ARTICLE OPEN ACCESS CLASS OF EVIDENCE Intravenous ...

ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Intravenous Immunoglobulin Therapy inPatients With Painful Idiopathic Small FiberNeuropathyMargot Geerts MSc Bianca TA de Greef MD PhD Maurice Sopacua MD Sander MJ van Kuijk PhD

Janneke GJ Hoeijmakers MD PhD Catharina G Faber MD PhD and Ingemar SJ Merkies MD PhD

Neurologyreg 202196e2534-e2545 doi101212WNL0000000000011919

Correspondence

Dr Faber

cfabermumcnl

AbstractObjectiveThis is the first double-blind randomized controlled trial evaluating the efficacy and safety of IVimmunoglobulin (IVIG) vs placebo in patients with idiopathic small fiber neuropathy (I-SFN)

MethodsBetween July 2016 and November 2018 60 Dutch patients with skin biopsyndashproven I-SFNrandomly received a starting dose of IVIG (2 gkg body weight) or matching placebo (09saline) Subsequently 3 additional infusions of IVIG (1 gkg) or placebo were administered at3-week intervals The primary outcome was a 1-point change in Pain Intensity NumericalRating Scale score at 12 weeks compared to baseline

ResultsThirty patients received IVIG and 30 received placebo In both groups 29 patients completedthe trial In 40 of patients receiving IVIG the mean average pain was decreased by at least 1point compared to 30 of the patients receiving placebo (p = 0588 odds ratio 156 95confidence interval 053ndash453) No significant differences were found on any of the otherprespecified outcomes including general well-being autonomic symptoms and overall func-tioning and disability

ConclusionsThis randomized controlled trial showed that IVIG treatment had no significant effect on painin patients with painful I-SFN

Trial Registration InformationClinicalTrialsgov Identifier NCT02637700 EudraCT 2015-002624-31

Classification of EvidenceThis study provides Class I evidence that for patients with painful I-SFN IVIG did notsignificantly reduce pain compared to placebo

RELATED ARTICLE

EditorialIVIG and Small FiberNeuropathy The OngoingSearch for Evidence

Page 929

MORE ONLINE

Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

NPuborgcoe

These authors contributed equally to this work

From the Department of Neurology (MG BTAdG MS JGJH CGF ISJM) School of Mental Health and Neuroscience and Department of Clinical Epidemiology and MedicalTechnology Assessment (SMJvK) Maastricht University Medical Center+ Department of Rehabilitation AdelanteMaastricht University Medical Center+ (MS) the Netherlandsand Department of Neurology (ISJM) Curaccedilao Medical Center Willemstad Curaccedilao

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge will be funded by Maastricht University

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

e2534 Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

Patients with small fiber neuropathy (SFN) commonlycomplain of length-dependent neuropathic pain symptomsdue to dysfunction and degeneration of thinly myelinated Aδand unmyelinated C fibers12 Pain symptoms occur sponta-neously (eg burning deep paroxysmal pain) and can beelicited by innocuous stimuli (eg light touch or pressurewarm and cold water) Different underlying systemicillnesses3-11 and genetic diseases12-16 are associated with SFNHowever in 53 an underlying etiology remains unknown(idiopathic SFN [I-SFN]) Immunologic mechanisms havebeen speculated to contribute to patients with I-SFN becauseseveral immune-mediated disorders such as sarcoidosisSjogren disease and systemic lupus erythematosus haveshown some association with SFN3717-19 In addition auto-antibodies have been seen in patients with SFN20-23 in-flammatory modifications in nerves have been noticed2425

raised proinflammatory cytokines potentially influence thepathophysiology of pain in SFN26 and peripheral and centralglial-mediated neuroimmune activation has been reported inmaintaining chronic pain27

IV immunoglobulin (IVIG) is a successful commonly usedtreatment for chronic immune-mediated polyneuropathiessuch as chronic inflammatory demyelinating polyneuropathyand multifocal motor neuropathy28-30 Several open-label caseseries have reported IVIG to be efficacious in immune-mediated SFN31-37 and a recent retrospective study suggestedIVIG as an effective treatment option for patients with SFNwith autoimmune diseases or nonspecific blood test markersfor autoimmunity38 As a consequence patients are frequentlytreated with this highly expensive drug39 despite the lack ofproven effectiveness for IVIG in I-SFN through controlledtrials We present the results of a double-blind randomizedcontrolled trial evaluating the efficacy and safety of IVIG vsplacebo in patients with I-SFN

MethodsThe IVIG in I-SFN study was a randomized placebo-controlled double-blind study A complete report of the studydesign has been published earlier40 and the outline is givenbelow

Standard Protocol Approvals Registrationsand Patient ConsentsThe study was performed in accordance with the guidelines ofthe Declaration of Helsinki and International Conference onHarmonization Good Clinical Practice Guidelines The study

protocol was approved by the local Medical Ethics CommitteeAll patients in this trial gave written informed consent This trialis registered with ClinicalTrialsgov (NCT02637700) andEudraCT (2015-002624-31)

Study Design and ParticipantsAll consecutive patients not from a prevalent pool were in-cluded and treated at the SFN Center at the MaastrichtUniversity Medical Center+ the Netherlands between July2016 and March 2019 after giving written informed consentPatients with I-SFN were eligible after meeting the in-ternational diagnostic criteria of SFN (ie typical SFN-relatedsymptoms described mainly as a burning sensation shootingpains prickling or itching predominantly in a length-dependent pattern with a minimum pain intensity score ofge5 on the Pain Intensity Numeric Rating Scale [PI-NRS]combined with a reduced distal intraepidermal nerve fiberdensity in skin biopsy excluding large fiber involvement) andwithout an underlying etiology (such as diabetes mellitusSCN9ASCN10ASCN11A mutations hypothyroidism vi-tamin B12 deficiency Fabry disease Sjogren syndrome sar-coidosis and celiac disease)121541 which was routinely testedin all patients before study entry Exclusion criteria includedprominent nonndashlength-dependent pattern predominant clini-cal picture of large nerve fiber involvement (ie weakness lossof vibration sense hypoflexiaareflexia abnormal nerve con-duction studies of tibial peroneal and sural nerves includingdistal latency amplitude and conduction velocity using surfaceelectrodes with standard placement) receiving IVIG treatmentor any other immunomodulatoryimmunosuppressive agents(eg steroids) within the 12 weeks before screening and car-diac insufficiency (New York Heart Association class IIIIV)cardiomyopathy or significant cardiac dysrhythmia The use ofpain medication was allowed and registered if this remainedstable in the 30 days before randomization A change in dosageof (analgesicantineuropathic) pain medication was notallowed throughout the study Permissible medications wereacetaminophen and nonsteroidal anti-inflammatory drugs suchas ibuprofen which were allowed during the trial as premed-ications for study drug infusions A complete report of theinclusion and exclusion criteria was published previously40

Randomization and MaskingPatients were randomly allocated in 2 groups (IVIG or pla-cebo) using the ALEA randomization software provided byFormsVision BV (Abcoude the Netherlands) with the min-imization technique Patients were stratified according to ageand sex All participants care providers and study personnelincluding those assessing outcomes except for those in the

GlossaryDSIS = daily sleep interference scale I-SFN = idiopathic SFN ITT = intention-to-treat NPS = Neuropathic Pain ScalePGIC = patientsrsquo global impression of change PI-NRS = Pain Intensity Numeric Rating Scale PP = per-protocol RT-SFN-SIQ = Rasch-transformed 13-item SFN Symptoms Inventory Questionnaire SAE = serious adverse event SF-36 = Short Form36 Health Survey SFN = small fiber neuropathy SFN-RODS = Rasch-transformed SFN Overall Disability Scale

NeurologyorgN Neurology | Volume 96 Number 20 | May 18 2021 e2535

pharmacy were blinded for treatment assignment IVIG andmatching placebo were provided in ethylene vinyl acetateinfusion bags with masking covers for IV administration Foroptimal masking orange infusion lines (B Braun Cyto-SetInfusomat Space PZN10759513) were used The blindingcodes were intact during the complete study

Study Medication and ProceduresThe study medication was Gamunex (Grifols USA LLC LosAngeles CA) 10 100 mgmL solution for infusion of hu-man normal immunoglobulin Placebo was supplied as 09saline Figure 1 presents the study algorithm40 The studystarted with a screening period (maximum 10 days) Eligibleindividuals subsequently entered the study treatment period(duration 12 weeks) and were randomized to conceive eitherIVIG with an uploading dose of 2 gkg body weight or pla-cebo over 2 serial days with a maximum dose of 80 g IVIG perinfusion day In addition 3 infusions with a dose of 1 gkgbody weight were dispensed with a 3-week interval Thisregimen was chosen as previously applied in patients withchronic inflammatory demyelinating polyneuropathy forevaluating the IVIG efficacy28 A final visit took place for allpatients 3 weeks after the last infusion or after withdrawal forany reason during this period After treatment completionthere was a 3-month-extension follow-up phase evaluating thepossible long-term effect of IVIG on pain if any

Trial OutcomesThe primary research question of this study was as followsdoes IVIG significantly reduces pain compared to placebo forpatients with painful I-SFN (Class I evidence)

The primary efficacy outcome was the proportion of pa-tients after the treatment period having at least a 1-pointimprovement on the 11-point PI-NRS (0 = no pain 10 =worst imaginable pain) of their average pain compared tobaseline which is considered the minimum clinically im-portant difference according to unified rule of 05 SD andthe guidelines4243 Patients also completed a daily sleepinterference scale (DSIS) (11-point numerical scale 0 =pain does not interfere with sleep 10 = pain completelyinterferes with sleep)44 Participants completed the PI-NRSand the DSIS 2 times per week in the morning and eveningat scheduled time points Additional questionnaires (pa-tientsrsquo global impression of change [PGIC]4243 the Rasch-transformed 13-item SFN Symptoms Inventory Question-naire [RT-SFN-SIQ]45 the Neuropathic Pain Scale[NPS]46 the Short Form 36 Health Survey [SF-36] and theRasch-transformed SFN Overall Disability Scale [SFN-RODS]45 and the amount of pain relief [on a 5-point Likertscale])47 were completed at each visit during the treatmentperiod during the telephone calls and at the final follow-upvisit In addition all pharmacologic pain treatments andpain-relieving activities were recorded Safety evaluationcharacteristics included adverse events laboratory tests andvital signs

Secondary efficacy outcomes were the proportion of pa-tients having ge2-point average pain improvement com-pared to their baseline PI-NRS scores and changes in themean maximum and average scores on the PI-NRS NPSDSIS PGIC Pain Relief RT-SFN-SIQ SFN-RODS andSF-36

Figure 1 Schematic Diagram Representing Overall Study Design and Study Visits

Red triangles represent the treatment visits The first uploading treatment period was spread out over 2 consecutive days The other treatment visitsconsisted of 1 day IVIg = IV immunoglobulin

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Statistical AnalysesThe sample size of 24 participants per group was determinedwith an assumed response rate of 25 in the placebo group and60 in the IVIG group a 1-sided α of 5 and 80 powerbetween the 2 groups (χ2 test) including the assumption of adropout rate of 20 (6 patients) Therefore the aim was toinclude in total 60 patients in the study An independent stat-istician (SMJvK) analyzed the results according to theintention-to-treat (ITT) protocol40 For the primary ITTanalysis for success missing values were included as no successParticipants were analyzed for efficacy according to random-ized treatment For all questionnaires the difference betweenbaseline (screening period) and the end of the treatment period(outcomes of the 12th week) was calculated To determine thebaseline scores all available data before randomization weretaken No data imputation was performed for missing obser-vations For the primary outcome the proportion of patientswith a decrease of at least 1 point was compared between theIVIG and placebo groups with a χ2 test In addition the pro-portion of ge2-point decrease was compared When the PI-NRSscore after 12 weeks was missing (because of dropout ormissing diaries) patients were labeled as nonresponders

The differences in DSIS NPS and SF-36 scores betweenbaseline and 12 weeks of treatment were compared betweenthe 2 groups For these continuous outcome measures the ttest was used For the PGIC the proportion of patients whowere (very) much improved was compared to the proportionof patients with little or no improvement For the RT-SFN-SIQ and SFN-RODS the proportions of patients with

significant deterioration significant improvement and nosignificant change were calculated and compared between theIVIG and placebo groups according to the distribution-basedminimum clinically important differencendashstandard errormethod with a meaningful change with a score ge196 stan-dard error48 For pain relief the proportion of patients withnoslight relief was compared with the proportion of patientswith moderategoodcomplete relief The χ2 test or Fisherexact test when needed was used to calculate the differencesbetween the 2 treatment groups

All the above-mentioned tests were repeated in the per-protocol (PP) analysis Patients were included in the PPanalysis if they had an available PI-NRS score at baseline and a12-week postbaseline mean weekly pain PI-NRS score

During the trial the protocol was amended once to add afollow-up period to remove the PGIC and Pain Relief ques-tionnaires from the screening visit to adjust the visit windowto add questions to patientsrsquo pain diary and to adjust theinfusion rates according to the protocol of the hospital

Data AvailabilityAnonymized data not published in the article will be shared byrequest

ResultsPatientsAfter a thorough investigation 64 patients met the inclusionand exclusion criteria as shown in figure 2 These patientswere screened and gave informed consent for participating inthe IVIG-SFN study Four patients (63) were excluded dueto anemia abnormal EMG vitamin B12 deficiency and glu-cose intolerance (all n = 1)

Sixty patients were randomized 30 patients (50) to IVIGand 30 to the placebo arm Two patients (333) withdrewtheir participation due to side effects (nausea anxiety fatigueheadache and diarrhea) after the first uploading study med-ication dose at entry visit (1 patient was randomized to theIVIG arm the other to placebo) Ultimately 29 patients whoreceived IVIG and 29 patients who received placebo com-pleted the study

All 60 patients were randomly assigned to received IVIG orplacebo and 294 of the 300 scheduled volumes (gt95) wereactually dispensed Patients endured a maximum volume of240mLh of the uploading dose and amaximal volume of 560mLh for the additional infusions Infusion time for theuploading dose was asymp5 hours and for the additional infusions3 hours

Baseline CharacteristicsBaseline characteristics are shown in table 1 Patients in the 2groups were similar in demographic clinical and disease-

Figure 2 Flowchart of the Trial

IVIg = IV immunoglobulin

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related characteristics at baseline The baseline scores of thequestionnaires are provided in table 2 For the ITT analysesall 60 patients were used and for the PP analysis 10 patientswere excluded (50 used 24 in the IVIG group and 26 in theplacebo group)

Primary OutcomeThe primary outcome of the mean average pain scores basedon the PI-NRS before and after treatment are shown in table3 40 of patients receiving IVIG and 30 of patients re-ceiving placebo had at least a 1-point improvement in theaverage pain (p = 0588 odds ratio 156 95 confidenceinterval 053ndash453) The PP analysis and the 2-point decreaseon the PI-NRS (ITT and PP analysis) also showed no sig-nificant differences

Secondary OutcomesOnly a few of the secondary outcomes showed significantdifferences after 24 weeks (PI-NRS maximum night painafter 24 weeks p = 0029 DSIS p = 0010 NPS intense pain p= 0118 NPS hot pain p = 0031) SF-36 health changeshowed a significant difference after 12 weeks (p = 0007)however most secondary outcomes showed no significantdifference between the effect of IVIG and the effect of pla-cebo (table 3)

Table 1 Baseline Characteristics of the Patients

IVIG(n = 30)

Placebo(n = 30)

Age (at inclusion) mean (SD) y 487 (111) 507 (97)

Male n () 10 (333) 12 (400)

BMI mean (SD) kgm2 291 (50) 277 (51)

Duration of complaints SFN median(range) y

78(13ndash585)

74(17ndash349)

White n () 28 (933) 29 (967)

Presence of comorbidity n ()

Hypertension 6 (200) 4 (133)

Hypercholesterolemia 7 (233) 5 (167)

Cardiac history 1 (33) 1 (33)

Age at skin biopsydiagnosis mean (SD) y 457 (98) 483 (107)

IENFD mean (SD)a 32 (17) 31 (15)

TTT abnormal n () 20 (667) 25 (833)

Diagnosis based on n ()

Abnormal skin biopsy 10 (333) 5 (167)

Abnormal skin biopsy and TTT deviation 20 (667 25 (833)

Presence of typical SFN symptoms n ()

Burning feet 27 (900) 26 (867)

Allodynia 22 (733) 20 (667)

Diminished pain or temperaturesensation

21 (700) 21 (700)

Dry eyes or mouth 26 (867) 26 (867)

Orthostatic dizziness 21 (700) 12 (400)

Bowel disturbances 19 (633) 22 (733)

Urinary disturbances 18 (600) 18 (600)

Sweat changes 20 (667) 24 (800)

Visual accommodation problems orblurred vision

19 (633) 17 (567)

Hot flashespalpitations 21 (700) 16 (533)

Impotence diminished ejaculation orlubrication

11 (367) 13 (433)

Total typical SFN symptoms median(range) n

8 (2ndash11) 7 (3ndash11)

IgG before treatment mean (SD) 131 (96) 95 (22)

Use of (neuropathic) painmedication n ()

Analgesics

Acetaminophen 13 (433) 8 (267)

NSAID

Ibuprofen 5 (167) 3 (100)

Diclofenac 2 (67) 2 (67)

Table 1 Baseline Characteristics of the Patients (continued)

IVIG(n = 30)

Placebo(n = 30)

TCA

Amitriptyline 1 (33) 3 (100)

Nortriptyline 1 (33) 1 (33)

SNRI

Duloxetine 5 (167) 5 (167)

Anticonvulsant

Gabapentin 5 (167) 1 (33)

Pregabalin 3 (100) 3 (100)

Carbamazepin 1 (33) 1 (33)

Opioids

Oxycodone 4 (133) 1 (33)

Tramadol 2 (67) 1 (33)

Local anesthetics

Capsaicin creme 0 (00) 1 (33)

Abbreviations BMI = body mass index IENFD = intraepidermal nerve fiberdensity IgG = immunoglobulin G IVIG = IV immunoglobulins NSAID =nonsteroidal anti-inflammatory drugs SFN = small fiber neuropathy SNRI =selective serotonin and noradrenalin reuptake inhibitor TCA = tricyclic an-tidepressants TTT = temperature threshold testinga Collected at the distal side of the right leg 10 cm above the lateral mal-leolus all patients had an abnormal IENFD (value below the fifth percentileof normal)

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After 12 weeks 7 (241) patients in the IVIG group and 4(138) in the placebo group were much or very much im-proved according to the PGIC (p = 0505) and after 24weeks 4 (138) patients in the IVIG group vs 3 (111) inthe placebo group (p = 1000) were much or very much

improved The PP analysis showed similar results In additionno differences were found in autonomic symptoms overalldisability and pain relief the RT-SFN-SIQ SFN-RODS andPain Relief questionnaires respectively showed no significantdifferences between the 2 groups

Table 2 Baseline Scores of Patients

IVIG (n = 30) Placebo (n = 30) Total (n = 60)

PI-NRS score median (range)

Mean day pain 56 (30ndash83) 66 (23ndash95) 60 (23ndash95)

Mean night pain 58 (10ndash85) 54 (00ndash95) 57 (00ndash95)

Mean average pain 55 (20ndash83) 58 (17ndash95) 58 (17ndash95)

Maximum day pain 70 (37ndash100) 78 (33ndash100) 72 (33ndash100)

Maximum night pain 72 (15ndash95) 64 (00ndash100) 70 (00ndash100)

Maximum average pain 70 (30ndash98) 70 (22ndash100) 70 (22ndash100)

DSIS score median (range) 55 (10ndash87) 58 (00ndash90) 55 (00ndash90)

SFN-SIQ score median (range) 175 (60ndash350) 170 (60ndash350) 170 (60ndash350)

SFN-RODS score median (range) 450 (270ndash640) 505 (310ndash640) 490 (270ndash640)

NPS score median (range)

Intense 70 (40ndash100) 70 (20ndash100) 70 (20ndash100)

Sharp 80 (00ndash100) 70 (00ndash100) 75 (00ndash100)

Hot 75 (00ndash100) 70 (00ndash90) 70 (00ndash100)

Dull 50 (00ndash100) 45 (00ndash90) 50 (00ndash100)

Cold 50 (00ndash90) 50 (00ndash100) 50 (00ndash100)

Sensitive 55 (00ndash100) 60 (00ndash100) 60 (00ndash100)

Itchy 15 (00ndash100) 50 (00ndash90) 40 (00ndash100)

Unpleasant 75 (40ndash100) 70 (30ndash100) 70 (30ndash100)

Intense deep 80 (10ndash100) 80 (00ndash100) 80 (00ndash100)

Intense surface 60 (20ndash90) 60 (20ndash100) 60 (20ndash100)

SF-36 score median (range)

Physical Functioning 500 (00ndash1000) 500 (150ndash950) 500 (00ndash1000)

Social Functioning 500 (00ndash1000) 500 (00ndash1000) 500 (00ndash1000)

RolendashPhysical 281 (00ndash875) 281 (00ndash813) 281 (00ndash875)

RolendashEmotional 833 (00ndash1000) 750 (83ndash1000) 792 (00ndash1000)

Mental Health 750 (250ndash1000) 700 (250ndash1000) 750 (250ndash1000)

Vitality 375 (00ndash938) 375 (63ndash813) 375 (00ndash938)

Bodily Pain 327 (00ndash796) 357 (102ndash694) 337 (00ndash796)

General Health 350 (50ndash750) 275 (00ndash900) 325 (00ndash900)

Health change 250 (00ndash750) 250 (00ndash1000) 250 (00ndash1000)

Abbreviations DSIS = daily sleep interference scale IVIG = IV immunoglobulin NPS = Neuropathic Pain Scale PI-NRS = Pain Intensity Numerical Rating ScaleSF-36 = generic Short-Form 36 Health Survey SFN-RODS = Rasch-transformed Small Fiber Neuropathy Overall Disability Scale SFN-SIQ = Small FiberNeuropathy Symptoms Inventory Questionnaire

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Table 3 Primary and Secondary Outcomes

Primary outcome

ITT PP

Proportion of responders IVIG vs placebo(baseline vs 3 mo)

pValue

Proportion of responders IVIG vs placebo(baseline vs 3 mo)

pValue

ge1-Point decrease inaverage pain n ()

12 (40) vs 9 (30) OR 156 (95 CI 054ndash463) 0588 12 (50) vs 9 (346) OR 189 (95 CI 061ndash604) 0415

ge2-Point decrease inaverage pain n ()

7 (2335) vs 5 (167) OR 152 (95 CI 043ndash578) 0747 7 (292) vs 5 (192) OR 173 (95 CI 047ndash679) 0624

Secondary outcomes

ITT PP

Differencebaseline vs 3 moIVIG vs placebo

pValue

Differencebaseline vs 6 moIVIG vs placebo

pValue

Differencebaseline vs 3 moIVIG vs placebo

pValue

Differencebaseline vs 6 moIVIG vs placebo

pValue

Continuous outcomes

PI-NRS score mean(SEM)

Mean day pain minus082 (041) vsminus084 (038)

0973 minus072 (026) vsminus046 (026)

0474 minus082 (041) vsminus084 (038)

0973 minus082 (027) vsminus051 (028)

0431

Mean night pain minus123 (054) vsminus028 (045)

0185 minus108 (045) vs007 (033)

0046 minus123 (054) vsminus028 (045)

0185 minus116 (049) vsminus005 (037)

0075

Mean average pain minus089 (038) vsminus051 (036)

0472 minus090 (028) vsminus019 (025)

0067 minus089 (038) vsminus051 (036)

0472 minus099 (030) vsminus028 (028)

0086

DSIS scoremean (SEM) minus157 (051) vsminus018 (044)

0045 minus117 (038) vsminus043 (027)

0010 minus157 (051) vsminus018 (044)

0045 minus164 (053) vs051 (053)

0006

NPS score mean (SEM)

Intense minus19 (047) vs minus07(029)

0033 minus172 (038) vsminus043 (027)

0118 minus233 (050) vsminus077 (030)

0011 minus046 (041) vsminus056 (026)

0073

Sharp minus14 (062) vs minus06(043)

0260 minus031 (057) vsminus046 (037)

0821 minus192 (071) vsminus046 (044)

0089 minus075 (063) vsminus056 (038)

0797

Hot minus16 (055) vs 02(044)

0017 minus138 (051) vs018 (048)

0031 minus175 (063) vs015 (048)

0021 minus129 (058) vs020 (052)

0062

Dull minus18 (070) vs minus08(062)

0273 minus107 (084) vs014 (057)

0237 minus150 (080) vsminus096 (067)

0608 minus063 (095) vs016 (059)

0488

Cold minus14 (062) vs minus07(053)

0354 minus186 (066) vsminus018 (064)

0072 minus158 (057) vsminus046 (050)

0146 minus183 (061) vsminus028 (063)

0085

Sensitive minus19 (053) vs minus09(038)

0108 minus028 (053) vsminus064 (047)

0608 minus196 (063) vsminus073 (039)

0107 minus029 (064) vsminus060 (051)

0708

Itchy minus06 (039) vs minus10(061)

0604 minus048 (051) vsminus061 (055)

0868 minus075 (042) vsminus115 (057)

0573 minus046 (051) vsminus076 (050)

0674

Unpleasant minus17 (048) vs minus06(031)

0052 minus093 (042) vsminus046 (034)

0392 minus208 (051) vsminus062 (034)

0022 minus125 (039) vsminus044 (037)

0142

Intense deep minus15 (048) vs minus16(057)

0889 minus076 (038) vsminus039 (050)

0565 minus175 (055) vsminus127 (058)

0548 minus088 (044) vsminus016 (053)

0307

Intense surface minus09 (052) vs minus03(044)

0365 minus086 (049) vs025 (044)

0097 minus142 (054) vsminus069 (042)

0295 minus122 (052) vsminus012 (041)

0106

SF-36 score mean(SEM)

Physical Functioning 84 (355) vs 12(223)

0090 45 (461) vs 29(307)

0773 123 (381) vs (211(227)

0027 1022 (428) vs460 (313)

0296

Social Functioning 56 (441) vs 69(360)

0821 45 (558) vs 13(413)

0655 890 (476) vs 625(381)

0553 924 (584) vs 150(464)

0305

RolendashPhysical 136 (409) vs 06(383)

0025 65 (445) vs (33(422)

0612 1328 (478) vs216 (407)

0083 870 (530) vs 425(459)

0529

Continued

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SafetyThirty patients in the IVIG group (100) had at least 1adverse event (table 4) compared to 29 in the placebogroup (967) In total 6 serious adverse events (SAEs)were reported including aorta coarctation repair gastro-intestinal hemorrhage headache hospitalization (multiple

complaints) pulmonary embolism and suicide attemptOnly 1 SAE (aorta coarctation repair) occurred in theplacebo group the others occurred in the IVIG group Thegastrointestinal hemorrhage was diagnosed before ran-domization Only 1 SAE in the IVIG group hospitalization(multiple complaints) could have been caused by the use of

Table 3 Primary and Secondary Outcomes (continued)

Secondary outcomes

ITT PP

Differencebaseline vs 3 moIVIG vs placebo

pValue

Differencebaseline vs 6 moIVIG vs placebo

pValue

Differencebaseline vs 3 moIVIG vs placebo

pValue

Differencebaseline vs 6 moIVIG vs placebo

pValue

RolendashEmotional 14 (496) vs minus32(393)

0471 minus68 (522) vs minus24(507)

0542 417 (340) vsminus481 (424)

0106 minus435 (425) vsminus300 (563)

0849

Mental Health 29 (239) vs 12(219)

0596 minus13 (307) vs 20(254)

0423 333 (257) vs 115(236)

0535 minus196 (357) vs220 (265)

0355

Vitality 75 (396) vs minus04(181)

0075 47 (347) vs 00(190)

0243 859 (359) vsminus024 (189)

0036 707 (378) vs 025(199)

0120

Bodily pain 120 (395) vs 59(303)

0229 77 (419) vs 27(332)

0358 1531 (424) vs573 (337)

0084 1136 (446) vs302 (365)

0156

General health 90 (295) vs 57(259)

0408 38 (232) vs 34(260)

0919 1021 (341) vs558 (281)

0300 543 (263) vs 300(289)

0536

Health change 345 (673) vs 112(490)

0007 205 (576) vs 89(431)

0113 3438 (687) vs1250 (542)

0016 2174 (635) vs1100 (458)

0178

Discrete outcomes

PGIC n () 0505 1000 0490 1000

Verymuch improved 7 (241) vs 4 (14) 4 (14) vs 3 (11) 6 (25) vs 4 (15) 4 (17) vs 3 (13)

Little or notimproved

22 (759) vs 25 (86) 25 (86) vs 26 (89) 18 (75) vs 22 (85) 20 (83) vs 23 (87)

RT-SFN-SIQ n () 0194 03574 0340 0355

Significantdeterioration (1)

0 (0) vs 0 (0) 0 (0) vs 2 (7) 0 (0) vs 0 (0) 0 (0) vs 2 (8)

No significantchange (0)

24 (83) vs 28 (97) 26 (90) vs 25 (89) 21 (88) vs 25 (96) 21 (88) vs 22 (88)

Significantimprovement (21)

5 (17) vs 1 (3) 3 (10) vs 1 (4) 3 (13) vs 1 (4) 3 (13) vs 1 (4)

SFN-RODS n () 0378 0378 0122 0375

Significantdeterioration (21)

2 (7) vs 4 (14) 6 (21) vs 5 (19) 0 (0) vs 3 (12) 3 (13) vs 4(17)

No significantchange (0)

23 (79) vs 24 (83) 17 (59) vs 19 (73) 20 (83) vs 22 (85) 15 (63) vs 18 (75)

Significantimprovement (1)

4 (14) vs 1 (3) 6 (21) vs 2 (8) 4 (17) vs 1 (4) 6 (25) vs 2 (8)

Pain-relief n () 0214 0254 0348 0245

Noslight relief 19 (79) vs 17 (94) 23 (79) vs 25 (93) 16 (80) vs 16 (94) 18 (75) vs 22 (92)

ModerateGoodcomplete relief

5 (21) vs 1 (6) 6 (21) vs 2 (7) 4 (20) vs 1 (6) 6 (25) vs 2 (8)

Abbreviations CI = confidence interval DSIS = daily sleep interference scale IVIG = IV immunoglobulin ITT = intention-to-treat NPS =Neuropathic Pain ScaleOR = odds ratio PGIC = patientsrsquo global impression of change PI-NRS = Pain Intensity Numerical Rating Scale PP = per-protocol RT-SFN-SIQ = Rasch-transformed 13-item Small Fiber Neuropathy Symptoms Inventory Questionnaire SF-36 = generic Short-Form 36 Health Survey SFN-RODS = Rasch-transformed Small Fiber Neuropathy Overall Disability Scale SFN-SIQ = Small Fiber Neuropathy Symptom Inventory Questionnaire

NeurologyorgN Neurology | Volume 96 Number 20 | May 18 2021 e2541

IVIG because it occurred 2 weeks after the first loadingdose The other 3 SAEs seemed not to have been caused bythe use of IVIG because they occurred in the follow-upphase (2ndash4 weeks after the last infusion)

The adverse events that occurred in at least 5 of the pa-tients are shown in table 4 All patients in the IVIG group(100) had headache compared to 567 in the placebogroup Nausea (633 vs 233) vomiting (367 vs 00)and rash (267 vs 00) occurred significantly more fre-quently in the IVIG group compared to the placebo grouprespectively

Because patients were allowed to use their own medicationsduring the study (see table 1 for neuropathic pain medicationuse at baseline) the differences between patients with andwithout the use of neuropathic pain medication were in-vestigated regarding the primary outcome (table 5) No sig-nificant differences between the groups were found

DiscussionThis is the first randomized placebo-controlled study thatinvestigated the efficacy of IVIG in patients with painful

Table 4 Adverse Events

IVIG (n = 30) n () Placebo (n = 30) n () p Value

Patients with at least 1 adverse event 30 (100) 29 (967) 1000

All SAEs

Aorta coarctation repair 0 (00) 1 (33) 1000

Gastrointestinal hemorrhage 1 (33) 0 (00) 1000

Headache 1 (33) 0 (00) 1000

Hospitalization 1 (33) 0 (00) 1000

Pulmonary embolism 1 (33) 0 (00) 1000

Suicide attempt 1 (33) 0 (00) 1000

Most common adverse eventsa

Headache 30 (100) 17 (567) lt0001

Nausea 19 (633) 7 (233) 0004

Other pain 18 (600) 14 (467) 0438

Vomiting 11 (367) 0 (00) 0001

Chills 9 (300) 3 (100) 0104

Dizziness 8 (267) 9 (300) 1000

Rash 8 (267) 0 (00) 0005

Fatigue 7 (233) 11 (367) 0399

Influenza 7 (233) 2 (67) 0146

Arthralgia 4 (133) 6 (200) 0731

Hyperhidrosis 4 (133) 3 (100) 1000

Pyrexia 4 (133) 4 (133) 1000

Diarrhea 3 (100) 0 (00) 0237

Myalgia 2 (67) 2 (67) 1000

Nasopharyngitis 1 (33) 2 (67) 1000

Vision blurred 1 (33) 3 (100) 0612

Cough 1 (33) 2 (67) 1000

Migraine 0 (00) 2 (67) 0492

Abbreviations IVIG = IV immunoglobulin SAE = serious adverse eventsa Only the adverse events that occurred in at least 5 of the patients are given

e2542 Neurology | Volume 96 Number 20 | May 18 2021 NeurologyorgN

I-SFN The results of this study showed no significant effect ofIVIG compared to placebo in patients with painful I-SFN Nosignificant differences were found in 1-point and 2-point re-sponders on pain PGIC overall disability autonomic symp-toms and pain relief Statistically significant differences werefound inmaximum night pain daily sleep interference intenseand hot pain and some domains of the quality of life howeverthey were not in a consistent pattern and were not consideredto be of meaningful clinical relevance in the treatment goal ofthis highly expensive drug Six SAEs occurred 5 of them in theIVIG group and all patients in the IVIG group experienced atleast 1 adverse event of which headache nausea vomitingand rash occurred significantly more frequently compared tothe placebo group All of these are adverse events of IVIG thatare known to occur at rates gt1028 It can therefore beconcluded that IVIG has no place in the standard treatment ofpainful I-SFN

The results of this study are in contrast to open-label caseseries which included many patients with an immune-mediated underlying condition31-3335-37 and a retrospectivestudy suggesting the efficacy of IVIG in SFN313238 Howeveraccording to those reports patients with SFN without orwithout a clear autoimmune condition are increasingly beingtreated with IVIG39 It is important to point out that certainpatients with immune-confirmed SFN etiologies may benefitfrom IVIG treatment and it is crucial for effective neuropathicpain treatment to perform detailed upfront testing on auto-immune diseases in patients with SFN15 Nevertheless futuretrials in these setting are necessary to determine the value ofIVIG treatment in this specific cohort

Our study has some limitations First the investigated cohortwas relatively small and limited to patients with painful I-SFNThis outlined cohort was chosen because we aimed to dem-onstrate a possible proof of concept which could be used forfuture studies involving larger groups of patients diagnosedwith painful I-SFN The sample size of 60 patients was cal-culated on the basis of the assumption that the IVIG-treatedgroup would have a response rate of asymp60 based on the

Initiative on Methods Measurement and Pain Assessment inClinical Trials criteria43 and the placebo-treated group wouldhave a response rate of asymp25 according to a meta-analysis ofthe placebo effect in pain studies49 Second the study waspowered to find a difference between 60 response rate in theIVIG group and 25 in the placebo group The observedscore proportions were 40 and 30 respectively whichwere below our expectations and thereby underline ourfindings that IVIG is not a proven treatment for patients withpainful I-SFN Even though the 10 difference in responserate could be a statistically significant difference when thesample size of the study was much larger this is not a clinicallyrelevant difference Third the exclusion criteria did not de-scribe fibromyalgia syndrome or complex regional pain syn-drome so unexpectedly these patients could have beeninvolved in the investigated cohort However before beingdiagnosed with SFN some patients of our study with un-explained complaints could be (falsely) labeled as havingfibromyalgia syndrome or complex regional pain syndromebecause the clinical picture may show similarities but an ab-normal skin biopsy has now been found labeling them ashaving SFN Fourth our study was limited to those withpainful I-SFN so statements about IVIG to treat pain in thosewith autoimmune diseases underlying SFN are limited Ourresults discourage the use of IVIG in this setting until ran-domized controlled trials are completed Finally althoughpatients with psychiatric disorders were not excluded from thestudy in some cases the hospital psychiatry department wasconsulted before inclusion For future IVIG treatment studieswith larger groups of patients with painful I-SFN it is rec-ommend to assess and evaluate psychiatric comorbiditybeforehand

Some might argue that although the study was statisticallynegative more (40) in the IVIG-treated group respondedthan in the placebo-treated group (30) and they would stillwant to treat patients to find responders Thus 10 patientswould need to be treated with IVIG to find 1 nonplaceboresponder (for the 1-point decrease in average pain) becauseof the 4 of 10 who will respond to IVIG 3 would be expected

Table 5 Neuropathic Pain Medication During the Study

Patients using neuropathic pain medication

IVIG groupResponders vs gonrespondersn () p Value

Placebo groupResponders vs gonrespondersn () p Value

ITT population

ge1-Point decrease in pain 8 (667) vs 11 (611) 1000 7 (778) vs 11 (524) 0249

ge2-Point decrease in pain 5 (714) vs 14 (609) 1000 4 (800) vs 14 (560) 0622

PP population

ge1-Point decrease in pain 8 (667) vs 6 (500) 0679 7 (778) vs 9 (529) 0399

ge2-Point decrease in pain 5 (714) vs 9 (529) 0653 4 (800) vs 12 (571) 0617

Abbreviations ITT = intention-to-treat IVIG = IV immunoglobulin PP = per-protocol

NeurologyorgN Neurology | Volume 96 Number 20 | May 18 2021 e2543

to be a placebo responder For the 2-point decrease in pain 15patients should be treated to find 1 IVIG responder The costper gram of IVIG in the Netherlands is euro816450 For a 75-kgpatient assuming a 1ndashgkg dose the cost for this study of 5infusions in 3 months was euro30615 Thus finding 1 IVIGresponder with a 1-point decrease in pain will cost euro306150and finding 1 IVIG responder with a 2-point decrease in painwill cost euro459225 for 3 months only (without even takinginto account the costs for the inpatient admission or homenurse visit infusion pump disposables etc) Furthermore allpatients in the IVIG group experienced adverse events in-cluding 6 SAEs which carry significant risks and can furtherincrease the costs associated with IVIG use

This randomized controlled trial showed that IVIG has nosignificant effect on pain in patients with painful I-SFN andtherefore has no role in the treatment of patients with painfulI-SFN

Study FundingThis study is funded by the Grifols Investigator-SponsoredResearch Program and Lamepro BV

DisclosureM Geerts Bianca TA de Greef Maurice Sopacua andSander MJ van Kuijk have nothing to disclose Janneke GJHoeijmakers reports a grant from the Prinses Beatrix Spier-fonds (WOK17-09) outside the submitted work CG Faberreports grants from European Unionrsquos Horizon 2020 researchand innovation programme Marie Sklodowska-Curie grantfor PAIN-Net Molecule-to-Man Pain Network (grant721841) grants from Prinses Beatrix Spierfonds (WOR15-25) grants from Grifols and Lamepro for a trial on IVIG inSFN and other from steering committteesadvisory board forstudies in SFN of BiogenConvergence and Vertex outsidethe submitted work ISJ Merkies reports grants and non-financial support from Grifols and grants from Lameproduring the conduct of the study as well as other from par-ticipation in steering committees of the Talecris ICE StudyCSL Behring LFB Novartis Octapharma Biotest and UCBoutside the submitted work Go to NeurologyorgN for fulldisclosures

Publication HistoryReceived by Neurology August 12 2020 Accepted in final formFebruary 24 2021

References1 Hoeijmakers JG Faber CG Lauria G Merkies IS Waxman SG Small-fibre

neuropathies-advances in diagnosis pathophysiology and management Nat RevNeurol 20128369ndash379

2 Cazzato D Lauria G Small fibre neuropathy Curr Opin Neurol 201730490ndash4993 Hoitsma E Marziniak M Faber CG et al Small fibre neuropathy in sarcoidosis

Lancet 20023592085ndash20864 Sumner CJ Sheth S Griffin JW Cornblath DR Polydefkis M The spectrum of

neuropathy in diabetes and impaired glucose tolerance Neurology 200360108ndash1115 Brannagan TH III Hays AP Chin SS et al Small-fiber neuropathyneuronopathy

associated with celiac disease skin biopsy findings Arch Neurol 2005621574ndash15786 Gondim FA Brannagan TH III Sander HW Chin RL Latov N Peripheral neu-

ropathy in patients with inflammatory bowel disease Brain 2005128867ndash8797 Mori K Iijima M Koike H et al The wide spectrum of clinical manifestations in

Sjogrenrsquos syndrome-associated neuropathy Brain 20051282518ndash25348 Goransson LG Tjensvoll AB Herigstad A Mellgren SI Omdal R Small-diameter

nerve fiber neuropathy in systemic lupus erythematosus Arch Neurol 200663401ndash404

9 Orstavik K Norheim I Jorum E Pain and small-fiber neuropathy in patients withhypothyroidism Neurology 200667786ndash791

10 Zhou L Kitch DW Evans SR et al Correlates of epidermal nerve fiber densities inHIV-associated distal sensory polyneuropathy Neurology 2007682113ndash2119

11 Gorson KC Herrmann DN Thiagarajan R et al Non-length dependent small fibreneuropathyganglionopathy J Neurol Neurosurg Psychiatry 200879163ndash169

12 Stogbauer F Young P Kuhlenbaumer G et al Autosomal dominant burning feetsyndrome J Neurol Neurosurg Psychiatry 19996778ndash81

Appendix Authors

Name Location Contribution

MargotGeerts MSc

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands

Screening of patients datacollection data analysisand manuscript writing

Appendix (continued)

Name Location Contribution

Bianca TA deGreef MDPhD

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands

Screening of patients datacollection data analysisand manuscript writing

MauriceSopacua MD

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands Departmentof RehabilitationAdelanteMaastrichtUniversity MedicalCenter+ the Netherlands

Screening of patients datacollection and manuscriptwriting

Sander MJvan KuijkPhD

Department of ClinicalEpidemiology and MedicalTechnology AssessmentMaastricht UniversityMedical Center+ theNetherlands

Data analysis statisticalanalysis and manuscriptwriting

Janneke GJHoeijmakersMD PhD

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands

Conception design datacollection data analysisand manuscript writing

Catharina GFaber MDPhD

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands

Conception design datacollection data analysisand manuscript writing

Ingemar SJMerkies MDPhD

Department of NeurologySchool of Mental Healthand NeuroscienceMaastricht UniversityMedical Center+ theNetherlands Departmentof Neurology CuraccedilaoMedical CenterWillemstad

Conception design datacollection data analysisand manuscript writing

e2544 Neurology | Volume 96 Number 20 | May 18 2021 NeurologyorgN

13 Faber CG Hoeijmakers JG Ahn HS et al Gain of function NaV17 mutations inidiopathic small fiber neuropathy Ann Neurol 20127126ndash39

14 Faber CG Lauria G Merkies IS et al Gain-of-function Nav18 mutations in painfulneuropathy Proc Natl Acad Sci USA 201210919444ndash19449

15 de Greef BTA Hoeijmakers JGJ Gorissen-Brouwers CML Geerts M Faber CGMerkies ISJ Associated conditions in small fiber neuropathy a large cohort study andreview of the literature Eur J Neurol 201825348ndash355

16 Huang J Han C Estacion M et al Gain-of-function mutations in sodium channelNa(v)19 in painful neuropathy Brain 20141371627ndash1642

17 Bakkers M Merkies IS Lauria G et al Intraepidermal nerve fiber density and itsapplication in sarcoidosis Neurology 2009731142ndash1148

18 Goransson LG Herigstad A Tjensvoll AB Harboe E Mellgren SI Omdal R Pe-ripheral neuropathy in primary Sjogren syndrome a population-based study ArchNeurol 2006631612ndash1615

19 Goransson LG Brun JG Harboe E Mellgren SI Omdal R Intraepidermal nerve fiberdensities in chronic inflammatory autoimmune diseases Arch Neurol 2006631410ndash1413

20 Chamberlain JL Pittock SJ Oprescu AM et al Peripherin-IgG association withneurologic and endocrine autoimmunity J Autoimmun 201034469ndash477

21 Ferrari S Morbin M Nobile-Orazio E et al Antisulfatide polyneuropathy antibody-mediated complement attack on peripheral myelin Acta Neuropathol 199896569ndash574

22 Dabby R Weimer LH Hays AP Olarte M Latov N Antisulfatide antibodies inneuropathy clinical and electrophysiologic correlates Neurology 2000541448ndash1452

23 Levine TD Kafaie J Zeidman LA et al Cryptogenic small-fiber neuropathies serumautoantibody binding to trisulfated heparan disaccharide and fibroblast growth factorreceptor-3 Muscle Nerve 201961512ndash515

24 Zafrir B Zimmerman M Fellig Y Naparstek Y Reichman N Flatau E Small fiberneuropathy due to isolated vasculitis of the peripheral nervous system Isr Med Assoc J20046183ndash184

25 Kelkar P McDermott WR Parry GJ Sensory-predominant painful idiopathic neu-ropathy inflammatory changes in sural nerves Muscle Nerve 200226413ndash416

26 Uceyler N Kafke W Riediger N et al Elevated proinflammatory cytokine expressionin affected skin in small fiber neuropathy Neurology 2010741806ndash1813

27 Goebel A Immunoglobulin responsive chronic pain J Clin Immunol 201030(suppl1)S103ndashS108

28 Hughes RA Donofrio P Bril V et al Intravenous immune globulin (10 caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinatingpolyradiculoneuropathy (ICE study) a randomised placebo-controlled trial LancetNeurol 20087136ndash144

29 van Schaik IN Bouche P Illa I et al European Federation of Neurological SocietiesPeripheral Nerve Society guideline on management of multifocal motor neuropathyEur J Neurol 200613802ndash808

30 Eftimov F Winer JB Vermeulen M de Haan R van Schaik IN Intravenous immu-noglobulin for chronic inflammatory demyelinating polyradiculoneuropathyCochrane Database Syst Rev 2013CD001797

31 Parambil JG Tavee JO Zhou L Pearson KS Culver DA Efficacy of intravenousimmunoglobulin for small fiber neuropathy associated with sarcoidosis Respir Med2011105101ndash105

32 Wakasugi D Kato T Gono T et al Extreme efficacy of intravenous immunoglobulintherapy for severe burning pain in a patient with small fiber neuropathy associatedwith primary Sjogrenrsquos syndrome Mod Rheumatol 200919437ndash440

33 Gaillet A Champion K Lefaucheur JP Trout H Bergmann JF Sene D Intravenousimmunoglobulin efficacy for primary Sjogrenrsquos Syndrome associated small fiberneuropathy Autoimmun Rev 201918102387

34 Makonahalli R Seneviratne J Seneviratne U Acute small fiber neuropathy followingmycoplasma infection a rare variant of Guillain-Barre syndrome J Clin NeuromusculDis 201415147ndash151

35 Tavee JO Karwa K Ahmed Z Thompson N Parambil J Culver DA Sarcoidosis-associated small fiber neuropathy in a large cohort clinical aspects and response toIVIG and anti-TNF alpha treatment Respir Med 2017126135ndash138

36 Souayah N Chin RL Brannagan TH et al Effect of intravenous immunoglobulin oncerebellar ataxia and neuropathic pain associated with celiac disease Eur J Neurol2008151300ndash1303

37 Schofield JR Chemali KR How we treat autoimmune small fiber polyneuropathywith immunoglobulin therapy Eur Neurol 201880304ndash310

38 Liu X Treister R Lang M Oaklander AL IVIG for apparently autoimmune small-fiber polyneuropathy first analysis of efficacy and safety Ther Adv Neurol Disord2018111756285617744484

39 Oaklander AL NolanoM Scientific advances in and clinical approaches to small-fiberpolyneuropathy a review JAMA Neurol Epub 2019 Sep 9

40 de Greef BT Geerts M Hoeijmakers JG Faber CG Merkies IS Intravenous im-munoglobulin therapy for small fiber neuropathy study protocol for a randomizedcontrolled trial Trials 201617330

41 Tesfaye S Boulton AJ Dyck PJ et al Diabetic neuropathies update on definitions di-agnostic criteria estimation of severity and treatments Diabetes Care 2010332285ndash2293

42 Farrar JTWhat is clinically meaningful outcomemeasures in pain clinical trials Clin JPain 200016S106ndashS112

43 Dworkin RH Turk DC Wyrwich KW et al Interpreting the clinical importance oftreatment outcomes in chronic pain clinical trials IMMPACT recommendationsJ Pain 20089105ndash121

44 VernonMK BrandenburgNA Alvir JMGriesing T Revicki DA Reliability validity andresponsiveness of the daily sleep interference scale among diabetic peripheral neuropathyand postherpetic neuralgia patients J Pain Symptom Manage 20083654ndash68

45 Brouwer BA Bakkers M Hoeijmakers JG Faber CG Merkies IS Improving assess-ment in small fiber neuropathy J Peripher Nerv Syst 201520333ndash340

46 Galer BS JensenMP Development and preliminary validation of a pain measure specificto neuropathic pain the Neuropathic Pain Scale Neurology 199748332ndash338

47 Aaronson NKMuller M Cohen PD et al Translation validation and norming of theDutch language version of the SF-36 Health Survey in community and chronic diseasepopulations J Clin Epidemiol 1998511055ndash1068

48 Draak THP de Greef BTA Faber CG Merkies ISJ PeriNomS Study Group Theminimum clinically important difference which direction to take Eur J Neurol 201926850ndash855

49 McQuay H Carroll D Moore A Variation in the placebo effect in randomisedcontrolled trials of analgesics all is as blind as it seems Pain 199664331ndash335

50 Farmacotherapeutisch KompasmdashGamunexmdashlast visit 2019 Available at farm-acotherapeutischkompasnlbladerenpreparaattekstennnormaal_immunoglobu-line__iv_ Accessed May 19 2015

NeurologyorgN Neurology | Volume 96 Number 20 | May 18 2021 e2545

DOI 101212WNL0000000000011919202196e2534-e2545 Published Online before print March 25 2021Neurology

Margot Geerts Bianca TA de Greef Maurice Sopacua et al Neuropathy

Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber

This information is current as of March 25 2021

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