical Computing Version 340 (2017-04-21) The RFoundation for Statistical Computing
Data AvailabilityAnonymized data not published within this article are avail-able on reasonable request from any qualified investigatorwithin 5 years after publication
ResultsDemographic and Clinical CharacteristicsThirteen tertiary referral NEMOS centers participated in thestudy and 172 questionnaires were sent back to the readingcenter in Bochum for analysis The response rate was 831(data on response rate available for 7 centers addressing
Table 1 Demographic Characteristics andImmunotherapy
Mean (SD)Median(minndashmax)
Total number of patients(all AQP4-IgG seropositive)
166
FM ratio 821
EDSS 35 (00ndash90)
Age y 517 (134)
Disease duration y 91 (81)
ARR 11 (16)
Total number of ON episodes sinceonset
22 (41)
Total number of myelitis episodes sinceonset
46 (74)
Total number of involved spinalsegments
53 (41)
No of involved cervical segments 22 (21)
No of involved thoracic segments 32 (33)
AQP4-IgG titer (CBA) 1100 (110ndash125600)
Current immunotherapy N
Rituximab 627104a
Azathioprine 120 20
Anti-IL6 therapy (tocilizumab N = 11 SA237 N = 1) 72 12
Mycophenolate mofetil 48 8
Other therapies (methotrexate N = 2 prednisone N = 2mitoxantrone N = 2 IVIg N = 1 glatiramer acetate N = 1cyclosporin N = 1)
54 9
Prednisone as add-on therapy 102 17
No immunotherapy 78 13
Abbreviations ARR = annualized relapse rate AQP4 = aquaporin-4 CBA =cell-based assay EDSS = Expanded Disability Status Scale FM = femalemale ON = optic neuritisa Five in combination with oral immunosuppressive agents
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 3
711 of respondents) Data of 6 questionnaires were in-sufficient and had to be excluded In total 166 patients withAQP4-IgGndashseropositive NMOSD (148 female and 18 male)were included Main demographic and clinical characteristicsare described in table 1 Most patients in the cohort had ahistory of myelitis (152 916) or optic neuritis (114687) 95 (572) of both myelitis and optic neuritis Dataon the last available spinal MRI were available for 143 of 166patients (130 of 152 with a history of myelitis) and demon-strated a 2-peak distribution (C2-C6 and Th2-Th7) of lesionlocation (figure 1) Eleven of 21 patients without visible spinallesions had a history of myelitis Six patients only had a relapsein the previous 6 months
Overall Pain Prevalence andMain CharacteristicsOverall 125 (753) patients suffered from chronic NMOSD-associated pain The intensity ofNMOSD-associated chronic painwasmoderate to severe in 552of pain sufferers (figure 2A) Painwasmainly described as aching (904) tender (768) stabbing(688) or burning (664) on sensory dimensions and tiring-exhausting (680) on affective dimension Most prevalent werechronic pain without painless periods (n = 77 616) Isolated oroverlapping pain attacks reported 48 (384) and 40 (320)patients accordingly (figure 2B) Every second patient (n = 8853) reported pain as a symptom of the last relapse
Prevalence of Different Types of PainOne-third of pain sufferers had nociceptive (n = 39 307)probable neuropathic (n = 43 339) or definite neuropathicpain (n = 40 315) each in 3 patients the type of pain couldnot be identified (figure 2C) Pain was most often localized inlegs (728 in two-thirds of cases bilateral) followed by arms(488 in half of cases bilateral) trunk (344) and neckhead region (272) Most intense pain were reported bypatients with pain localization in the trunk (49 plusmn 17 vs 33 plusmn22 p lt 005) or legs (41 plusmn 22 vs 32 plusmn 20 p lt 005) Trunk
pains were more often of definite neuropathic than of prob-able neuropathic or nociceptive character (558 vs 279 vs163 p lt 005) whereas no changes were found for pains inother regions of the body
Two-thirds of the pain sufferers reported spasticity-associatedpain (n = 86 688) (figure 2D) It was significantly moreprevalent in patients with nociceptive than neuropathic pain(878 vs 558 p = 002) Thirty-three patients (264) hadshort-lasting PTS mostly in the legs (n = 28 848) andrarely in the arms (n = 6 182) These patients reportedapproximately 5 PTS episodes a day (49 plusmn 64) with a rangeof 26 attacks per day to 1 per week
Episodes of Myelitis Involving Upper ThoracicSegments Are Associated With Chronic PainChronic pain was not associated with age sex AQP4-IgGtiter disease duration overall disability (EDSS) or depressivestate (BDI gt 14) However the number of previous attackswas significantly associated with the occurrence of pain (OR112 [102ndash121] p = 0020) More detailed analysis revealedthat the total number of episodes of myelitis (OR 127[105ndash157] p = 0018) but not the number of optic neuritis(OR 102 [092ndash113] p = 0716) was relevant There was noassociation of pain prevalence or severity with the presence orany specific localization of persistent spinal lesions (table 2)However we found an association of the number of involvedspinal segments with pain (OR 114 [103ndash128] p = 0024)Moreover the number of lesions in the upper 6 thoracicsegments only (but not in cervical or lower thoracic lesions)was associated with the risk of having pain in general (OR 131[101ndash163] p = 0018) and was the only specific factor in-creasing the risk of spasticity-associated pain among painsufferers (OR 136 [110ndash167] p = 0002) We could not findany specific factors associated with short-lasting PTS De-pressive state was the only factor strongly associated withneuropathic pain (OR 344 [135ndash880] p = 0001)
Figure 1 Distribution of Persistent Spinal Lesions in Cervical and Thoracic Segments
Shown is the frequency () of patients (total n = 143) with a spinal lesion on MRI at the appropriate level
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Pain Severity Strongly Correlates WithReduction of Activities of Daily LivingEffects of pain on ADL are given in table 3 Correlationanalysis revealed a strong correlation of pain severity withgeneral activity (rho = 069 p lt 0001) and sleep (rho = 061p lt 0001) followed by mood (rho = 055 p lt 0001) walkingability (rho = 054 p lt 0001) normal work (rho = 052 p lt0001) enjoyment of life (rho = 050 p lt 0001) and relations
(rho = 046 p lt 0001) We observed an even stronger neg-ative effect of definite neuropathic pain on all evaluated ADLaspects compared with nociceptive pain
Chronic Pain But Not Physical Impairment IsAssociated With Depression in NMOSDSixty-six (398) patients suffered from depression mild in32 (193) moderate in 21 (116) and severe in 13 (78)
Figure 2 Main Characteristics of the NMOSD-Associated Pain
(A) Intensity (B) temporal patterns (a continuous pain with slight fluctuations b continuous pain with pain attacks c pain attacks with painless periods dpain attacks without painless periods) and (C and D) character of pain Values of pain intensity are given in median interquartile range and minimal andmaximal values Prevalence is given in () NMOSD = neuromyelitis optica spectrum disorder NRS = Numeric Rating Scale PTS = painful tonic spasm
Table 2 Prevalence and Severity of Pain in 143 Patients With Spinal Lesions of Different Localizations
Localization of spinal lesions Prevalence of pain BPI-PSI PainDetect score
No persistent lesions (N = 21) 682 (N = 15)a 36 plusmn 24 135 plusmn 51
Isolated cervical lesions (N = 27) 667 (N = 18) 34 plusmn 19 150 plusmn 75
Isolated thoracic lesions (N = 33) 818 (N = 27) 43 plusmn 22 174 plusmn 67
Cervicothoracic lesions (N = 62) 770 (N = 47) 37 plusmn 22 162 plusmn 66
Abbreviation BPI-PSI = Pain Severity Index of Brief Pain InventoryBPI-PSI and PainDetect Score values are given in mean plusmn SD for pain sufferers No significant differences were founda Seven of 15 patients had at least 1 myelitis episode in the history
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 5
cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
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![Page 2: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/2.jpg)
ConclusionsMyelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD Although pain intensity was lowerthan in previous studies pain and depression remain undertreated and strongly affect QoL Interventional studies on targetedtreatment strategies for pain are urgently needed in NMOSD
Neuromyelitis optica spectrum disorder (NMOSD) is anautoimmune inflammatory disorder that primarily affects thevisual pathway brain and spinal cord12 Autoantibodies tar-geting aquaporin-4 (AQP4) are present in the majority ofpatients and proved to be pathogenic in animal models34
NMOSD attacks often do not fully recover and residualclinical deficits remain in gt75 of attacks56 Beside severephysical impairments NMOSD can go along with symptomslike chronic pain cognitive deficits and depression78
Spinal pain girdle-like dysesthesia and painful spasms werenoted already in earliest disease descriptions in the 18th century9
Nowadays it has become clear that pain is a frequent and one ofthe most disabling symptoms of NMOSD810-15 ChronicNMOSD-associated pain affects quality of life (QoL) with painseverity being the most important predictive factor10121315
Possible underlying mechanisms include damage of the centralnociceptive and antinociceptive pathways particularly the dorsalhorn of the spinal cord and the dorsal root entry zone auto-nomic thoracolumbar nuclei the periaqueductal gray and hy-pothalamus Excessive levels of extracellular glutamate andincrease of proinflammatory factors such as interleukin (IL)-6IL-17 and C5a can additionally facilitate nociceptive process-ing16 Glutamate excitotoxicity can cause an imbalance betweenexcitation and inhibition in nociceptive system resulting inspontaneous neuropathic pain
Because of the rarity of NMOSD most previous studies ofpain were relatively small101117 Moreover several studiesincluded a mixed population of AQP4-IgGndashseropositive andndashseronegative patients10-1315 whereas recent clinical trialsclearly indicate that pathogenetic mechanisms are different inthese forms18 Accordingly data on clinical and paraclinicalpredictors of pain as well as its association with depressionand effects on QoL remain limited
We sought to investigate clinical characteristics risk factors andimpact of pain syndromes and depression in a Central Europeancohort of patients with AQP4-IgGndashseropositive NMOSD Fur-thermore we wanted to evaluate the efficacy of immunotherapiesand symptomatic treatment for both conditions and search for ashort screening question to detect patients with disabling pain
MethodsPatientsWe performed an exploratory questionnaire-based cross-sectional study in the years 2017ndash2019 Patients with AQP4-IgGndashseropositive NMOSD according to IPND criteria19 wereidentified through the registry of the German NeuromyelitisOptica Study Group (NEMOS nemos-netde) Details on theregistry participating centers and data collection quality andprocessing can be found in previous publications56 Inclusioncriteria were (1) age over 18 years and (2) positive AQP4-IgG confirmed in a cell-based assay Patients with knownrelevant cognitive deficits were excluded All patients were inremission during the study Clinical data including ExpandedDisability Status Scale (EDSS) therapies and localization ofspinal lesions in cervical and thoracic segments on MRI wereretrieved from the NEMOS database or local patient recordsData on current pain depression walking and visual im-pairment and QoL were captured by self-reporting ques-tionnaires Patients were instructed to report on NMOSD-associated pain syndromes only
QuestionnairesCurrent pain was assessed using the PainDetect questionnaire(PDQ)20 the short form of the Brief Pain Inventory (SF-BPI) and the McGill Pain Questionnaire Short Form (MPQ-SF)21 The questions of the SF-BPI consist of 2 categories (1)pain severity (present highest least and average pain) basedon a Numeric Rating Scale (NRS) from 0 (no pain) to 10(worst pain imaginable) within the last week The pain se-verity index score represents the average score of these 4 painintensity scores (2) Seven domains of pain-related in-terference in activity of daily living (ADL) rated from of 0 (nointerference) to 10 (complete interference) general activitymood walking ability working ability relations with otherpeople sleep and enjoyment of life The PDQ was adminis-tered to evaluate pain localization and discriminate betweendefinite neuropathic (PDQ score gt18) probable neuropathic(PDQ score 13ndash18) and nociceptive pain (PDQ score lt13)The MPQ-SF consists of 15 words describing sensory (11words) and affective (4 words) components of pain Patientsrate their intensity as 0 = none 1 = mild 2 = moderate or 3 =
GlossaryADL = activity of daily living BDI = Beck Depression Inventory EDSS = Expanded Disability Status Scale MCS = mentalcomponent summaryMPQ-SF =McGill Pain Questionnaire Short FormNMOSD = neuromyelitis optica spectrum disorderPDQ = PainDetect questionnaire PTS = painful tonic spasm
2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
severe Three pain scores are derived from the sum of the rankvalues (1) sensory (2) affective and (3) total descriptorsPainful tonic spasms (PTSs) were assessed asking the patientwhether they experienced recurrent attacks or short episodes(duration lt1 minute) of localized muscle spasms accompa-nied by severe pain
Depression was evaluated using Beck Depression Inventory II(BDI-II) scored from 0 (best) to 63 (worst) (lt9 no de-pressive affect 9ndash13 minimal mood disturbance 14ndash20 milddepression 21ndash28 moderate depression and ge29 severe de-pression) Clinically relevant depression was defined by a scoreof ge14 Health-related QoL was measured with the SF-36questionnaire consisting of 36 items in 8 subscales A Physical
Component Summary (PCS) and a Mental ComponentSummary (MCS) were calculated using norm-based attainingvalues from 0 (worst) to 100 (best)
Standard Protocol Approvals Registrationsand Patient ConsentsEthics approval was obtained from the Institutional ReviewBoard of the Ruhr-University Bochum (15-5534) Ethicsapproval of the NEMOS registry was obtained in participatingcenters locally Patients provided written informed consentThe study was performed according to International Con-ference on HarmonizationGood Clinical Practice and cur-rent legal requirements
Statistical AnalysisDescriptive statistics were used to describe sample data Com-parisons of interval-scaled variables were performed using the2-sample t test for normally distributed variables the Mann-Whitney-Wilcoxon rank-sum test for nonparametric or ordinal-scaled variables and the χ2 test for categorical variables We usedbinary logistic regression to evaluate factors associated withoverall pain (yes vs no) as well as neuropathic (neuropathic vsnociceptive pain) and spasticity-related pain (spasticity-associatedvs other [nonndashspasticity-associated] pain) as dependent variablesThe following independent variables were included into the lo-gistic model sex age EDSS disease duration AQP4-IgG titeroverall number of previous relapses number of myelitis attacksand number of involved spinal segments Concerning depressivestate sex age disease duration walking and visual impairmentwere included into analysis A multiple robust regression modelwith backward feature selection was used to determine predictorsfor hrQoL with PCS and MCS composites as dependent vari-ables and age sex disease duration walking and visual impair-ment pain severity and Beck depression index as independentvariables22 To check for correlations between pain intensity anddifferent aspects of ADL we performed the Spearman correlationtest This study was an exploratory pilot study with no a priorisample size calculation For the same reason statistical signifi-cance was set at p lt 005 without adjustment for multiple testingNumerical calculations were performed by SPSS Statistics Ver-sion 25 SPSS Inc an IBM Company and The R Project forStatistical Computing Version 340 (2017-04-21) The RFoundation for Statistical Computing
Data AvailabilityAnonymized data not published within this article are avail-able on reasonable request from any qualified investigatorwithin 5 years after publication
ResultsDemographic and Clinical CharacteristicsThirteen tertiary referral NEMOS centers participated in thestudy and 172 questionnaires were sent back to the readingcenter in Bochum for analysis The response rate was 831(data on response rate available for 7 centers addressing
Table 1 Demographic Characteristics andImmunotherapy
Mean (SD)Median(minndashmax)
Total number of patients(all AQP4-IgG seropositive)
166
FM ratio 821
EDSS 35 (00ndash90)
Age y 517 (134)
Disease duration y 91 (81)
ARR 11 (16)
Total number of ON episodes sinceonset
22 (41)
Total number of myelitis episodes sinceonset
46 (74)
Total number of involved spinalsegments
53 (41)
No of involved cervical segments 22 (21)
No of involved thoracic segments 32 (33)
AQP4-IgG titer (CBA) 1100 (110ndash125600)
Current immunotherapy N
Rituximab 627104a
Azathioprine 120 20
Anti-IL6 therapy (tocilizumab N = 11 SA237 N = 1) 72 12
Mycophenolate mofetil 48 8
Other therapies (methotrexate N = 2 prednisone N = 2mitoxantrone N = 2 IVIg N = 1 glatiramer acetate N = 1cyclosporin N = 1)
54 9
Prednisone as add-on therapy 102 17
No immunotherapy 78 13
Abbreviations ARR = annualized relapse rate AQP4 = aquaporin-4 CBA =cell-based assay EDSS = Expanded Disability Status Scale FM = femalemale ON = optic neuritisa Five in combination with oral immunosuppressive agents
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 3
711 of respondents) Data of 6 questionnaires were in-sufficient and had to be excluded In total 166 patients withAQP4-IgGndashseropositive NMOSD (148 female and 18 male)were included Main demographic and clinical characteristicsare described in table 1 Most patients in the cohort had ahistory of myelitis (152 916) or optic neuritis (114687) 95 (572) of both myelitis and optic neuritis Dataon the last available spinal MRI were available for 143 of 166patients (130 of 152 with a history of myelitis) and demon-strated a 2-peak distribution (C2-C6 and Th2-Th7) of lesionlocation (figure 1) Eleven of 21 patients without visible spinallesions had a history of myelitis Six patients only had a relapsein the previous 6 months
Overall Pain Prevalence andMain CharacteristicsOverall 125 (753) patients suffered from chronic NMOSD-associated pain The intensity ofNMOSD-associated chronic painwasmoderate to severe in 552of pain sufferers (figure 2A) Painwasmainly described as aching (904) tender (768) stabbing(688) or burning (664) on sensory dimensions and tiring-exhausting (680) on affective dimension Most prevalent werechronic pain without painless periods (n = 77 616) Isolated oroverlapping pain attacks reported 48 (384) and 40 (320)patients accordingly (figure 2B) Every second patient (n = 8853) reported pain as a symptom of the last relapse
Prevalence of Different Types of PainOne-third of pain sufferers had nociceptive (n = 39 307)probable neuropathic (n = 43 339) or definite neuropathicpain (n = 40 315) each in 3 patients the type of pain couldnot be identified (figure 2C) Pain was most often localized inlegs (728 in two-thirds of cases bilateral) followed by arms(488 in half of cases bilateral) trunk (344) and neckhead region (272) Most intense pain were reported bypatients with pain localization in the trunk (49 plusmn 17 vs 33 plusmn22 p lt 005) or legs (41 plusmn 22 vs 32 plusmn 20 p lt 005) Trunk
pains were more often of definite neuropathic than of prob-able neuropathic or nociceptive character (558 vs 279 vs163 p lt 005) whereas no changes were found for pains inother regions of the body
Two-thirds of the pain sufferers reported spasticity-associatedpain (n = 86 688) (figure 2D) It was significantly moreprevalent in patients with nociceptive than neuropathic pain(878 vs 558 p = 002) Thirty-three patients (264) hadshort-lasting PTS mostly in the legs (n = 28 848) andrarely in the arms (n = 6 182) These patients reportedapproximately 5 PTS episodes a day (49 plusmn 64) with a rangeof 26 attacks per day to 1 per week
Episodes of Myelitis Involving Upper ThoracicSegments Are Associated With Chronic PainChronic pain was not associated with age sex AQP4-IgGtiter disease duration overall disability (EDSS) or depressivestate (BDI gt 14) However the number of previous attackswas significantly associated with the occurrence of pain (OR112 [102ndash121] p = 0020) More detailed analysis revealedthat the total number of episodes of myelitis (OR 127[105ndash157] p = 0018) but not the number of optic neuritis(OR 102 [092ndash113] p = 0716) was relevant There was noassociation of pain prevalence or severity with the presence orany specific localization of persistent spinal lesions (table 2)However we found an association of the number of involvedspinal segments with pain (OR 114 [103ndash128] p = 0024)Moreover the number of lesions in the upper 6 thoracicsegments only (but not in cervical or lower thoracic lesions)was associated with the risk of having pain in general (OR 131[101ndash163] p = 0018) and was the only specific factor in-creasing the risk of spasticity-associated pain among painsufferers (OR 136 [110ndash167] p = 0002) We could not findany specific factors associated with short-lasting PTS De-pressive state was the only factor strongly associated withneuropathic pain (OR 344 [135ndash880] p = 0001)
Figure 1 Distribution of Persistent Spinal Lesions in Cervical and Thoracic Segments
Shown is the frequency () of patients (total n = 143) with a spinal lesion on MRI at the appropriate level
4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Pain Severity Strongly Correlates WithReduction of Activities of Daily LivingEffects of pain on ADL are given in table 3 Correlationanalysis revealed a strong correlation of pain severity withgeneral activity (rho = 069 p lt 0001) and sleep (rho = 061p lt 0001) followed by mood (rho = 055 p lt 0001) walkingability (rho = 054 p lt 0001) normal work (rho = 052 p lt0001) enjoyment of life (rho = 050 p lt 0001) and relations
(rho = 046 p lt 0001) We observed an even stronger neg-ative effect of definite neuropathic pain on all evaluated ADLaspects compared with nociceptive pain
Chronic Pain But Not Physical Impairment IsAssociated With Depression in NMOSDSixty-six (398) patients suffered from depression mild in32 (193) moderate in 21 (116) and severe in 13 (78)
Figure 2 Main Characteristics of the NMOSD-Associated Pain
(A) Intensity (B) temporal patterns (a continuous pain with slight fluctuations b continuous pain with pain attacks c pain attacks with painless periods dpain attacks without painless periods) and (C and D) character of pain Values of pain intensity are given in median interquartile range and minimal andmaximal values Prevalence is given in () NMOSD = neuromyelitis optica spectrum disorder NRS = Numeric Rating Scale PTS = painful tonic spasm
Table 2 Prevalence and Severity of Pain in 143 Patients With Spinal Lesions of Different Localizations
Localization of spinal lesions Prevalence of pain BPI-PSI PainDetect score
No persistent lesions (N = 21) 682 (N = 15)a 36 plusmn 24 135 plusmn 51
Isolated cervical lesions (N = 27) 667 (N = 18) 34 plusmn 19 150 plusmn 75
Isolated thoracic lesions (N = 33) 818 (N = 27) 43 plusmn 22 174 plusmn 67
Cervicothoracic lesions (N = 62) 770 (N = 47) 37 plusmn 22 162 plusmn 66
Abbreviation BPI-PSI = Pain Severity Index of Brief Pain InventoryBPI-PSI and PainDetect Score values are given in mean plusmn SD for pain sufferers No significant differences were founda Seven of 15 patients had at least 1 myelitis episode in the history
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 5
cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
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References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
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severe Three pain scores are derived from the sum of the rankvalues (1) sensory (2) affective and (3) total descriptorsPainful tonic spasms (PTSs) were assessed asking the patientwhether they experienced recurrent attacks or short episodes(duration lt1 minute) of localized muscle spasms accompa-nied by severe pain
Depression was evaluated using Beck Depression Inventory II(BDI-II) scored from 0 (best) to 63 (worst) (lt9 no de-pressive affect 9ndash13 minimal mood disturbance 14ndash20 milddepression 21ndash28 moderate depression and ge29 severe de-pression) Clinically relevant depression was defined by a scoreof ge14 Health-related QoL was measured with the SF-36questionnaire consisting of 36 items in 8 subscales A Physical
Component Summary (PCS) and a Mental ComponentSummary (MCS) were calculated using norm-based attainingvalues from 0 (worst) to 100 (best)
Standard Protocol Approvals Registrationsand Patient ConsentsEthics approval was obtained from the Institutional ReviewBoard of the Ruhr-University Bochum (15-5534) Ethicsapproval of the NEMOS registry was obtained in participatingcenters locally Patients provided written informed consentThe study was performed according to International Con-ference on HarmonizationGood Clinical Practice and cur-rent legal requirements
Statistical AnalysisDescriptive statistics were used to describe sample data Com-parisons of interval-scaled variables were performed using the2-sample t test for normally distributed variables the Mann-Whitney-Wilcoxon rank-sum test for nonparametric or ordinal-scaled variables and the χ2 test for categorical variables We usedbinary logistic regression to evaluate factors associated withoverall pain (yes vs no) as well as neuropathic (neuropathic vsnociceptive pain) and spasticity-related pain (spasticity-associatedvs other [nonndashspasticity-associated] pain) as dependent variablesThe following independent variables were included into the lo-gistic model sex age EDSS disease duration AQP4-IgG titeroverall number of previous relapses number of myelitis attacksand number of involved spinal segments Concerning depressivestate sex age disease duration walking and visual impairmentwere included into analysis A multiple robust regression modelwith backward feature selection was used to determine predictorsfor hrQoL with PCS and MCS composites as dependent vari-ables and age sex disease duration walking and visual impair-ment pain severity and Beck depression index as independentvariables22 To check for correlations between pain intensity anddifferent aspects of ADL we performed the Spearman correlationtest This study was an exploratory pilot study with no a priorisample size calculation For the same reason statistical signifi-cance was set at p lt 005 without adjustment for multiple testingNumerical calculations were performed by SPSS Statistics Ver-sion 25 SPSS Inc an IBM Company and The R Project forStatistical Computing Version 340 (2017-04-21) The RFoundation for Statistical Computing
Data AvailabilityAnonymized data not published within this article are avail-able on reasonable request from any qualified investigatorwithin 5 years after publication
ResultsDemographic and Clinical CharacteristicsThirteen tertiary referral NEMOS centers participated in thestudy and 172 questionnaires were sent back to the readingcenter in Bochum for analysis The response rate was 831(data on response rate available for 7 centers addressing
Table 1 Demographic Characteristics andImmunotherapy
Mean (SD)Median(minndashmax)
Total number of patients(all AQP4-IgG seropositive)
166
FM ratio 821
EDSS 35 (00ndash90)
Age y 517 (134)
Disease duration y 91 (81)
ARR 11 (16)
Total number of ON episodes sinceonset
22 (41)
Total number of myelitis episodes sinceonset
46 (74)
Total number of involved spinalsegments
53 (41)
No of involved cervical segments 22 (21)
No of involved thoracic segments 32 (33)
AQP4-IgG titer (CBA) 1100 (110ndash125600)
Current immunotherapy N
Rituximab 627104a
Azathioprine 120 20
Anti-IL6 therapy (tocilizumab N = 11 SA237 N = 1) 72 12
Mycophenolate mofetil 48 8
Other therapies (methotrexate N = 2 prednisone N = 2mitoxantrone N = 2 IVIg N = 1 glatiramer acetate N = 1cyclosporin N = 1)
54 9
Prednisone as add-on therapy 102 17
No immunotherapy 78 13
Abbreviations ARR = annualized relapse rate AQP4 = aquaporin-4 CBA =cell-based assay EDSS = Expanded Disability Status Scale FM = femalemale ON = optic neuritisa Five in combination with oral immunosuppressive agents
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 3
711 of respondents) Data of 6 questionnaires were in-sufficient and had to be excluded In total 166 patients withAQP4-IgGndashseropositive NMOSD (148 female and 18 male)were included Main demographic and clinical characteristicsare described in table 1 Most patients in the cohort had ahistory of myelitis (152 916) or optic neuritis (114687) 95 (572) of both myelitis and optic neuritis Dataon the last available spinal MRI were available for 143 of 166patients (130 of 152 with a history of myelitis) and demon-strated a 2-peak distribution (C2-C6 and Th2-Th7) of lesionlocation (figure 1) Eleven of 21 patients without visible spinallesions had a history of myelitis Six patients only had a relapsein the previous 6 months
Overall Pain Prevalence andMain CharacteristicsOverall 125 (753) patients suffered from chronic NMOSD-associated pain The intensity ofNMOSD-associated chronic painwasmoderate to severe in 552of pain sufferers (figure 2A) Painwasmainly described as aching (904) tender (768) stabbing(688) or burning (664) on sensory dimensions and tiring-exhausting (680) on affective dimension Most prevalent werechronic pain without painless periods (n = 77 616) Isolated oroverlapping pain attacks reported 48 (384) and 40 (320)patients accordingly (figure 2B) Every second patient (n = 8853) reported pain as a symptom of the last relapse
Prevalence of Different Types of PainOne-third of pain sufferers had nociceptive (n = 39 307)probable neuropathic (n = 43 339) or definite neuropathicpain (n = 40 315) each in 3 patients the type of pain couldnot be identified (figure 2C) Pain was most often localized inlegs (728 in two-thirds of cases bilateral) followed by arms(488 in half of cases bilateral) trunk (344) and neckhead region (272) Most intense pain were reported bypatients with pain localization in the trunk (49 plusmn 17 vs 33 plusmn22 p lt 005) or legs (41 plusmn 22 vs 32 plusmn 20 p lt 005) Trunk
pains were more often of definite neuropathic than of prob-able neuropathic or nociceptive character (558 vs 279 vs163 p lt 005) whereas no changes were found for pains inother regions of the body
Two-thirds of the pain sufferers reported spasticity-associatedpain (n = 86 688) (figure 2D) It was significantly moreprevalent in patients with nociceptive than neuropathic pain(878 vs 558 p = 002) Thirty-three patients (264) hadshort-lasting PTS mostly in the legs (n = 28 848) andrarely in the arms (n = 6 182) These patients reportedapproximately 5 PTS episodes a day (49 plusmn 64) with a rangeof 26 attacks per day to 1 per week
Episodes of Myelitis Involving Upper ThoracicSegments Are Associated With Chronic PainChronic pain was not associated with age sex AQP4-IgGtiter disease duration overall disability (EDSS) or depressivestate (BDI gt 14) However the number of previous attackswas significantly associated with the occurrence of pain (OR112 [102ndash121] p = 0020) More detailed analysis revealedthat the total number of episodes of myelitis (OR 127[105ndash157] p = 0018) but not the number of optic neuritis(OR 102 [092ndash113] p = 0716) was relevant There was noassociation of pain prevalence or severity with the presence orany specific localization of persistent spinal lesions (table 2)However we found an association of the number of involvedspinal segments with pain (OR 114 [103ndash128] p = 0024)Moreover the number of lesions in the upper 6 thoracicsegments only (but not in cervical or lower thoracic lesions)was associated with the risk of having pain in general (OR 131[101ndash163] p = 0018) and was the only specific factor in-creasing the risk of spasticity-associated pain among painsufferers (OR 136 [110ndash167] p = 0002) We could not findany specific factors associated with short-lasting PTS De-pressive state was the only factor strongly associated withneuropathic pain (OR 344 [135ndash880] p = 0001)
Figure 1 Distribution of Persistent Spinal Lesions in Cervical and Thoracic Segments
Shown is the frequency () of patients (total n = 143) with a spinal lesion on MRI at the appropriate level
4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Pain Severity Strongly Correlates WithReduction of Activities of Daily LivingEffects of pain on ADL are given in table 3 Correlationanalysis revealed a strong correlation of pain severity withgeneral activity (rho = 069 p lt 0001) and sleep (rho = 061p lt 0001) followed by mood (rho = 055 p lt 0001) walkingability (rho = 054 p lt 0001) normal work (rho = 052 p lt0001) enjoyment of life (rho = 050 p lt 0001) and relations
(rho = 046 p lt 0001) We observed an even stronger neg-ative effect of definite neuropathic pain on all evaluated ADLaspects compared with nociceptive pain
Chronic Pain But Not Physical Impairment IsAssociated With Depression in NMOSDSixty-six (398) patients suffered from depression mild in32 (193) moderate in 21 (116) and severe in 13 (78)
Figure 2 Main Characteristics of the NMOSD-Associated Pain
(A) Intensity (B) temporal patterns (a continuous pain with slight fluctuations b continuous pain with pain attacks c pain attacks with painless periods dpain attacks without painless periods) and (C and D) character of pain Values of pain intensity are given in median interquartile range and minimal andmaximal values Prevalence is given in () NMOSD = neuromyelitis optica spectrum disorder NRS = Numeric Rating Scale PTS = painful tonic spasm
Table 2 Prevalence and Severity of Pain in 143 Patients With Spinal Lesions of Different Localizations
Localization of spinal lesions Prevalence of pain BPI-PSI PainDetect score
No persistent lesions (N = 21) 682 (N = 15)a 36 plusmn 24 135 plusmn 51
Isolated cervical lesions (N = 27) 667 (N = 18) 34 plusmn 19 150 plusmn 75
Isolated thoracic lesions (N = 33) 818 (N = 27) 43 plusmn 22 174 plusmn 67
Cervicothoracic lesions (N = 62) 770 (N = 47) 37 plusmn 22 162 plusmn 66
Abbreviation BPI-PSI = Pain Severity Index of Brief Pain InventoryBPI-PSI and PainDetect Score values are given in mean plusmn SD for pain sufferers No significant differences were founda Seven of 15 patients had at least 1 myelitis episode in the history
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 5
cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/4.jpg)
711 of respondents) Data of 6 questionnaires were in-sufficient and had to be excluded In total 166 patients withAQP4-IgGndashseropositive NMOSD (148 female and 18 male)were included Main demographic and clinical characteristicsare described in table 1 Most patients in the cohort had ahistory of myelitis (152 916) or optic neuritis (114687) 95 (572) of both myelitis and optic neuritis Dataon the last available spinal MRI were available for 143 of 166patients (130 of 152 with a history of myelitis) and demon-strated a 2-peak distribution (C2-C6 and Th2-Th7) of lesionlocation (figure 1) Eleven of 21 patients without visible spinallesions had a history of myelitis Six patients only had a relapsein the previous 6 months
Overall Pain Prevalence andMain CharacteristicsOverall 125 (753) patients suffered from chronic NMOSD-associated pain The intensity ofNMOSD-associated chronic painwasmoderate to severe in 552of pain sufferers (figure 2A) Painwasmainly described as aching (904) tender (768) stabbing(688) or burning (664) on sensory dimensions and tiring-exhausting (680) on affective dimension Most prevalent werechronic pain without painless periods (n = 77 616) Isolated oroverlapping pain attacks reported 48 (384) and 40 (320)patients accordingly (figure 2B) Every second patient (n = 8853) reported pain as a symptom of the last relapse
Prevalence of Different Types of PainOne-third of pain sufferers had nociceptive (n = 39 307)probable neuropathic (n = 43 339) or definite neuropathicpain (n = 40 315) each in 3 patients the type of pain couldnot be identified (figure 2C) Pain was most often localized inlegs (728 in two-thirds of cases bilateral) followed by arms(488 in half of cases bilateral) trunk (344) and neckhead region (272) Most intense pain were reported bypatients with pain localization in the trunk (49 plusmn 17 vs 33 plusmn22 p lt 005) or legs (41 plusmn 22 vs 32 plusmn 20 p lt 005) Trunk
pains were more often of definite neuropathic than of prob-able neuropathic or nociceptive character (558 vs 279 vs163 p lt 005) whereas no changes were found for pains inother regions of the body
Two-thirds of the pain sufferers reported spasticity-associatedpain (n = 86 688) (figure 2D) It was significantly moreprevalent in patients with nociceptive than neuropathic pain(878 vs 558 p = 002) Thirty-three patients (264) hadshort-lasting PTS mostly in the legs (n = 28 848) andrarely in the arms (n = 6 182) These patients reportedapproximately 5 PTS episodes a day (49 plusmn 64) with a rangeof 26 attacks per day to 1 per week
Episodes of Myelitis Involving Upper ThoracicSegments Are Associated With Chronic PainChronic pain was not associated with age sex AQP4-IgGtiter disease duration overall disability (EDSS) or depressivestate (BDI gt 14) However the number of previous attackswas significantly associated with the occurrence of pain (OR112 [102ndash121] p = 0020) More detailed analysis revealedthat the total number of episodes of myelitis (OR 127[105ndash157] p = 0018) but not the number of optic neuritis(OR 102 [092ndash113] p = 0716) was relevant There was noassociation of pain prevalence or severity with the presence orany specific localization of persistent spinal lesions (table 2)However we found an association of the number of involvedspinal segments with pain (OR 114 [103ndash128] p = 0024)Moreover the number of lesions in the upper 6 thoracicsegments only (but not in cervical or lower thoracic lesions)was associated with the risk of having pain in general (OR 131[101ndash163] p = 0018) and was the only specific factor in-creasing the risk of spasticity-associated pain among painsufferers (OR 136 [110ndash167] p = 0002) We could not findany specific factors associated with short-lasting PTS De-pressive state was the only factor strongly associated withneuropathic pain (OR 344 [135ndash880] p = 0001)
Figure 1 Distribution of Persistent Spinal Lesions in Cervical and Thoracic Segments
Shown is the frequency () of patients (total n = 143) with a spinal lesion on MRI at the appropriate level
4 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Pain Severity Strongly Correlates WithReduction of Activities of Daily LivingEffects of pain on ADL are given in table 3 Correlationanalysis revealed a strong correlation of pain severity withgeneral activity (rho = 069 p lt 0001) and sleep (rho = 061p lt 0001) followed by mood (rho = 055 p lt 0001) walkingability (rho = 054 p lt 0001) normal work (rho = 052 p lt0001) enjoyment of life (rho = 050 p lt 0001) and relations
(rho = 046 p lt 0001) We observed an even stronger neg-ative effect of definite neuropathic pain on all evaluated ADLaspects compared with nociceptive pain
Chronic Pain But Not Physical Impairment IsAssociated With Depression in NMOSDSixty-six (398) patients suffered from depression mild in32 (193) moderate in 21 (116) and severe in 13 (78)
Figure 2 Main Characteristics of the NMOSD-Associated Pain
(A) Intensity (B) temporal patterns (a continuous pain with slight fluctuations b continuous pain with pain attacks c pain attacks with painless periods dpain attacks without painless periods) and (C and D) character of pain Values of pain intensity are given in median interquartile range and minimal andmaximal values Prevalence is given in () NMOSD = neuromyelitis optica spectrum disorder NRS = Numeric Rating Scale PTS = painful tonic spasm
Table 2 Prevalence and Severity of Pain in 143 Patients With Spinal Lesions of Different Localizations
Localization of spinal lesions Prevalence of pain BPI-PSI PainDetect score
No persistent lesions (N = 21) 682 (N = 15)a 36 plusmn 24 135 plusmn 51
Isolated cervical lesions (N = 27) 667 (N = 18) 34 plusmn 19 150 plusmn 75
Isolated thoracic lesions (N = 33) 818 (N = 27) 43 plusmn 22 174 plusmn 67
Cervicothoracic lesions (N = 62) 770 (N = 47) 37 plusmn 22 162 plusmn 66
Abbreviation BPI-PSI = Pain Severity Index of Brief Pain InventoryBPI-PSI and PainDetect Score values are given in mean plusmn SD for pain sufferers No significant differences were founda Seven of 15 patients had at least 1 myelitis episode in the history
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 5
cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
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References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/5.jpg)
Pain Severity Strongly Correlates WithReduction of Activities of Daily LivingEffects of pain on ADL are given in table 3 Correlationanalysis revealed a strong correlation of pain severity withgeneral activity (rho = 069 p lt 0001) and sleep (rho = 061p lt 0001) followed by mood (rho = 055 p lt 0001) walkingability (rho = 054 p lt 0001) normal work (rho = 052 p lt0001) enjoyment of life (rho = 050 p lt 0001) and relations
(rho = 046 p lt 0001) We observed an even stronger neg-ative effect of definite neuropathic pain on all evaluated ADLaspects compared with nociceptive pain
Chronic Pain But Not Physical Impairment IsAssociated With Depression in NMOSDSixty-six (398) patients suffered from depression mild in32 (193) moderate in 21 (116) and severe in 13 (78)
Figure 2 Main Characteristics of the NMOSD-Associated Pain
(A) Intensity (B) temporal patterns (a continuous pain with slight fluctuations b continuous pain with pain attacks c pain attacks with painless periods dpain attacks without painless periods) and (C and D) character of pain Values of pain intensity are given in median interquartile range and minimal andmaximal values Prevalence is given in () NMOSD = neuromyelitis optica spectrum disorder NRS = Numeric Rating Scale PTS = painful tonic spasm
Table 2 Prevalence and Severity of Pain in 143 Patients With Spinal Lesions of Different Localizations
Localization of spinal lesions Prevalence of pain BPI-PSI PainDetect score
No persistent lesions (N = 21) 682 (N = 15)a 36 plusmn 24 135 plusmn 51
Isolated cervical lesions (N = 27) 667 (N = 18) 34 plusmn 19 150 plusmn 75
Isolated thoracic lesions (N = 33) 818 (N = 27) 43 plusmn 22 174 plusmn 67
Cervicothoracic lesions (N = 62) 770 (N = 47) 37 plusmn 22 162 plusmn 66
Abbreviation BPI-PSI = Pain Severity Index of Brief Pain InventoryBPI-PSI and PainDetect Score values are given in mean plusmn SD for pain sufferers No significant differences were founda Seven of 15 patients had at least 1 myelitis episode in the history
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 5
cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
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References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
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cases There was no association between a depressive state(BDI gt 14) and age sex or disease duration Univariate re-gression analyses revealed pain severity as well as walking andvisual impairment to be associated with depressive state Inthe multiple logistic regression analysis pain intensity (OR153 [122ndash191] p lt 0001) remained the only factor in-dependently associated with a depressive state
Pain Depression andWalking Impairment Are3 Main QoL PredictorsThe physical but not the mental composite subscale wassignificantly lower in pain sufferers (table 4) Among painsufferers patients with definite neuropathic pain had signifi-cantly lower scores in both SF-36 composites comparing tothose with nociceptive pain Multivariate regression analysisidentified pain severity (p lt 0001) and walking impairment(p lt 0001) as 2 independent predictors explaining 539 ofthe physical QoL composite variability Depression measuredby the BDI score (p lt 0001) and to a lesser extent walkingimpairment (p = 0043) determined 397 of the mental QoLcomposite variability
Symptomatic Pain Treatment Is InsufficientlyEffective in Real-Life PracticeTwo-thirds (n = 81 648) of the 125 pain sufferers tookpain medications antidepressants or both Most of themtook 1 (n = 44 352) or 2 (n = 25 200) pain medica-tions Nine patients (72) had 3 different pain medicationsand 3 patients had 4 5 and 6 medications each Pain med-ication included nonopioid analgesics (including non-steroidal anti-inflammatory drugs) (n = 47 376)antiepileptic medications for neuropathic pain (includinggabapentin pregabalin carbamazepine and oxcarbazepine)
(n = 51 408) and opioids (n = 13 104) Antidepres-sants were taken by 21 (168) pain sufferers Surprisinglyonly one-third (n = 10 294) of those with at least mod-erate depression (BDI gt 20) took antidepressants Seven of10 suffered from pain with a median pain intensity of 50(20ndash80) so that antidepressant medication could be acomponent of pain therapy
Patients with definite neuropathic pain took symptomatictherapy significantly more often compared with those withnociceptive pain (850 vs 513 p = 0002 table 5) How-ever among the 40 patients with neuropathic pain only 23(575) took specific medications Retrospectively patientsreported a substantial reduction of the pain intensity throughpain medications median 60 (range 0ndash100) in all patients50 (0ndash100) in those with definite neuropathic pain 65(0ndash100) in those with nociceptive pain Only 4 patients(49) were pain-free and 25 patients (309) reported mildpain Most patients still reported moderate (n = 41 506) orsevere (n = 11 136) pain despite symptomatic treatmentOnly 288 of those with spasticity-associated pain receivedantispastic medications
Effects of Immunotherapies onPain ExperienceThere was no difference in terms of pain prevalence or intensityin patients with different immunotherapies Retrospectively395 of pain sufferers reported improvement of pain after startof immunotherapy 28 of 75 (373) under rituximab 6 of 15(400) under azathioprine 2 of 6 (333) under mycophe-nolate mofetil and 6 of 9 (667) under tocilizumab
Pain Pattern Question Can Be an EffectiveScreening ToolFinally we searched for a short screening question allowingidentification of those patients most affected by pain inNMOSD We used the 4 pain patterns from the PDQ (table6) Patients suffering from pain attacks without painless in-tervals (patterns 2 and 4) had significantly more intense painsand a significantly lower physical QoL component Moreoverthe majority of those with pattern 4 suffered frommoderate orsevere depression (875) and neuropathic pain (625) andhad lower mental QoL
DiscussionWe evaluated a large cohort of patients with AQP4-IgGndashseropositive NMOSD for pain and comorbid de-pression As much as 753 of all patients suffered fromNMOSD-associated chronic pain in line with previouslyreported 80ndash86 in smaller studies from other geographicareas10-121423 The majority of patients reported continuouspain often superimposed by pain attacks Pain localizationwas in the legs in 34 and around the trunk and in arms in 12each Overall pain intensity was lower in our cohort comparedwith previous studies conducted a decade ago10-12 and only 10
Table 3 Effects of Neuropathic and Nociceptive Pain onADL
All painsufferers(N = 125)
Patients withdefiniteneuropathic pain(N = 40)
Patients withdefinitenociceptive pain(N = 39)
Generalactivity
46 plusmn 26 57 plusmn 23a 36 plusmn 26
Mood 40 plusmn 31 54 plusmn 29a 30 plusmn 27
Walkingability
47 plusmn 34 58 plusmn 32a 32 plusmn 31
Normalwork
50 plusmn 32 66 plusmn 27a 39 plusmn 31
Relations 34 plusmn 33 50 plusmn 32a 24 plusmn 28
Sleep 41 plusmn 32 58 plusmn 30a 28 plusmn 27
Enjoymentof life
37 plusmn 33 51 plusmn 32a 28 plusmn 29
Abbreviation ADL = activity of daily livingValues are given in mean plusmn SDa p lt 0001 t test
6 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
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httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
![Page 7: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/7.jpg)
suffered from severe pain Both median EDSS and the totalnumber of involved spinal segments were lower than in previousstudies Less aggressive disease course probably due to earlierdiagnosis andor more effective immunotherapy could explainthese differences Indeed two-thirds of our patients received rit-uximab and about 40 reported reduction of pain under currentimmunotherapy A positive selection bias could be another pos-sible explanation No data on questionnaire response rates havebeen reported in 2 of 3 abovementioned smaller surveys1112 Ofinterest similar to one of the previous studies we achieved arelative high response rate and pain severity was very similar inboth studies (36 plusmn 28 other study 38 plusmn 21 our cohort)10
Using the PDQ 24 of our patients had definite neuropathicpain and further 26 signs of possible neuropathic pain Twoprevious studies reported a significantly higher prevalence ofneuropathic pain 62 and 86 respectively based on theDouleur Neuropathique 4 questionnaire and less clearly de-fined clinical criteria1223 In a recent PainDetect-based smallstudy definite neuropathic pain was present in 7 only14
We were able to identify several predictors of pain in ourcohort The number of myelitis episodes and the extent ofspinal cord lesions independently contributed to the risk ofNMOSD-associated pain Previous smaller studies
demonstrated contradictory results111223 Although a correla-tion between pain intensity and an overall length of the spinallesions was reported this could not be confirmed in anotherstudy1112 It is likely that different severity and location (bothsagittal and axial) of injuries have different effects on pain per-ception In contrast to a recentUK study23 we could not confirma protective effect of persistent cervical lesions however injuriesin the upper thoracic (but not cervical or lower thoracic) seg-ments were critical for development of chronic pain Previouslya causative relationship between upper thoracic lesions andneuropathic pain was postulated23 As known patients withspinal lesions develop both neuropathic and nociceptive pain24
To evaluate a link between spinal lesions and neuropathic painwe compared patients with a definite nociceptive and definiteneuropathic pain We could not confirm a specific association ofthe latter with any extent or any precise sagittal lesions locationIn contrast the number of involved upper thoracic segments wassignificantly associated with the risk of spasticity-associated painobserved in two-thirds of pain sufferers Spasticity was one of themain mechanisms underlying nociceptive NMOSD-associatedpain in our cohort being present in almost 90 of these patients
Similar to previous studies we found that approximately 20of all respondents suffered from short-lasting PTSs17 Despitea previously supported association of PTS to incompletely
Table 4 Quality of Life in Patients With and Without NMOSD-Associated Pain
SF-36domain
All patients(N = 166)
Patientswithout pain (N= 41)
Patients withpain (N = 125)
Patients with definitenociceptive pain(N = 39)
Patients with definiteneuropathic pain(N = 40)
Patientswith BDI0ndash14(N = 99)
Patientswith BDIgt14(N = 66)
SF-36PF
477 plusmn 360 633 plusmn 391 434 plusmn 337a 521 plusmn 369 361 plusmn 286b 596 plusmn 352 307 plusmn 295c
SF-36RP
410 plusmn 413 447 plusmn 243 369 plusmn 388a 391 plusmn 371 289 plusmn 387 536 plusmn 416 222 plusmn 330c
SF-36BP
522 plusmn 301 781 plusmn 329 447 plusmn 243a 541 plusmn 236 339 plusmn 201b 599 plusmn 272 416 plusmn 306c
SF-36GH
441 plusmn 204 517 plusmn 195 418 plusmn 202a 465 plusmn 201 366 plusmn 158b 513 plusmn 202 331 plusmn 153c
SF-36VT
431 plusmn 219 523 plusmn 206 403 plusmn 217a 457 plusmn 213 312 plusmn 187b 538 plusmn 186 270 plusmn 158c
SF-36SF
666 plusmn 297 773 plusmn 258 636 plusmn 301a 683 plusmn 276 578 plusmn 302 777 plusmn 257 505 plusmn 275c
SF-36RE
685 plusmn 420 819 plusmn 346 653 plusmn 430a 769 plusmn 376 521 plusmn 458b 823 plusmn 352 479 plusmn 432c
SF-36MH
655 plusmn 209 680 plusmn 185 647 plusmn 217 707 plusmn 209 567 plusmn 243b 768 plusmn 136 486 plusmn 185c
SF-36PCS
347 plusmn 122 439 plusmn 125 322 plusmn 108a 344 plusmn 109 296 plusmn 93b 381 plusmn 120 296 plusmn 107c
SF-36MCS
480 plusmn 116 492 plusmn 102 476 plusmn 120 505 plusmn 122 431 plusmn 116b 532 plusmn 80 400 plusmn 116c
Abbreviations BP = bodily pain GH = general health MCS = mental component summary NMOSD = neuromyelitis optica spectrum disorder PF = physicalfunctioning QOL = quality of life RE = role-emotional RP = role-physical SF = social functioning SF-36 = short form 36 and its different domains VT = vitalityValues are given in mean plusmn SDa Significant lower comparing to patients without painb Significant lower comparing to patients with a nociceptive painc Significant lower comparing to patients without a depressive state t test
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 7
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
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References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/8.jpg)
remyelinated spinal lesions we could not confirm this findingeither In MS PTSs are supposed to be associated with tha-lamocortical lesions2526
The 19 prevalence of moderate to severe depression in ourcohort was lower compared with an earlier reported 28 inNMOSD27 Similar to previous studies only pain severity butnot disability disease activity or any other demographic pa-rameter was associated with depression Depression was theonly factor associated with neuropathic but not nociceptivepain however identification of causative relationships be-tween these conditions is impossible in a cross-sectionalstudy Bidirectional relationships between depression andneuropathic pain are well known and especially in in-flammatory diseases share common underlying mecha-nisms28 It is noteworthy that a specific direct link betweenNMOSD and depression has been supposed in experimentalstudies AQP4 deficiency itself results in a decreased hippo-campal neurogenesis which could contribute to the patho-genesis of depression29
Despite being mild to moderate pain and depression can haveenormous negative effects on patientrsquos life Pain markedlyreduced all aspects of ADL Pain intensity and walking im-pairment were 2 main factors independently associated withlower physical QoL whereas the latter and depression had animpact on the mental QoL Comparing patients with noci-ceptive and neuropathic pain the latter had significantly lowerADL as well as both lower physical and mental composites ofQoL Of interest 2 temporal pain patterns (persistent painwith pain attacks and pain attacks with pain between them)were associated with a markedly higher pain intensity de-pression prevalence and lower QoL This simple image-basedquestion allowing prompt identification of most disabledpatients might be useful for pain screening in NMOSD
In previous NMOSD studies an insufficient symptomatictherapy has been reported15 In our cohort 65 received painmedications and two-thirds of them reported a significantpain relief Despite multiple medications pain intensitymostly remained moderate and only a minority of patients
Table 5 Prevalence and Efficacy of Symptomatic Therapy in Pain Sufferers
All painsufferers(N = 125)
Patients with definite nociceptive pain(N = 39)
Patients with definite neuropathic pain(N = 40)
Symptomatic therapy 638 (81) 513 (20) 85 (34)
Pain reduction by symptomatictherapy in the last week (medianminndashmax)
60 (0ndash100) 65 (0ndash100) 50 (0ndash100)
Mean pain intensity 43 plusmn 20 33 plusmn 16 50 plusmn 20a
Pain-free 4 (49) 1 (50) 0
Mild pain (1ndash3 NRS) 25 (309) 10 (500) 9 (265)
Moderate pain (4ndash6 NRS) 41 (506) 9 (450) 15 (441)
Severe pain (gt6 NRS) 11 (136) 0 10 (294)
Abbreviation NRS = Numeric Rating ScaleIf not otherwise specified values are given inmean plusmn SD Patients with ambiguous pain character (probable neuropathic or nociceptive) were excluded fromthis analysisa p lt 0001 t test
Table 6 Association of 4 Pain Patterns With Pain Characteristics Depression and QoL
Pain patternAverage painintensity
Prevalence of definitiveneuropathic pain
Prevalence of depression(BDI gt 14)
PhysicalQoL
MentalQoL
Continuous pain with slightfluctuations
39 plusmn 20 222 405 332 plusmn 96 479 plusmn117
Continuous pain with painattacks
48 plusmn 20a 355 438 279 plusmn 93a 487 plusmn109
Pain attacks with painlessperiods
30 plusmn 20 354 333 340 plusmn 111 479 plusmn124
Pain attacks without painlessperiods
56 plusmn 18a 625b 875b 249 plusmn 98a 386 plusmn134b
Abbreviations QOL = quality of life BDI = Beck Depression Inventory IIValues are given in mean plusmn SDa Significant difference vs patterns 1 and 3 ANOVAb Significant difference vs patterns 1 2 and 3 ANOVA or Fisher exact test respectively
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
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httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/9.jpg)
was pain-free Insufficient on-target medication could be oneof the reasons antispastic medications were administered inonly 29 of those with a spasticity-associated pain and only58 of patients with neuropathic pain had specific treatment
Compared with pain depression was less often adequatelytreated Twenty-nine percent of those with moderate to se-vere depression received antidepressants The actual numberof patients receiving adequate antidepressant pharmacother-apy is probably even lower as at least in some of them an-tidepressants were administered as a part of pain therapy
The strengths of our study are inclusion of a relatively largecohort of purely AQP4-IgGndashseropositive NMOSD patients andthe definition of clinical and paraclinical predictors of pain as wellas its association with depression and effects on QoL There arealso limitations Because we only asked for pharmacologic treat-ments no information about nonpharmacologic pain therapiesand psychotherapy is available Transcutaneous electric nervestimulation was recently reported to reduce persistent centralneuropathic pain inNMOSD30 BecauseMRI data were retrievedby record review we could not perform a precise analysis oftransverse localization and size of the spinal lesions In additionno brain MRI was performed to evaluate central nociceptivepathways There were no sufficient data on lumbar MRI rarelyinvolved by seropositive NMOSD The analysis of lesion exten-sion in the acute phase of myelitis could be also promising assome injured foci become invisible afterward Moreover pro-spective evaluation of the type and severity of pain in the first 6months after acutemyelitis could be helpful for precise analysis ofpossible underlying mechanisms A relatively high proportion ofpain sufferers (35) took no pain medications during the studyIt remains unclear whether the medications have not been ad-ministered due to low pain intensity or stopped due to lowefficacy and side effects It would be important to address thispoint in further studies Finally we did not perform an analysis offatigue an important factor influencing depression and QoL
In conclusion chronic pain and depression are highly prevalentand strongly affect QoL and ADL in AQP4-IgGndashseropositiveNMOSD Both conditions remain undertreated and thereforeshould be asked for in the diagnostic workup Pain attackswithout painless periods are typical for NMOSD and have themost severe impact Episodes of myelitis involving upper tho-racic segments are main drivers of pain in NMOSD and shouldbe prevented and aggressively treated Adequate immunother-apy has a beneficial effect on pain experience Higher awarenessand interventional studies on targeted symptomatic treatmentof neuropathic and spasticity-associated pain including char-acteristic and very intense short-lasting PTSs are warranted andcould change a real-life clinical practice in NMOSD
AcknowledgmentI Ayzenberg and I Kleiter had full access to all the data in thestudy and take responsibility for the integrity of the data andthe accuracy of the data analysis The authors thank allpatients for participating in the study
Study FundingThe study was funded in part by an unrestricted educa-tional grant from Chugai Ltd Japan The NEMOS cohortNationNMO is supported by the German Ministry forEducation and Research (BMBF) as part of the GermanCompetence Network Multiple Sclerosis (KKNMSfor NEMOS NationNMO-DAB FKZ 01GI1602C to J-PStellmannNationNMO-PATFKZ 01GI1602B toO Aktas andNationNMO-LAB FKZ 01GI1602A to B Wildemann)
DisclosureI Ayzenberg has received travel grants from Biogen Idec and theGuthy-Jackson Charitable Foundation served on scientific advi-sory boards for Roche andAlexion and received research supportfrom Diamed none related to this manuscript D Richter and EHenke have no conflicts of interest SA received travel grant fromCelgene and speakerrsquos honorary from Roche and Bayer F Paulserves as Academic Editor for PLoS One Associate Editor forNeurology Neuroimmunology amp Neuroinflammation is a memberof the Novartis OCTIMS study steering committeeMedImmuneViela Bio steering committee reports speakerhonoraria and travel grants from Bayer Novartis Biogen IdecTeva Sanofi-AventisGenzyme and Merck Serono AlexionChugai MedImmune Shire Roche Actelion Celgene andconsultancies for Sanofi Genzyme Biogen Idec MedImmuneShire Alexion received research support from Bayer NovartisBiogen Idec Teva Sanofi-AventisGenzyme Alexion andMerckSerono German Research Council (DFG Exc 257) WerthStiftung of the City of Cologne German Ministry of Educationand Research (BMBFCompetence NetworkMultiple Sclerosis)Arthur Arnstein Stiftung Berlin EU FP7 Framework Program(combimseu) Arthur Arnstein Foundation Berlin Guthy-Jackson Charitable Foundation National Multiple Sclerosis So-ciety of the USA C Trebst has received honoraria for consul-tation and expert testimony from Biogen IdecGmbH GenzymeGmbH Novartis Pharma GmbH MERCK Chugai PharmaGermany GmbH and Roche Pharma GmbH None of this in-terfered with the current report MW Hummert reports nodisclosures T Kumpfel has received speaker honoraria includingadvisory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi-AventisGenzyme Roche Pharma andBiogen as well as grant support fromNovartis andChugai Pharmain the past J Babla reports grants for OCT research from theFriedrich-Baur-Stiftung andMerck personal fees and nonfinancialsupport from Alexion Biogen Celgene Heidelberg EngineeringMerck Novartis Roche Santhera and Sanofi Genzyme andnonfinancial support of the Guthy-Jackson Charitable Founda-tion all outside the submitted work J Havla is (partially) fundedby the German Federal Ministry of Education and Research(Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H](DIFUTURE)) M Ringelstein received speaker honorariafrom Novartis Bayer Roche Alexion and Ipsen and travel re-imbursement from Bayer Schering Biogen Idec Merz GenzymeTeva Grifols Roche and Merck none related to this study OAktas has received personal fees from Alexion Bayer HealthCareBiogen Celgene Merck Serono MedImmune Novartis Roche
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 9
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
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References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/10.jpg)
Teva and Zambon outside of the submitted work S Jarius re-ports no conflicts of interest B Wildemann received grants fromthe German Ministry of Education and Research German Re-search Foundation Dietmar Hopp Foundation Klaus TschiraFoundation grants and personal fees from Merck Novartis andSanofi Genzyme and personal fees from Bayer Biogen Rocheand Teva none related to this work V Hauszligler has no conflict ofinterest J-P Stellmann receives research funding from DeutscheForschungsgemeinschaft and reports a grant from Biogen thatpartially funded the submitted work A further grant is reportedfrom Genzyme outside the submitted work J-P Stellmann alsoreceived travel support and personal fees from Alexion Biogenand Genzyme outside the submitted work M Senel has receivedconsulting andor speaker honoraria from Alexion Bayer Bio-gen Merck Roche and SanofiGenzyme She has received travelfunding from Celgene and Teva She has received researchfunding from the Hertha-Nathorff-Program L Klotz receivedcompensation for serving on scientific advisory boards (AlexionJanssen Novartis Merck Serono Sanofi Genzyme and Roche)speaker honoraria and travel support (Biogen Novartis MerckSerono Sanofi Genzyme Roche and Teva) and research sup-port (Biogen Idec Merck Serono Novartis and Sanofi Gen-zyme) HL Pellkofer received honoraria for lectures from BayerHealthCare Biogen Idec and Teva Pharma and travel re-imbursement from Novartis MS Weber receives researchsupport from theDeutsche Forschungsgemeinschaft (DFGWE35475-1) and fromNovartis Teva Biogen Idec Roche Merckand the ProFutura Programm of the UniversitatsmedizinGottingen MS Weber is serving as an editor for PLoS One Hereceived travel funding andor speaker honoraria from BiogenIdec Merck Serono Novartis Roche Teva Bayer and Gen-zyme M Pawlitzki received travel accommodation and meetingreimbursement from Novartis PS Rommer has received hon-oraria for lectures or consultancy from Alexion Almirall BiogenMerck Novartis Roche Sandoz and Sanofi Genzyme He hasreceived research grants from Amicus Biogen Merck andRoche none related to this manuscript A Berthele has receivedpersonal compensations speaker honoraria and funding fortravel from Alexion Bayer HealthCare Biogen Celgene MerckSerono Mylan Novartis Roche Sanofi Genzyme and Teva K-D Wernecke reports no disclosures K Hellwig received con-sultant and speaker honoraria and grant support from BayerBiogen Merck Novartis Sanofi Genzyme Roche and Teva RGold received speakerrsquos and board honoraria from Baxter BayerSchering Biogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department receivedgrant support from Bayer Schering Biogen Idec GenzymeMerck Serono Novartis and Teva all not related to the contentof this manuscript I Kleiter has received speaker honoraria andtravel funding from Alexion Bayer Biogen Novartis MerckSanofi Genzyme and Roche speaker honoraria from Mylantravel funding from the Guthy-Jackson Charitable Foundationconsulted for Alexion Bayer Biogen Celgene Chugai IQVIANovartis Merck and Roche and received research support fromChugai and Diamed Go to NeurologyorgNN for fulldisclosures
Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationNovember 18 2020 Accepted in final form February 2 2021
Appendix 1 Authors
Name Location Contribution
IlyaAyzenbergMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design and analysisor interpretation of data
DanielRichter MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
EugeniaHenke MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
SusannaAsseyer MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data andanalysis or interpretation ofdata
FriedemannPaul MD
Berlin Institute ofHealth Berlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
CorinnaTrebst MD
Hannover MedicalSchool HannoverGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin WHummertMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
JoachimHavla MD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
TaniaKumpfelMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MariusRingelsteinMD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
OrhanAktas MD
Heinrich HeineUniversity DusseldorfDusseldorf Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/11.jpg)
Appendix 1 (continued)
Name Location Contribution
BrigitteWildemannMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Sven JariusMD
University ofHeidelberg HeidelbergGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
VivienHauszligler MD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Jan-PatrickStellmannMD
Zentrum fur MolekulareNeurobiologieHamburg Germany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
MakbuleSenel MD
University of Ulm UlmGermany
Draftingrevision of themanuscript for contentincluding medical writingfor content and major rolein the acquisition of data
Luisa KlotzMD
University HospitalMunster MunsterGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Hannah LPellkoferMD
Ludwig-MaximiliansUniversity MunichMunich Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Martin SWeber MD
University MedicalCenter GottingenGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
MarcPawlitzkiMD
University HospitalMunster Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Paulus SRommerMD
Medical University ofVienna Vienna Austria
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
AchimBertheleMD
Technical University ofMunich MunichGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Klaus-DieterWerneckeMD
CRO SOSTANA GmbHBerlin Germany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and analysis orinterpretation of data
Appendix 1 (continued)
Name Location Contribution
KerstinHellwig MD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ralf GoldMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent and major role in theacquisition of data
Ingo KleiterMD
Ruhr-UniversityBochum BochumGermany
Draftingrevision of themanuscript for contentincluding medical writing forcontent major role in theacquisition of data studyconcept or design andanalysis or interpretation ofdata
Appendix 2 Coinvestigators
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
PhilippAlbrecht
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
KlemensAngstwurmMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
AntoniosBayas MD
University HospitalAugsburg Germany
Co-investigator
OrganizationalSupport
JudithBellmann-Strobl MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
Felix BischofMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
StefanBittner MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
TobiasBottcher MD
Johanna-Odebrecht-Stiftung GreifswaldGermany
Co-investigator
OrganizationalSupport
ButtmannMathias MD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
AnkelienDuchow
UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
BarbaraEttrich MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Jurgen FaissMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
Continued
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 11
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/12.jpg)
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
BenediktFrank MD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
Anna GahlenMD
Ruhr-UniversityBochum Germany
Co-investigator
OrganizationalSupport
Achim GassMD
University HospitalMannheim Germany
Co-investigator
OrganizationalSupport
Christian Geis Department ofNeurology JenaUniversity HospitalGermany
Co-investigator
OrganizationalSupport
MatthiasGrothe MD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
KerstinGuthke MD
Klinikum GorlitzGermany
Co-investigator
OrganizationalSupport
AxelHaarmannMD
University ofWurzburg Germany
Co-investigator
OrganizationalSupport
Hans-PeterHartung MD
Heinrich HeineUniversityDusseldorf Germany
Co-investigator
OrganizationalSupport
BernhardHemmer MD
Technical UniversityMunich Germany
Co-investigator
OrganizationalSupport
FrankHoffmannMD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
OlafHoffmannMD
St Josefs-KrankenhausPotsdam Germany
Co-investigator
OrganizationalSupport
UlrichHofstadt-vanOy MD
Klinikum WestfalenDortmund Germany
Co-investigator
OrganizationalSupport
JuttaJunghans MD
KrankenhausMartha-Maria HalleGermany
Co-investigator
OrganizationalSupport
MatthiasKaste MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
BarbaraKaulen MD
University HospitalHamburg Germany
Co-investigator
OrganizationalSupport
Peter KernMD
Asklepios KlinikTeupitz Germany
Co-investigator
OrganizationalSupport
PawelKermer MD
Nordwest HospitalSanderbusch SandeGermany
Co-investigator
OrganizationalSupport
ChristophKleinschnitzMD
University HospitalEssen Germany
Co-investigator
OrganizationalSupport
WolfgangKohler MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
MarkusKowarik MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
MarkusKraemer
Alfried-Krupp-Krankenhaus EssenGermany
Co-investigator
OrganizationalSupport
MarkusKrumbholzMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Stefan LangelMD
LandeskrankenhausRheinhessenGermany
Co-investigator
OrganizationalSupport
MartinLiebetrauMD
St Josefs-HospitalWiesbaden Germany
Co-investigator
OrganizationalSupport
Ralf LinkerMD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
De-HyungLee MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Felix LuessiMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinMarziniakMD
Isar-Amper Klinik OstMunich Germany
Co-investigator
OrganizationalSupport
ChristophMayer MD
NeurologischenGemeinschaftspraxisim BienenkorbhausFrankfurt Germany
Co-investigator
OrganizationalSupport
StefanieMeister MD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
ArthurMelms MD
Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany
Co-investigator
OrganizationalSupport
Imke MetzMD
University HospitalGottingen Germany
Co-investigator
OrganizationalSupport
OliverNeuhaus MD
SRH KrankenhausSigmaringenGermany
Co-investigator
OrganizationalSupport
SabineNiehaus MD
Klinikum DortmundGermany
Co-investigator
OrganizationalSupport
FlorencePache MD
Charite UniversityMedicine BerlinGermany
Co-investigator
OrganizationalSupport
Hans-UlrichPuhlmannMD
Schlosspark-KlinikBerlin Germany
Co-investigator
OrganizationalSupport
Refik Pul MD University HospitalEssen Germany
Co-investigator
OrganizationalSupport
PaulusRommer MD
Medical University ofWien Austria
Co-investigator
OrganizationalSupport
12 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/13.jpg)
References1 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo Clin
Proc 201792(4)663ndash6792 Fujihara K Neuromyelitis optica spectrum disorders still evolving and broadening
Curr Opin Neurol 201932(3)385ndash3943 Paul F Jarius S Aktas O et al Antibody to aquaporin 4 in the diagnosis of neuro-
myelitis optica PLoS Med 20074(4)e1334 Hillebrand S Schanda K Nigritinou M et al Circulating AQP4-specific auto-
antibodies alone can induce neuromyelitis optica spectrum disorder in the rat ActaNeuropathol 2019137(3)467ndash485
5 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914
6 Kleiter I Gahlen A Borisow N et al Neuromyelitis optica evaluation of 871 attacksand 1153 treatment courses Ann Neurol 201679(2)206ndash216
7 Moore P Methley A Pollard C et al Cognitive and psychiatric comorbidities inneuromyelitis optica J Neurol Sci 20163604ndash9
8 Beekman J Keisler A Pedraza O et al Neuromyelitis optica spectrum disorderpatient experience and quality of life Neurol Neuroimmunol Neuroinflamm 20196(4)e580
9 Jarius S Wildemann B The history of neuromyelitis optica Part 2 lsquoSpinal amaurosisrsquoor how it all began J Neuroinflammation 201916(1)280
10 Kanamori Y Nakashima I Takai Y et al Pain in neuromyelitis optica and its effect onquality of life a cross-sectional study Neurology 201177(7)652ndash658
11 Qian P Lancia S Alvarez E et al Association of neuromyelitis optica with severe andintractable pain Arch Neurol 201269(11)1482ndash1487
12 Zhao S Mutch K Elsone L et al Neuropathic pain in neuromyelitis optica affectsactivities of daily living and quality of life Mult Scler 201420(12)1658ndash1661
13 Kong Y Okoruwa H Revis J et al Pain in patients with transverse myelitis and itsrelationship to aquaporin 4 antibody status J Neurol Sci 201636884ndash88
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
KevinRostasy MD
Vestische Caritas-Kliniken GmbHDatteln Germany
Co-investigator
OrganizationalSupport
LiobaRuckriemMD
MediClin Hedon-Klinik Lingen (Ems)Germany
Co-investigator
OrganizationalSupport
KlemensRuprecht MD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ChristophRuschil MD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
SvenSchipplingMD
University HospitalZurich Switzerland
Co-investigator
OrganizationalSupport
MatthiasSchwab MD
University HospitalJena Germany
Co-investigator
OrganizationalSupport
Jorn PeterSieb MD
HeliosHanseklinikumStralsund Germany
Co-investigator
OrganizationalSupport
Nadja SiebertMD
Charite-UniversitatsmedizinBerlin Germany
Co-investigator
OrganizationalSupport
ClaudiaSommer MD
University HospitalWurzburg Germany
Co-investigator
OrganizationalSupport
AnnetteSpreer MD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
MartinStangel MD
Hannover MedicalSchool HannoverGermany
Co-investigator
OrganizationalSupport
AndreaSteinbrecherMD
Helios KlinikumErfurt Germany
Co-investigator
OrganizationalSupport
HeikeStephanikMD
University HospitalMagdeburgGermany
Co-investigator
OrganizationalSupport
MurielStoppe MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
Marie SuszligeMD
University HospitalGreifswald Germany
Co-investigator
OrganizationalSupport
BjornTackenbergMD
University HospitalMarburg Germany
Co-investigator
OrganizationalSupport
Florian Then-Bergh MD
University HospitalLeipzig Germany
Co-investigator
OrganizationalSupport
JohannesTunnerhoffMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
HayrrettinTumani MD
University HospitalUlm Germany
Co-investigator
OrganizationalSupport
AnnetteWalter MD
Klinikum HerfordHerford Germany
Co-investigator
OrganizationalSupport
Appendix 2 (continued)
Members of the Neuromyelitis Optica Study Group (NEMOS) are listedbelow in alphabetical order
Name Location Role Contribution
Klaus-PeterWandingerMD
University MedicalCenter Schleswig-Holstein CampusLubeck Germany
Co-investigator
OrganizationalSupport
ClemensWarnke MD
University HospitalKoln Germany
Co-investigator
OrganizationalSupport
RobertWeissert MD
University HospitalRegensburgGermany
Co-investigator
OrganizationalSupport
Heinz WiendlMD
University HospitalMunster Germany
Co-investigator
OrganizationalSupport
ChristianWilke MD
NervenzentrumPotsdam Germany
Co-investigator
OrganizationalSupport
AlexanderWinkelmannMD
University HospitalRostock Germany
Co-investigator
OrganizationalSupport
YavorYalachkovMD
University HospitalFrankfurt Germany
Co-investigator
OrganizationalSupport
Lena ZeltnerMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Uwe Zettl University HospitalRostock Germany
Co-investigator
OrganizationalSupport
Ulf ZiemannMD
University HospitalTubingen Germany
Co-investigator
OrganizationalSupport
Frauke ZippMD
University MedicalCenter of theJohannes GutenbergUniversity MainzGermany
Co-investigator
OrganizationalSupport
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 13
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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 14: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/14.jpg)
14 Asseyer S Schmidt F Chien C et al Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders Mult Scler J Exp Transl Clin 20184(3)2055217318796684
15 Hyun JW Jang H Yu J et al Comparison of neuropathic pain in neuromyelitis opticaspectrum disorder and multiple sclerosis J Clin Neurol 202016(1)124ndash130
16 Bradl M Kanamori Y Nakashima I et al Pain in neuromyelitis opticamdashprevalencepathogenesis and therapy Nat Rev Neurol 201410(9)529ndash536
17 Kim SM Go MJ Sung JJ et al Painful tonic spasm in neuromyelitis opticaincidence diagnostic utility and clinical characteristics Arch Neurol 201269(8)1026ndash1031
18 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114ndash2124
19 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177ndash189
20 Freynhagen R Baron R Gockel U et al painDETECT a new screening questionnaireto identify neuropathic components in patients with back pain Curr Med Res Opin200622(10)1911ndash1920
21 Melzack R The short-form McGill pain questionnaire Pain 198730(2)191ndash19722 Fox J Weisberg A An R Companion to Applied Regression 3rd ed SAGE Publi-
cations Inc 2018
23 Tackley G Vecchio D Hamid S et al Chronic neuropathic pain severity is de-termined by lesion level in aquaporin 4-antibody-positive myelitis J Neurol Neuro-surg Psychiatry 201788(2)165ndash169
24 Muller R BrinkhofMW Arnet U et al Prevalence and associated factors of pain in theSwiss spinal cord injury population Spinal Cord 201755(4)346ndash354
25 Tuzun E Akman-Demir G Eraksoy M Paroxysmal attacks in multiple sclerosis MultScler 20017(6)402ndash404
26 Spissu A Cannas A Ferrigno P et al Anatomic correlates of painful tonic spasms inmultiple sclerosis Mov Disord 199914(2)331ndash335
27 Chavarro VS Mealy MA Simpson A et al Insufficient treatment of severe depressionin neuromyelitis optica spectrum disorder Neurol Neuroimmunol Neuroinflamm20163(6)e286
28 Walker AK Kavelaars A Heijnen CJ et al Neuroinflammation and comorbidity ofpain and depression Pharmacol Rev 201466(1)80ndash101
29 Skucas VA Mathews IB Yang J et al Impairment of select forms of spatial memoryand neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4J Neurosci 201131(17)6392ndash6397
30 Mealy MA Kozachik SL Cook LJ et al Scrambler therapy improves pain inneuromyelitis optica a randomized controlled trial Neurology 202094(18)e1900ndashe07
14 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 3 | May 2021 NeurologyorgNN
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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 15: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/15.jpg)
DOI 101212NXI000000000000098520218 Neurol Neuroimmunol Neuroinflamm
Ilya Ayzenberg Daniel Richter Eugenia Henke et al Seropositive PatientsminusCross-Sectional Study of 166 AQP4 Antibody
Pain Depression and Quality of Life in Neuromyelitis Optica Spectrum Disorder A
This information is current as of April 20 2021
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 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
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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 16: Pain, Depression, and Quality of Life in Neuromyelitis Optica ...ARTICLE OPEN ACCESS Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder A Cross-Sectional](https://reader035.vdocument.in/reader035/viewer/2022071514/6135b6a20ad5d20676478d54/html5/thumbnails/16.jpg)
ServicesUpdated Information amp
httpnnneurologyorgcontent83e985fullhtmlincluding high resolution figures can be found at
References httpnnneurologyorgcontent83e985fullhtmlref-list-1
This article cites 29 articles 4 of which you can access for free at
Subspecialty Collections
httpnnneurologyorgcgicollectionneuropathic_painNeuropathic pain
httpnnneurologyorgcgicollectiondevics_syndromeDevics syndrome
httpnnneurologyorgcgicollectioncentral_painCentral pain
httpnnneurologyorgcgicollectionall_painAll Pain
httpnnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing 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 2021 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