The Second Edition Expert Consensus Statements on the Use of IVIg in Neurology
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Transcript of The Second Edition Expert Consensus Statements on the Use of IVIg in Neurology
SECOND EDITIONPrepared by the Asia Pacific Immunoglobulins in Neurology Advisory BoardRevised November 2008
BRINGINGCONSENSUS TOTHE USE OF IVIG IN NEUROLOGY
EXPERT CONSENSUSSTATEMENTS ON THE USE OF IVIG IN NEUROLOGY2nd EDITIONPREPARED BY THE ASIA PACIFIC IMMUNOGLOBULINS IN NEUROLOGY ADVISORY BOARD NOVEMBER 2008
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BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
Copyright® Asia Pacific Immunoglobulins in Neurology Advisory Board Inc.
Apart from any fair dealing for the use of private study, research, criticism, or review as permitted under the Copyright Act, no part of this book may be transmitted or reproduced in any form, electronic or mechanical, or by any information storage
and retrieval system, without the written permission of the publishers.
This publication has been made possible by an unrestricted educational grant from CSL Bioplasma.
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TABLE OF CONTENTS
TABLE OF CONTENTSForeword.................................................................................................................................................................. 10.
The Mechanism of Action of Intravenous Immunoglobulin in the Treatment of Autoimmune Neurological
Diseases.................................................................................................................................................................... 1�..
. Abstract............................................................................................................................................................... 1�
. Introduction......................................................................................................................................................... 1�.
. References.......................................................................................................................................................... 18
Guillain-Barré Syndrome........................................................................................................................................22
. Introduction.........................................................................................................................................................22
. Treatment.in.GBS................................................................................................................................................23
. Expert.Consensus...............................................................................................................................................26
. References..........................................................................................................................................................27
Chronic Inflammatory Demyelinating Polyneuropathy.......................................................................................31
. Introduction.........................................................................................................................................................31
. Diagnosis.............................................................................................................................................................31
. Differential.Diagnosis...........................................................................................................................................32
. Natural.History.....................................................................................................................................................32
. Pathogenesis.......................................................................................................................................................32
. Treatment............................................................................................................................................................33
. Suggested.Approach.to.Management................................................................................................................3�
. Expert.Consensus...............................................................................................................................................3�
. References..........................................................................................................................................................3�
Multifocal Motor Neuropathy.................................................................................................................................39..
. Definition.............................................................................................................................................................39
. Diagnosis.............................................................................................................................................................39
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BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
. Pathogenesis.......................................................................................................................................................�0
. Natural.History.....................................................................................................................................................�0
. Pathology.............................................................................................................................................................�0
. Treatment............................................................................................................................................................�0
. Summary.............................................................................................................................................................�1
. Expert.Consensus...............................................................................................................................................�1
. References..........................................................................................................................................................�2
IgM Paraproteinemic Neuropathies.......................................................................................................................��.
. Introduction.........................................................................................................................................................��.
. Definition.............................................................................................................................................................��.
. General.Information.............................................................................................................................................��.
. Pathogenesis.......................................................................................................................................................��.
. Clinical.Presentation............................................................................................................................................�6.
. Investigations......................................................................................................................................................�7.
. Objectives............................................................................................................................................................�7.
. IVIG.in.Igm.Paraproteinemic.Neuropathies.........................................................................................................�7.
. Summary.............................................................................................................................................................�8.
. Expert.Consensus...............................................................................................................................................�9..
. Other.Immunosuppresants.being.considered.....................................................................................................�9.
. References..........................................................................................................................................................�9
Brachial and Lumbosacral Plexopathies...............................................................................................................�1
Neuralgic.Amyotrophy/Brachial.Neuritis..............................................................................................................�1.
. Pathogenetic.Mechanisms.in.Neuralgic.Amyotrophy..........................................................................................�2.
. Treatment.of.Neuralgic.Amyotrophy....................................................................................................................�2.
. Immune.Modulating.Therapy.in.Neuralgic.Amyotrophy,.including.IVIG..............................................................�2.
. Diabetic.Lumbosacral.Plexopathy........................................................................................................................�2.
. Idiopathic.Lumbosacral.Plexopathy.....................................................................................................................�2.
. Pathogenetic.Mechanisms.of.Diabetic.and.Idiopathic.Lumbosacral.Plexopathy................................................�3.
. Therapy.in.Diabetic.and.Idiopathic.Lumbosacral.Plexopathy...............................................................................�3..
. Expert.Consensus...............................................................................................................................................�3.
. References..........................................................................................................................................................�3
Myasthenia Gravis...................................................................................................................................................��
. Clinical.Information..............................................................................................................................................��.
. Objectives............................................................................................................................................................�8
. Intravenous.Immunoglobulin.for.MG.Exacerbations.and.Myasthenic.Crisis.......................................................�8..
. Intravenous.Immunoglobulin.for.MG.with.Worsening.Weakness.......................................................................�9.
. Intravenous.Immunoglobulin.for.Moderate.to.Severe.Stable.MG......................................................................�9
. Summary.............................................................................................................................................................60
. Expert.Consensus...............................................................................................................................................60
. References..........................................................................................................................................................60
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TABLE OF CONTENTS
Amyotrophic Lateral Sclerosis...............................................................................................................................66
. Clinical.Information..............................................................................................................................................66.
. IVIG.as.Maintenance.Therapy..............................................................................................................................67..
. Objective.............................................................................................................................................................67
. Summary.............................................................................................................................................................67
. Expert.Consensus...............................................................................................................................................67
. References..........................................................................................................................................................67
Lambert-Eaton Myasthenic Syndrome..................................................................................................................69
. Clinical.Information..............................................................................................................................................69
. Objectives............................................................................................................................................................70
. Intravenous.Immunoglobulin.for.LEMS...............................................................................................................70
. Summary.............................................................................................................................................................71
. Expert.Consensus...............................................................................................................................................71
. References..........................................................................................................................................................71
Neuromyotonia (Isaacs’ Syndrome)...................................................................................................................... 7�
. Background.......................................................................................................................................................... 7�
. Intravenous.Immunoglobulin.for.Neuromyotonia................................................................................................7�
. Summary.............................................................................................................................................................7�
. Expert.Consensus...............................................................................................................................................7�
. References..........................................................................................................................................................7�
Inflammatory Myopathies......................................................................................................................................77
. Background..........................................................................................................................................................77
. Treatment.of.DM.and.PM...................................................................................................................................79
. Treatment.of.IBM................................................................................................................................................79
. Summary.............................................................................................................................................................80
. Expert.Consensus...............................................................................................................................................81
. References..........................................................................................................................................................81
Chronic Fatigue Syndrome.....................................................................................................................................8�
. Background..........................................................................................................................................................8�
. Etiology,.Pathophysiology.and.Laboratory.Observations....................................................................................8�.
. Chronic.Fatigue.Syndrome..................................................................................................................................8�.
. Therapy.in.CFS....................................................................................................................................................8�.
. IVIG.in.CFS..........................................................................................................................................................86.
. Expert.Consensus...............................................................................................................................................87
. References..........................................................................................................................................................87
Paraneoplastic Neurological Disorders.................................................................................................................90
. Introduction.........................................................................................................................................................90
. Clinical.Features..................................................................................................................................................90
. Pathogenesis.......................................................................................................................................................92
. Treatment.for.Paraneoplastic.Neurological.Disorders.........................................................................................92
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BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
. Summary.............................................................................................................................................................93
. Expert.Consensus...............................................................................................................................................9�
. References..........................................................................................................................................................9�
Stiff-Person Syndrome............................................................................................................................................97
. Background..........................................................................................................................................................97
. Neurophysiology..................................................................................................................................................97
. Auto-Antibodies.and.Immunopathogenesis........................................................................................................98
. Therapies.............................................................................................................................................................98
. IVIG.in.SPS..........................................................................................................................................................98
. Summary.............................................................................................................................................................99
. Expert.Consensus...............................................................................................................................................99
. References..........................................................................................................................................................99
Epilepsy.................................................................................................................................................................. 101
. Background........................................................................................................................................................ 101
. Intractable.Epilepsies........................................................................................................................................ 101
. Basis.for.Using.Immunomodulation.................................................................................................................. 102
. IVIG.in.Epilepsy................................................................................................................................................. 103
. Summary........................................................................................................................................................... 10�..
. Expert.Consensus............................................................................................................................................. 10�
. References........................................................................................................................................................ 10�
Opsoclonus–Myoclonus–Ataxia........................................................................................................................... 108
. Background........................................................................................................................................................ 108
. Conventional.Management............................................................................................................................... 109
. IVIG.in.OMA...................................................................................................................................................... 109
. Summary........................................................................................................................................................... 109
. Expert.Consensus..............................................................................................................................................110
. References.........................................................................................................................................................110
Acute Disseminated Encephalomyelitis.............................................................................................................. 112.
. Clinical.Features................................................................................................................................................ 112.
. Etiology.............................................................................................................................................................. 112.
. Pathogenesis..................................................................................................................................................... 112.
. Diagnosis........................................................................................................................................................... 113.
. Treatment.......................................................................................................................................................... 113.
. Role.of.IVIG.in.Adem......................................................................................................................................... 113.
. Expert.Consensus............................................................................................................................................. 11�.
. References........................................................................................................................................................ 11�
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Multiple Sclerosis.................................................................................................................................................. 116
Clinical.Features................................................................................................................................................ 116
. Etiological.Factors.and.Pathogenesis.................................................................................................................117
. Diagnosis............................................................................................................................................................117
. Treatment.......................................................................................................................................................... 118
. Immunomodulatory.Treatments........................................................................................................................ 118
. Beta-Interferons................................................................................................................................................. 118..
. Corticosteroids.................................................................................................................................................. 119.
. Beta-Interferons................................................................................................................................................. 119..
. Other.EmergingTreatments............................................................................................................................... 119
. Role.of.IVIG.in.MS............................................................................................................................................. 119
. RRMS................................................................................................................................................................ 120
. Progressive.MS................................................................................................................................................. 120
. Expert.Consensus............................................................................................................................................. 120
. References........................................................................................................................................................ 121
Neuromyelitis Optica............................................................................................................................................ 12�.
. Introduction....................................................................................................................................................... 12�.
. Clinical.Features................................................................................................................................................ 12�.
. Pathology.and.Pathogenesis............................................................................................................................. 12�.
. Treatment.......................................................................................................................................................... 12�.
. Expert.Consensus............................................................................................................................................. 126.
. References........................................................................................................................................................ 126.
Appendices............................................................................................................................................................. 129
. Appendix.A........................................................................................................................................................ 129
. Appendix.B........................................................................................................................................................ 129..
. Appendix.C........................................................................................................................................................ 130
Membership of Scientific Committee................................................................................................................. 131.
Commentary on Interpretation of Publications Reviewed................................................................................ 133.
Acknowledgements............................................................................................................................................... 13�.
Waiver of Liability.................................................................................................................................................. 13�
TABLE OF CONTENTS
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BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
FOREWORDBRINGING CONSENSUS TO THE USE OF IVIg IN NEUROLOGY. serves. to. support. neurologists. and.clinicians. in. their. use. of. intravenous. immunoglobulin.(IVIg). in. neurological. practice. by. providing. expert.consensus.statements.on.the.use.of.IVIg.in.neurology...This.second.edition.of.the.expert.consensus.statements.has.been.extensively.revised.to.reflect.information.that.has.come.to.light.since.the.first.edition.was.published.in.late.200�,.and.covers.a.number.of.new.topics.
In. the. field. of. Neurology,. IVIg. has. a. dramatic.impact. in. the. treatment.of.autoimmune.disorders,.and.generally. results. in. a. significant. improvement. in. the.quality.of.life.experienced.by.our.patients...The.success.of. IVIg. therapy.has. led.to. its.use. in.an.ever. increasing.number. of. disorders.. .The. optimal. use. of. IVIg. in. the.treatment. of. neurological. disorders. is. therefore. an.important.goal.
Over.the.last.few.years,.there.has.been.increasing.attention. paid. to. the. development. of. clinical. practice.guidelines.and.expert.consensus.statements.in.a.variety.of. medical. disciplines,. as. the. use. of. such. documents.can.bring.about.changes.in.clinical.practice.which.result.in. optimised. use. of. therapies,. improved. patient.outcomes,.and.hence.improved.care.. .Once.effectively.implemented,.these.documents.also.reinforce.the.choice.of. therapies. known. to. deliver. optimal. benefit. and.minimised.adverse.effects.at.an.acceptable.cost...
However,. clinical. practice. guidelines. and. expert.consensus.statements.are.only.one.element.of.clinical.decision. making.. The. patient’s. preference,. clinician’s.experience,. and. most. importantly,. the. availability..of. resources. and. therapies. must. also. be. taken..into.account.
In. the. Asia. Pacific,. where. half. of. the. world’s.population. lives,. there. is. a. wide. spectrum. of. clinical.expertise.and.a.variety.of.health.systems.. .Guidelines.adopted. in. one. country. may. not. be. applicable. to.another...To.this.end,.an.Asia.Pacific.Immunoglobulins.in.Neurology. Advisory. Board. was. assembled. to. review.and. synthesise. the. region’s. relevant. guidelines. and.consensus. statements. with. a. view. to. developing.regional. consensus. statements.. . The. Asia. Pacific.Immunoglobulins. in. Neurology. Advisory. Board. is.comprised. of. experts. in. neurological. practice,. and..also. enjoys. input. from. many. world-renowned..opinion.leaders.
Preparation.of.these.expert.consensus.statements.began. at. the. first. Asia. Pacific. Immunoglobulins. in.Neurology.Advisory. Board. Meeting. held. in. December.2003...The.format.of.the.expert.consensus.statements.were. agreed. at. that. meeting,. and. each. consensus.statement.now.comprises.a:
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consensus.statements.in.November.200�...The.second.edition. includes. a. mini-review. on. the. mechanisms. of.action.of.IVIg.in.neurological.disease.(Marinos.Dalakas).and.new.topics.including:•. acute.disseminated.encephalomyelitis.(ADEM)•. brachipathies•. IgM.paraproteinemic.neuropathies.•. multiple.sclerosis.(MS)•. neuromyelitis.optica.(NMO).
Apart. from. the. development. of. expert. consensus.statements,. the. charter. of. the. Asia. Pacific.Immunoglobulins.in.Neurology.Advisory.Board.includes.the.development.of.an.educational.program.for.the.Asia.Pacific..During.November.2008.our.third.such.educational.program,.the.3rd.INDAPS,.will.be.held.and.I.am.sure.it.will.continue.and.consolidate.the.work.that.commenced.in. Singapore. at. the. inaugural. INDAPS,. and. that. was.progressed. in.November.200�. in. the.Blue.Mountains,.Australia,.at.our.second.INDAPS..
The.second.edition.of.the.Consensus.Statements.is.being.released.at.the.3rd.INDAPS.conference..
Publications. like.this.do.not.happen.without.a. lot.of. effort,. planning. and. hard. work.. . The. Asia. Pacific.Immunoglobulins. in. Neurology. Advisory. Board. has.worked. tirelessly. to.make. this. possible.. . I. thank.each.and. every. member. for. their. strong. support. and.tremendous.effort.in.achieving.this.major.milestone... Through. the. generous,. undirected. educational.funding. provided. by. CSL Bioplasma,. the. Asia. Pacific.Immunoglobulins. in. Neurology. Advisory. Board. will.continue.to.consolidate.on.the.important.education.that.BRINGING CONSENSUS TO THE USE OF IVIg IN NEUROLOGY, and INDAPS, provide.
A/Prof.Andrew.J..KornbergChairman,. Asia. Pacific. Immunoglobulins. in. Neurology.Advisory.BoardNovember.2008
•. background.on.the.relevant.disorder•. summary.of.the.diagnostic.process.and... differential.diagnosis•. review.of.the.literature.for.all.therapies.in.the... relevant.condition
•. detailed.review.of.IVIg.as.a.therapy.in.the... relevant.condition•. an.evidence.based.approach.to.the.interpretation... of.all.treatment.studies
•. an.expert.summary.statement.of.the.place.of... IVIg.therapy.in.the.relevant.condition.with.a... clinical.perspective.from.a.group.of.experts.in... their.field.Members. of. the. Asia. Pacific. Immunoglobulins. in.Neurology. Advisory. Board. were. assigned. topics. to.cover,. and. all. available. literature. was. reviewed.. .The.specific.topics.reviewed.included:•. Guillain-Barré.syndrome.(GBS)•. chronic.inflammatory.demyelinating.polyneuropa-.. thy.(CIDP)•. multifocal.motor.neuropathy.(MMN)•. amyotrophic.lateral.sclerosis.(ALS)•. myasthenia.gravis•. Lambert-Eaton.myasthenic.syndrome.(LEMS).•. neuromyotonia.(Isaacs’.syndrome).•. dermatomyositis,.polymyositis,.inclusion... body.myositis•. chronic.fatigue.syndrome•. paraneoplastic.neurological.disorders•. stiff-person.syndrome•. epilepsy•. opsoclonus-myoclonus.syndrome-ataxia.
The.conditions.chosen. for. review.reflect. the.disorders.commonly. treated,. or. considered. for. treatment,. with.IVIg. in. neurological. practice.. .The. first. edition. of. the.expert. consensus. statements. was. published. in.November. 200�. and. launched. at. the. inaugural. IVIg. in.Neurological.Disease.Asia.Pacific.Symposium.(INDAPS).in.Singapore...It.discussed.the.evidence.for.IVIg.use.in.the.above.mentioned.disorders..
As. mentioned. above,. the. second. edition. of. the.expert. consensus. statements. has. been. updated. and.revised. to. reflect. information. and. literature. that. has.become. available. since. first. publication. of. the. expert.
FOREWORD
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BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
WaIVER Of LIaBILItYThe.information.contained.in.this.document.is.intended.to. serve. as. a. guideline. only.. . Neither. the. contributing.authors. nor. the. Asia. Pacific. Immunoglobulins. in.Neurology.Advisory.Board.shall.be.liable.for.any.actions,.claims,. damages,. costs. or. obligations. that. may. arise.from. the. inappropriate. use. or. misuse. of. the. material.contained.in.this.document.
tERMINOLOGYStandards. Australia. and. virtually. all. national. bodies.around. the. world. are. following. the. rules. set. down. by.the. International. Standards. Organisation. (ISO). for. the.use.of.the.terms.‘shall,.‘should’.and.‘may’...The.Expert.Consensus.Statements.for.the.use.of.IVIg.in.Neurology.have.used.the.definitions.of.these.terms.for.consistency.with.current.international.usage.
•. The.term.‘shall’.indicated.a.mandatory... requirement;.however.this.does.not.imply... mandatory.or.legal.requirement.•. The.term.‘should’.implies.a.recommendation... where.guidance.is.intended.and.does.not.preclude... other.acceptable.practices.•. The.term.’may’.is.used.to.indicate.an.acceptable... alternative.or.addition.to.the.prescribed.practice.
These. consensus. statements. are. based. on. evidence.base.literature.research.and.expert.opinion...The.continuing.development.of.knowledge,.opinion.and.practice.neces-sitates.ongoing.revision.of.practice..It.is.the.intent.of.the.authors. that. these. expert. consensus. statements. be.reviewed.annually.or.as.the.need.arises.
Comments.and.suggestions.for.revision.are.welcomed.and.can.be.forwarded.to:
A/Prof.Andrew.J..KornbergChairman,.Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.BoardDepartment.of.NeurologyRoyal.Children’s.HospitalParkville.Victoria.30�[email protected]
COMMENtaRY ON thE INtERpREtatION Of pUBLICatIONs REVIEWEdThis. updated. literature. review. considered. all. relevant.studies. and. commentaries. published. in. English. from.1966.to.2008.
For.search.strategy.please.refer.to.Appendix.C
aCRONYMs aNd aBBREVIatIONs AIDP. Acute.Inflammatory.Demyelinating.
Polyneuropathy
ALS.. Amyotrophic.Lateral.Sclerosis
CIDP. Chronic.Inflammatory.Demyelinating.Polyneuropathy
CREAN Chronic.relapsing.experimental..autoimmuneneuritis
DM.. Dermatomyositis
EAN. Experimental.autoimmune.neuritis
EBM. Evidence.Based.Medicine
GBS. Guillain-Barré.syndrome
IBM. Inclusion.body.myositis
IV. . Intravenous
IVIg.. Intravenous.Immunoglobulin
LEMS. Lambert-Eaton.Myasthenic.Syndrome
MMN. Multifocal.Motor.Neuropathy
MRC. Medical.Research.Council
13
SouRCE:.NHMRC.1999.A Guide to the Development, Implementation and Evaluation of Clinical Practice Guidelines. National.Health.and.Medical.Research.Council,.Canberra.
NHMRC. National.Health.and.Medical.Research.Council
PE. . Plasma.exchange
PM.. PolymyositisBIBLIOGRaphY aNd LItERatURE REVIEWPlease.see.Appendix.C
LEVELSofEVIDENCERAtINGSI. Evidence.obtained.from.a.systematic.review.of.all.
relevant.randomised.controlled.trials.
II. Evidence.obtained.from.at.least.one.properly.designed.randomised.controlled.trial.
III–i..Evidence.obtained.from.well.designed.pseudo-randomised.controlled.trials.(alternate.location.or.some.other.method).
III–ii.Evidence.obtained.from.comparative.studies.(including.systematic.reviews.of.such.studies).with.concurrent.controls.and.allocation.not.randomised,.cohort.studies,.case-controlled.studies,.or.interrupted.time.series.with.a..control.group.
IV. Evidence.obtained.from.comparative.studies.with.historical.control,.two.or.more.single.arms,.or.interrupted.time.series.without.a.parallel.group.
V. Evidence.obtained.from.case.series,.either.post.test.or.pre-test/post-tests.
FOREWORD
1�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
aBstRaCtIntravenous.Immunoglobulin.(IVIg).has.multiple.actions.
on. the. immunoregulatory. network. that. operate. in.
concert.with.each.other.. .Among. the.best.understood.
actions. of. IVIg. include:. a). suppression. of. pathogenic.
autoantibodies,.an.effect.relevant.in.Myasthenia.Gravis.
(MG),. Lambert-Eaton. myasthenic. syndrome. (LEMS),.
Guillain-Barré. syndrome. (GBS),. Chronic. Inflammatory.
Demyelinating. Polyneuropathy. (CIDP). and. Stiff-Person.
Syndrome.(SPS);.b).inhibition.of.complement.activation.
and. interception. of. membranolytic. attack. complex.
formation,. an. action. relevant. to. the. complement-
mediated.mechanisms. involved. in.GBS,.CIDP,.MG.and.
dermatomyositis.(DM);.c).modulation.of.the.inhibitory.or.
activation. Fc. receptors. on. macrophages. invading.
targeted.tissues.in.nerve.and.muscle,.as.seen.in.CIDP,.
GBS. and. myositis;. d). downregulation. of. pathogenic.
cytokines.and.adhesion.molecules;.e).suppression.of.T.
cell. functions.or. interference.with.antigen. recognition;.
and.f).alteration.of.certain.immunoregulatory,.adhesion.
molecule.or.remodeling.genes...Future.identification.in.
the. patients’. tissues. of. biologically. relevant. genes. or.
molecules.associated.with.clinical. response,.may.help.
us.determine.which.patients.are.more.likely.to.respond..
to.IVIg.
INtROdUCtIONIntravenous.immunoglobulin.(IVIg).has.multiple.actions.
which.may.operate.in.concert.with.each.other...For.each.
neuromuscular.disorder,.however,.there.appears.to.be.a.
predominant. mechanism. dictated. by. the. underlying.
immunopathogenetic.cause.of.the.respective.disorder...
Some.of.these.mechanisms.have.been.reasonably.well.
explored. in. vivo. or. in. vitro,. others. are. based. on.
information.derived.from.other.autoimmune.diseases.in.
which. IVIg. has. been. effective,. and. still. others. remain.
hypothetical. requiring. better. documentation.. . Among.
the.main.mechanisms.of.action.of.IVIg.(Kazatchine.and.
Kaveri,. 2001;. Dalakas. 200�a,b),. those. relevant. to. the.
efficacy. of. the. drug. in. autoimmune. neuromuscular.
disorders.include.the.following:.
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
1�
1.EffECtoNAutoANtIBoDIESThe.IgG.of.normal.humans.contains.low.titer.antibodies.
against. a.wide. spectrum.of.human.proteins,. and. anti-
idiotypic. antibodies. directed. against. Fαβ,. the. antigen-
binding.region.of.these.autoantibodies.(Dalakas,.1997b;.
Dwyer,. 1992;. Kazatchkine. et. al.,. 199�).. . Because. IVIg.
preparations. are. derived. from. a. large. pool. of. human.
donors,. the. IgG. molecules. within. the. IVIg. contain.
antibodies. with. a. wide. range. of. idiotypic. and. anti-
idiotypic.specificities...The.idiotypic.antibodies.have.the.
potential.to.bind.to.and.neutralize.pathogenic.autoanti-
bodies,. thereby. preventing. their. interaction. with. the.
autoantigen.. .This. effect. has. been. shown. experimen-
tally,.when.extracted.F(αβ')2.fragments.of.IVIg.bound.to.
and. neutralized. known. autoantibodies,. such. as. anti-
DNA,.anti-AChR,.anti-thyroglobulin,.anti-GM1.and.others.
(Dietrich. and. Kazatchkine,. 1990;. Kaveri. et. al.,. 1997;.
Kazatchkine. et. al.,. 199�;. Malik. et. al.,. 1996).. . The.
idiotypic/anti-idiotypic. effect. has. been. confirmed. in.
patients. with. GBS. and. some. chronic. demyelinating.
neuropathies. whose. serum. contains. various. glycolipid.
antibodies. against. GM1,. P0,. GD1a,. GQ1b. and. other.
glycoconjugates...In.an.in.vitro.nerve-muscle.preparation,.
the. idiotypic.antibodies.against.these.glycoconjugates,.
which.are.naturally.present.within.the.IVIg,.block.within.
minutes.and.neutralize.the.“blocking”.effect.exerted.by.
the.serum.of.acute.GBS.patients.on.the.quantal.release.
(Buchwald. et. al.,. 2002;. Dalakas,. 2002a).. . In. another.
antiganglioside. antibody-mediated. cytotoxicity. system,.
the.idiotypic.antibodies.within.the.IVIg.exerted.a.dose-
dependent. protection. of. cytotoxicity. induced. by. GBS.
sera.(Zhang.et.al.200�)...Additionally,.the.F(αβ‘)2,.but.not.
the.Fc.portion.of. the. IgG,.within. the. IVIg.preparations.
inhibits. the. binding. of. anti-. GM1. antibodies. to. GM1-
coated.ELISA.plates.and.the.binding.of.cholera.toxin.to.
GM1. ganglioside. (Malik. et. al. 1996;. Yuki. and. Miyagi.
1996),. in. a. dose-dependent. manner.. . In. patients. with.
stiff-person. syndrome. and. LEMS. after. treatment. with.
pROpOsEd MEChaNIsMs Of aCtION Of IVIG aNd thEIR RELEVaNCE IN thE REspECtIVE aUtOIMMUNE NEUROMUsCULaR dIsEasEs
ACtIoNSofIVIG
1.. .Effect.on.autoantibodies.by:
. .a).supplying.idiotypic.antibodies.that.neutralize.
pathogenic.autoantibodies;.b).suppressing.antibody.
production;.and.c).accelerating.catabolism.of.IgG.
antibodies.by.saturating.the.FcRn.transport.receptors
2.. .Inhibition.of.complement.binding.and.prevention.of.
Membranolytic.Attack.Complex.(MAC).formation
3.. .Fc.Receptor.modulation.and.blockade.on.invaded.
macrophages
�.. .Suppression.of.pathogenic.cytokines.and.adhesion.
molecules
�.. Modulation.of.T.cell.function
6.. Possible.effect.on.remyelination
NEuRoMuSCuLARDISEASES
a). .Myasthenia.gravis;.b).LEMS;.c).stiff-person.
syndrome;.d).autoimmune.demyelinating.neuropa-
thies.(CIDP,.GBS,.MMN)
a). .Dermatomyositis;.b).Guillain-Barré.syndrome;.c).
CIDP;.d).Myasthenia.gravis
a). .Guillain-Barré.syndrome;.b).CIDP;.c).Inflammatory.
myopathies
a). .Inflammatory.myopathies;.b)..Demyelinating.neu-
ropathies;.c)..Myasthenia.gravis
a). .Guillain-Barré.syndrome;.b)..CIDP;.c).inflammatory.
myopathies
a). Guillain-Barré.syndrome;.b).CIDP
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
16
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
IVIg,.the.levels.of.anti-GAD.or.anti-VGCC.antibodies.are.
reduced. within. days. suggesting. an. idiotypic. effect.
(Dalakas. 2003;. Bain. et. al. 1996).. . Other. proposed. but.
untested. mechanisms. include. the. suppression. of.
antibody. production. by. the. anti-idiotypic. antibodies.
within.IVIg.(Diegel.et.al.,.199�;.Uher.and.Dickler,.1986)...
And. the.possible. acceleration.of. catabolism.of. IgG.by.
saturating. the. FcRn. transport. receptors. (Yu. and..
Lennon,.1999)...
. The.above-mentioned.effects.of.IVIg.on.autoantibod-
ies. may. be. relevant. in. the. antibody-mediated.
autoimmune. neuromuscular. diseases. where. IVIg. is.
proven. effective,. such. as. myasthenia. gravis. (MG),.
Lambert-Eaton. myasthenic. syndrome,. stiff-person.
syndrome. and. the. antibody-mediated. demyelinating.
neuropathies.(GBS,.CIDP,.MMN).(Table)..
2.INHIBItIoNofCoMPLEMENtBINDINGANDPREVENtIoNofMEMBRANoLytICAttACkCoMPLEx(MAC)foRMAtIoNThe. effect. of. IVIg. on. complement. binding. has. been.
demonstrated.in.vitro,.in.animal.models,.and.in.patients.
who.received.IVIg...In.early.studies,.IVIg.was.shown.to.
prevent. death. in. guinea. pigs. from. the. complement-
dependent.Forssman.shock.by. inhibiting.the.uptake.of.
complement. C3. and. C�. fragments. to. the. endothelial.
cells.(Basta.et.al.1989)...In.patients.with.dermatomyosi-
tis,.which.is.a.complement-dependent.microangiopathy.
mediated.by.activation.of.C3.and.deposition.of.MAC.on.
the. endomysial. capillaries. (Dalakas. 1991;. Basta. et. al.
1989;. Dalakas. and. Hohlfeld. 2003),. IVIg. inhibits.
complement. uptake. and. intercepts. the. formation. and.
deposition.of.MAC.on.the.endomysial.capillaries.(Basta.
and.Dalakas.199�)...This.effect.is.associated.with.clinical.
improvement. (Dalakas. et. al. 1993).. . Post-IVIg,. but. not.
post-placebo.serum,.inhibits.the.uptake.of.C3b.and.C�b.
fragments.by.sensitized.in.vitro.targets,.probably.due.to.
formation. of. covalent. or. noncovalent. complexes.
between. C3. and. specific. receptor. sites. within. the.
infused. IgG.molecules. (Basta.and.Dalakas.199�).. .The.
effect.of.IVIg.on.the.complement.is.directly.relevant.not.
only.in.dermatomyositis.but.also.to.GBS,.CIDP.and.MG,.
where.the.complement.pathway.is.activated.(Basta.et.al.
1996). and. complement. fragments. are. fixed. in. the.
targeted. tissues. (Dalakas. 1999b).. . A. complement-
inhibiting. and. dose-dependent. effect. has. been. also.
shown.for.GBS.patients.in.an.in.vitro.cytotoxicity.assay.
when.IVIg.decreased.the.deposition.of.C3d.complement.
fragments.on.the.nerve.fibers.and.prevented.the.cyto-
toxicity.induced.by.the.GBS.sera.(Zhang.et.al.200�).
3.MoDuLAtIoNoRBLoCkADEoffCRECEPtoRSoNMACRoPHAGESThere.are.specific.Fc.receptors.for.each.class.of.immu-
noglobulin...IgG.molecules.bind.through.their.Fc.region.
of. Fcγ. receptors. on. hematopoietic. cells,. such. as.
macrophages.. . FcγR. receptors. with. intracellular.
“immune.receptor.tyrosine-based.activation.or.inhibition.
motifs”. mediate. inflammation. or. immune. effector.
functions.via.activation.or.inhibitory.signaling.(Kazatchkine.
and.Kaveri.2001;.Samuelsson.et.al.,.2001)...The.ratio.of.
expression.of.the.inhibitory.and.activation.FcγR.receptors.
determines.the.final.immune.response;.overexpression.
of.FcγR.I.and.FcγR.III.favor.activation,.whereas.overex-
pression.of.FcγR.II.infers.inhibition.of.phagocytosis.and.
interception.of.antibody-dependent.cell-mediated.cyto-
toxicity.(Kazatchkine.and.Kaveri.2001;.Samuelsson.et.al.
2001)...IVIg.upregulates.the.inhibitory.FcγR.II.receptors.
and.modulates.the.FcγR.II/.FcγR.III.ratio.on.macrophages.
(Samuelsson.et.al.2001)...An.increase.in.the.number.of.
monocytes.bearing.the.FcγR.II.inhibitory.receptors.and.
an. increase. in.the.FcγR.II/.FcγR.III. ratio.on.monocytes.
has.been.noted.one.week.after. IVIg. in.GBS.and.CIDP.
patients.who.started.to. improve,.suggesting.that.such.
inhibitory. signaling. may. be. clinically. relevant. (Creange.
et.al.2003)...Whether.IVIg.can.also.induce.blockade.of.
the. Fc. receptors. on. phagocytic. cells. by. saturating,.
altering,. or. downregulating. the. affinity. of. the. Fc.
receptors,. a. process. that. may. render. sensitized.
phagocytic. cells. unable. to. exert..
their. action. (Dalakas. 1997b;. 1998b),. remains. to..
be.determined.
4.SuPPRESSIoNofPAtHoGENICCytokINESANDotHERIMMuNoREGuLAtoRyMoLECuLESIn.vitro.and.in.vivo.studies.have.shown.that.IVIg.causes.
a.dose-dependent.downregulation.of.tissue.expression.
or.reduction.in.the.circulating.levels.of.cytokines,.metal-
17
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
loproteinases. (MMP-2,. MMP-9),. chemokines. and.
chemokine.receptors,.and.adhesion.molecules.and.their.
ligands.. . In. the. repeated. muscle. biopsies. of. patients.
with.dermatomyositis.who.improved.after.IVIg.therapy.
(Dalakas.et.al.1993).and.on.the.lymphocytes.or.sera.of.
GBS. patients. who. improved. after. infusion. with. IVIg.
(Sharief.MK.et.al.1999;.Damas.et.al.2001;.Senzaki.et.al.
2001;.Creange.et.al.2003).there.is.downregulation.in.a.
number. of. the. aforementioned. molecules. including.
ICAM-I,. LFA-1,. TNF-α,. IL1β,. TGF-β,. MHC,. IP-10,. Mig,.
MMP-2.and.MMP-9...Because.upregulation.of.cytokines.
and. chemokines. is. critical. in. the. immunoregulatory.
pathways.involved.in.almost.all.of.the.autoimmune.neu-
romuscular.diseases.in.which.IVIg.is.effective.(Dalakas.
1997b;.Stangel.et.al.1998),.a.downregulatory.effect.of.
these.molecules.by.the.infused.IVIg.is.pathogenetically.
relevant.(Table)...
MISCELLANEouS ACtIoNS tHAt MAy BE RELEVANt toAutoIMMuNENEuRoMuSCuLARDISEASESa) Modulation of T cell function and antigen recognition.
IVIg.contains.a.variable.amount.of.solubilized.CD�,.CD8,.
HLA-I. and. HLA-II. molecules. that. may. interfere. with.
antigen.recognition.by.T.cells.(Blasczyk.et.al.,.1993)...It.
also. contains. antibodies. that. recognize. a. highly.
conserved.peptide.sequence.of.the.α1.helix.of.the.HLA-
I.molecule.(Kaveri.et.al.,.1996)...These.antibodies.bind.to.
soluble. and. membrane-associated. HLA-I. . antigen. and.
may. theoretically. have. an. effect. on. inhibiting. CD8-
mediated. cytotoxicity,. a. process. relevant. to. several.T-
cell-mediated. autoimmune. neuromuscular. diseases,.
especially. polymyositis. (Dalakas. and..
Hohlfeld,.2003)...
b) Possible effect on remyelination.
Treatment. with. IVIg. suppresses. experimental. allergic.
encephalomyelitis. and. experimental. allergic. neuritis.
(Gabriel.et.al.1997),...probably.via.a.combined.effect.on.
the. immunoregulatory. network. mentioned. above...
Whether.it.also.enhances.remyelination.by.exerting.an.
effect.directly.on.the.myelin.sheath,.as.suggested.(van.
Engelson.et.al.199�),.remains.unclear...
c) Blockade of the death receptor Fas (CD 95)
Within.the.IVIg.preparations,.there.are.naturally.occuring.
Fas.(CD9�)-blocking.antibodies.(Prasad.et.al.1998).which.
may. be. relevant. in. explaining. the. action. of. IVIg. in.
diseases.where.Fas-mediated.tissue.destruction.plays.a.
pathogenic.role...In.one.study,.IVIg.completely.inhibited.
the.Fas-mediated.cell.death.by.blocking.the.Fas.receptor.
of. keratinocytes. in. vivo. and. on. lymphoblastoid. and.
hepatocarcinoma. cell. lines. in. vitro. (Viard. et. al. 1998)...
Whether.such.an.effect.is.relevant.in.the.efficacy.of.IVIg.
in.neuromuscular.disease.is.unclear.
d) Effect on Immunoregulatory genes
Genes. for. adhesion. molecules,. cytokines,. MHC,.
chemokines,.immunoglobulin.and.structural.proteins.are.
variably. upregulated. in. the. muscles. of. inflammatory.
myopathies.and.autoimmune.neuropathies. (Greenberg.
et.al.200�;.Raju.et.al.200�;.Renaud.et.al.200�)...Some.
of. these. genes. have. biological. relevance. as. demon-
strated.by.microarray.experiments.on.muscle.biopsies.
obtained. before. and. after. therapy. (Raju. et. al. 200�)...
Muscle.from.patients.with.DM.who.improved.after.IVIg.
infusions,.showed.alteration.of.2,206.genes;.in.contrast,.
1,700.of.the.same.genes.remained.unchanged.in.sIBM.
who.did.not.improve...Among.the.markedly.downregu-
lated. genes. in. DM,. but. not. sIBM,. were. IL-22,. KAL-1,.
ICAM-I,. Complement. C1q,. and. several. structural.
proteins...Examining.the.alterations.in.the.gene.profile.
of.tissues.and.lymphocytes.of.patients.with.CIDP,.GBS.
or.MG.after.IVIg,.may.help.us.understand.which.are.the.
biologically.relevant.genes.for.each.disease.and.predict.
which.patients.are.more.likely.to.respond.to.therapy.or.
what.genes.confer.resistance.to.IVIg.
18
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
REfERENCEsAbe.Y,.Horiuchi.A,.Miyake.M,.Kimura.S.. . (199�).. .Anti-
cytokine.nature.of.natural.human.immunoglobulin:.one.
possible.mechanism.of.the.clinical.effect.of.intravenous.
immunoglobulin.therapy...Immunol.Rev.139,.�-19...
Amemiya.K,.Semino-Mora.C,.Granger.RP,.Dalakas.MC...
(2000)..Downregulation.of.TGF-β1.mRNA.and.protein.in.
the.muscles.of.patients.with.inflammatory.myopathies.
after. treatment. with. high-dose. intravenous. immuno-
globulin...Clin.Immunol.9�,.99-10�.
Ankrust.P,.Muller.F,.Svenson.M,.Nordoy.I,.Bendtzen.K,.
Froland. SS.. . (1999).. . Administration. of. intravenous.
immunoglobulin.(IVIg).in.vivo.downregulatory.effects.on.
the.IL-1.system...Clin.Exp.Immunol.11�,.136-1�3.
Bain.PG,.Motomura.M,.Newsom-Davis.J,.et.al..(1996)...
Effects. of. intravenous. immunoglobulin. on. muscle.
weakness. and. calcium-channel. autoantibodies. in. the.
Lambert-Eaton. myasthenic. syndrome.. . Neurology.
�7:678-83.
Basta. M,. Dalakas. MC.. . (199�). High-dose. intravenous.
immunoglobulin. exerts. its. beneficial. effect. in. patients.
with.dermatomyositis.by.blocking.endomysial.deposition.
of.activated.complement. fragments.. .J.Clin. Invest.9�,.
1729-3�.
Basta.M,.Illa.I,.Dalakas.MC...(1996)...Increased.in.vitro.
uptake.of.the.complement.C3b.in.the.serum.of.patients.
with. Guillain. Barre’. syndrome,. myasthenia. gravis. and.
dermatomyositis...J.Neuroimmunol.71,.227-229.
Basta. M,. Kirshbom. P,. Frank. MM,. Fries. LF.. . (1989)...
Mechanisms. of. therapeutic. effect. of. high-dose.
intravenous. immunoglobulin.. . J. Clin. Invest. 8�,. 197�-
1981.
Bayry. J,. Lacroix-Desmazes. S,. Carbonneil. C,. Misra. N,.
Donkova.V,.Pashov.A,.Chevailler.A,.Mouthon.l,.Weill.B,.
Bruneval. P,. Kazatchkine. MD,. Kaveri. SV.. . (2003a)...
Inhibition.of.maturation.and.function.of.dendritic.cells.by.
intravenous.immunoglobulin...Blood.101,.7�8-76�.
.Bayry. J,. Lacroix-Desmazes. S,. Delignat. S,. Mouthon. L,.
Weill.B,.Kazatchkine.MD,.Kaveri.SV...(2003b)...Intravenous.
immunoglobulin. abrogates. dendritic. cell. differentiation.
induced.by.interferon-α.present.in.serum.from.patients.
with. systemic. lupus. erythematosus.. . Arthritis. Rheum.
�8,.3�97-3�02.
Blasczyk. R,. Westhoff. V,. Grosse-Wilde. H.. . (1993)...
Soluble. CD�,. CD8. and. HLA. molecules. in. commercial.
immunoglobulin.preparations...Lancet.3�1,.789-790.
Buchwald.B,.Ahangari.R,.Weishaupt.A,.Toyka.KV...(2002)...
Intravenous. immunoglobulins. neutralize. blocking.
antibodies. in.Guillain-Barré.syndrome.. .Ann.Neurol.�1,.
673-680.
Choi.Y,.Dalakas.MC.. .Expression.of.matrix.metallopro-
teinases. in. the. muscle. of. patients. with. Inflammatory.
Myopathies...Neurology..2000;��:6�-71.
Creange.A,.Gregson.NA,.Hughes.RA...(2003)...Intravenous.
immunoglobulin. modulates. lymphocyte. CD��. and.
monocyte. FCgammaRII. expression. in. patients. with.
chronic. inflammatory. neuropathies.. . J. Neuroimmunol.
13�,.91-9�.
Dalakas. MC.. . (1991).. . Polymyositis,. dermatomyositis.
and.inclusion-body.myositis...N.Engl.J.Med.32�,.1�87-
1�98...
Dalakas.MC...A.Therapeutic..Approach.to.Immunotherapy.
in. Inflammatory. Myopathies.. . In:. D.A.Drachman. (ed)...
Immunosuppressive. treatment. for. Neurologists,..
American.Academy.of.Neurology.Lecture.Series,.2�7:39-
�6;1993.
.Dalakas.MC...(199�c)...Basic.aspects.of.neuroimmunol-
ogy. as. they. relate. to. immunotherapeutic. targets:.
present. and. future. prospects.. . Ann. Neurol. 37,..
(S).2-13.
.Dalakas. MC.. . (1997b).. . Intravenous. immunoglobulin.
therapy.for.neurological.diseases...Ann.Intern.Med.126,.
721-730...
19
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
Dalakas. MC.. . (1998b).. . Mechanism. of. action. of.
intravenous. immunoglobulin. and. therapeutic. consider-
ations. in. the. Treatment. of. autoimmune. neurologic.
diseases...Neurology.�1(Suppl),.S2-S8.
.Dalakas.MC.. . (1999b).. . Intravenous. immunoglobulin. in.
the.treatment.of.autoimmune.neuromuscular.diseases:.
present. status. and. practical. therapeutic. guidelines...
Muscle.Nerve.22,.1�79-1�97.
Dalakas. MC,. Fujii. M,. Li. M,. et. al.. (2001).. . High-dose.
intravenous.immunoglobulin.for.Stiff-Person.Syndrome...
N.Engl.J.of.Med.3��:1870-1876.
Dalakas.MC...(2002a)...Blockade.of.blocking.antibodies.
in.Guillain-Barré.syndromes:.“unblocking”. the.mystery.
of. action. of. intravenous. immunoglobulin.. .Ann. Neurol.
�1,.667-669.
Dalakas. MC.. . (2002b).. . Mechanisms. of. action. of. IVIg.
and.therapeutic.considerations.in.the.treatment.of.acute.
and. chronic. demyelinating. neuropathies.. . Neurology..
�9(Suppl.6),.S13-21.
Dalakas.MC.. . (200�a).. . Intravenous.Immunoglobulin. in.
autoimmune. neuromuscular. Diseases.. . JAMA...
291:2367-237�.
Dalakas.MC.(200�b)...The.use.of.intravenous.immuno-
globulin. in. the. treatment. of. autoimmune. Neurological.
Disorders:.Evidence-based.indications.and.safety.profile...
Pharmacol.Therapeutics.102:177-193.
Dalakas.MC...(200�c)...Fifth.International.Symposium.of.
IVIg:.IVIg.in.the.third.millennium...Dalakas.MC,.Spath.PJ.
(Eds).UK...Parthenon.Publishers.
Dalakas.MC,. Illa. I,.Dambrosia.JM,.Soueidan.SA,.Stein.
DP,. Otero. C,. Dinsmore. ST,. McCrosky. S.. . (1993).. . A.
controlled.trial.of.high-dose.intravenous.immunoglobulin.
infusions.as. treatment. for.dermatomyositis.. .N.Engl. J.
Med.329,.1993-2000.
Dalakas. MC,. Quarles. RH,. Farrer. RG,. Dambrosia. J,.
Soueidan. S,. Stein. DP,. Cupler. EJ,. Sekul. EA,. Otero. C...
(1996)...A.controlled.study.of.intravenous.immunoglobu-
lin.in.demyelinating.neuropathy.with.IgM.gammopathy...
Ann.Neurol.�0,.792-79�.
Dalakas. MC,. Hohlfeld. R.. . (2003b).. . Polymyositis. and.
dermatomyositis...Lancet.362,.971-982.
Damas.JK,.Gullestad.L,.Aass.H,.et.al..(2001)...Enhanced.
gene.expression.of.chemokines.and.their.corresponding.
receptors. in. mononuclear. blood. cells. in. chronic. heart.
failure--modulatory.effect.of.intravenous.immunoglobu-
lin...J.Am.Coll.Cardiol...38:187-93.
De. Bleecker. JL,. De. Paepe. B,.Vanwalleghem. IE,. et. al..
(2002)...Differential.expression.of.chemokines.in.inflam-
matory.myopathies...Neurology.2�;�8:1779-8�.
Diegel.M...Rankin.B.Bolen.J...Dubois.P,.Kiener.P...(199�)...
Cross.linking.of.Fc.receptor.to.surface.immunoglobulin.
on.B.cells.provides.on. inhibitory.signal.that.closes.the.
plasma.membrane.calcium.channel...J.Biol.Chem.269,.
11�09-11�16.
Dietrich.G,.Kazatchkine.MD... (1990).. .Normal. immuno-
globulin. G. (IgG). for. therapeutic. use. (intravenous. Ig).
contains.anti-idiotypic.specificities.against.an. immuno-
dominant,.disease-associated,.cross-reactive.idiotype.of.
human.anti-thyroglobulin.autoantibodies.. . J.Clin. Invest.
8�,.620-9.
Dwyer. JM.. . Manipulating. the. immune. system. with.
immune.globulin...(1992)...N.Engl.J.Med..326,107-16.
Gabriel.CM,.Gregson.NA,.Redford.EJ,.Davies.M,.Smith.
KJ.. . RAC. Hughes.. . (1997).. . Human. immunoglobulin.
ameliorates.rat.experimental.allergic.neuritis...Brain.120,.
1�33-1��0.
Greenberg. SA,. Pinkus. JL,. Pinkus. GS,. et. al.. (200�)...
Interferon-alpha/beta-mediated. innate. immune.
mechanisms.in.dermatomyositis...Ann.Neurol.�7:66�-78.
20
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
Illa.I,.Ortiz.N,.Gallard.E,.Juarez.C,.Grau.JM,.Dalakas.MC...
Acute.axonal.Guillain.Barré.syndrome.with.IgG.antibodies.
against. motor. axons. following. parenteral. injection. of.
gangliosides...Ann.Neurol.38:218-22�;199�.
Jacobs. BC,. O'Hanlon. GM,. Bullens. RW,. et. al.. (2003)...
Immunoglobulins. inhibit. pathophysiological. effects. of.
anti-GQ1b-positive. sera. at. motor. nerve. terminals.
through. inhibition. of. antibody. binding.. . Brain. 126:.
2220-3�.
Kaveri.S,.Vassilev.T,.Hurex.V,.Lengagne.R,.Lefranc.C,.Cot.
S,.Pouletty.P,.Glotz.P,.Kazatchkine.MD.(1996).Antibodies.
to.a.conserved.region.of.HLA.class.I.molecules,.capable.
of.modulating.CD8.T.cell-mediated.function,.are.present.
in.pooled.normal.immunoglobulin.for.therapeutic.use...J.
Clin.Invest.97,.868-869.
Kazatchkine.MD,.Dietrich.G,.Hurez,.V,.Ronda.N,.Bellon.
B,. Rossi. F,. Kaveri. SV.. . (199�).. . V. region-mediated.
selection. of. autoreactive. repertoires. by. intravenous.
immunoglobulin...Immunol.Rev.139,.79-107.
Kazatchkine.MD,.Kaveri.SV...(2001)...Immunomodulation.
of. autoimmune. and. inflammatory. diseases. with.
intravenous.immune.globulin...N.Engl.J.Med.3��,.7�7-
7��.
Kieseier. BC,. Clements. JM,. Pischel. HB,. et. al.. (1998)...
MMP-9. and. MMP-7. are. expressed. in. experimental.
autoimmune. neuritis. and. the. Guillain-Barre. syndrome...
Ann.Neurol...1998.�3:�27-3�.
Kieseier.BC,.Dalakas.MC,.Hartung.HP...(2002)...Immune.
mechanisms. in. chronic. inflammatory. demyelinating.
neuropathy...Neurology.�9(Suppl.6),.S7-12.
Koffman.BM,.Dalakas.MC...(1997)...Effect.of.high-dose.
intravenous. immunoglobulin. on. serum. chemistry,.
hematology. and. lymphocyte. subpopulations:.
assessments. based. on. controlled. treatment. trials. in.
patients.with.neurological.diseases...Muscle.Nerve.20,.
1102-1107.
Malik. U.. . Oleksowicz. L,. Latov. N,. Cardo. LJ.. . (1996)...
Intravenous.y-globulin.inhibits.binding.of.anti-GMI.to.its.
target.antigen...Ann.Neurol.39,136-139.
Marchalonis. JJ,. Kaymaz. H,. Dedeoglu. F,. Schluter. SF,.
Yocum.DE,.Edmundson.AB.. . (1992).. .Human.autoanti-
bodies.reactive.with.synthetic.autoantigens.from.T.cell.
receptor.Vβ. chain.. . Proc.Natl.Acad.Sci.USA.89,. 332�-
3329.
Prasad. NK,. Papoff. G,. Zeuner. A,. et. al.. . Therapeutic.
preparations. of. normal. polyspecific. IgG. (IVIg). induce.
apoptosis. in. human. lymphocytes. and. monocytes:. a.
novel. mechanism. of. action. of. IVIg. involving. the. Fas.
apoptotic.pathway...J.Immunol.1998;161:3781-3790.
Raju.R,.Dalakas.MC.(200�)...Gene.expression.profile.in.
the.muscles.of.patients.with.inflammatory.myopathies:.
effect. of. therapy. with. IVIg. and. biologic. validation. of.
clinical.relevant.genes...Brain.128:1887-96.
Renaud. S,. Hays. AP,. Brannagan.TH. 3rd,. et. al.. (200�)...
Gene.expression.profiling.in.chronic.inflammatory.demy-
elinating.polyneuropathy..J.Neuroimmunol.1�9(1-2):203-
1�...
Rigal.D,.Vermot-Desroches.C,.Heitz.S,.Bernaud.J,.Alfonsi.
F,.Monier.JC...(199�)...Effect.of.IVIg.in.peripheral.blood.
B,. NK,. and. T. cell. subpopulations. in. women. with.
recurrent. spontaneous. abortions:. . specific. effect. on.
LFA-1.and.CD�6.molecules...Clin.Immunol.Immunopathol.
71,.309-1�.
Roux.KH,.Tankersley.DL...(1990)...A.view.of.the.human.
idiotypic. repertoire.. . Electron. microscopic. and.
immunologic. analyses. of. spontaneous. idiotype--anti-
idiotype.dimers.in.pooled.human.IgG...J.Immunol.1��,.
1387-92.
Samuelsson. A,.Towers.TL,. Ravetch. JV.. . (2001).. . Anti-
inflammatory. activity. of. IVIG. mediated. through. the.
inhibitory.Fc.receptor...Science.291,.�8�-�86.
21
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
Sekul. EA,. Cupler. EJ,. Dalakas. MC.. . (199�).. . Aseptic.
meningitis.associated.with.high-dose.intravenous.immu-
noglobulin. therapy:. frequency. and. risk. factors.. . Ann.
Intern.Med.121,.2�9-62.
Senzaki. H,. Masutani. S,. Kobayashi. J,. et. al.. (2001)...
Circulating.matrix.metalloproteinases.and.their.inhibitors.
in. patients. with. Kawasaki. disease.. . Circulation...
21;10�:860-3.
Sharief. MK,. Ingram. DA,. Swash. M,. et. al.. (1999).. . I.V...
immunoglobulin. reduces. circulating. proinflammatory.
cytokines. in. Guillain-Barre. syndrome.. . Neurology.
�2:1833-8.
Stangel. M,. Hartung. H-P,. Marx. P,. Gold. R.. . (1998)...
Intravenous. immunoglobulin. treatment. of. neurological.
autoimmune.diseases...J.Neurol.Sci.1�3,.203-21�.
Svenson.M,.Hansen.MB,.Bendtzen.K...(1993)...Binding.
of.cytokines.to.pharmaceutically.prepared.human.immu-
noglobulin...J.Clin.Invest.92,.2�33-9.
Takei. S,. Arora. YK,. Walker. SM.. . (1993).. . Intravenous.
immunoglobulin. contains. specific. antibodies. inhibitory.
of.activation.of.T.cells.by.staphylococcal.toxin.superanti-
gens...J.Clin.Invest.91,.602-607.
Tankersley. DL,. Preston. MS,. Finlayson. JS.. . (1988)...
Immunoglobulin. G. dimer:. an. idiotype--anti-idiotype.
complex...Mol.Immunol.2�,.�1-�8.
Uher. F,. Dickler. HB.. . (1986).. . Cooperativity. between. B.
lymphocytes.membrane.molecules:.independent.ligand.
occupancy.and.crosslinking.of.antigen.receptors.and.Fc.
gamma.receptors.downregulates.B.lymphocyte.function...
J.Immunol.137,.312�-3129.
van. Engelson. BGM,. Miller. DJ,. Pavelko. KD,. Hommes.
OR,.Rodriguez.M...(199�)...romotion.of.remyelination.by.
polyclonal. immunoglobulin. in. Theiler’s. virus-induced.
demyelination. and. in. multiple. sclerosis.. . J. Neurol.
Neuros.Psych.(Suppl).�7.Suppl,.6�-68.
Vassilev.T,. Gelin. C,. Kaveri. SV,. Xilber. MT,. Boumsell. L,.
Kazatchkine. MD.. . (1993).. . Antibodies. to. the. CD�.
molecule. in. Normal. Human. immunoglobulins. for.
therapeutic. use. (intravenous. immunoglobulins,. IVIg)...
Clin.Exp.Immunol.92,.369-72.
Viard. I,. Wehrli. P,. Bullani. R,. Schneider. P,. Holler. N,.
Salomon. N,. Hunziker.T,. Saurat. JH,.Tschopp. J,. French.
LE...(1998)...Inhibition.of.toxic.epidermal.necrolysis.by.
blockade. of. CD9�. with. human. intravenous. immuno-
globulin...Science.282,..�90-�93.
Yu.Z,.Lennon.VA.. . (1999).. .Mechanism.of. intravenous.
immune. globulin. therapy. in. antibody-mediated.
autoimmune.diseases...N.Engl.J.Med.3�0,.227-228.
Yuki. N,. Miyaga. F.. . (1996).. . Possible. mechanism. of.
intravenous. immunoglobulin. treatment. on. anti-GM1.
antibody-mediated.neuropathies...J.Neurol.Sci.139,160-
162.
Zhang.G,.Lopez.PH,.Li.CY,.et.al..(200�)...Anti-ganglioside.
antibody-mediated. neuronal. cytotoxicity. and. its.
protection.by.intravenous.immunoglobulin:.implications.
for.immune.neuropathies...Brain.127:108�-100.
22
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
GUILLAIN-BARRÉ SYNDROMEINtROdUCtIONThe. Guillain-Barré. syndrome. (GBS). is. the. commonest.
cause. of. acute. flaccid. paralysis. in. the. West,. and.
probably. in.other.parts.of. the.world.where.polio. is.no.
longer.endemic.. .Reported. incidences.vary.between.1.
to. �. per. 100,0002�.. .The. syndrome. typically. presents.
with. rapidly. progressive,. relatively. symmetrical,.
ascending.limb.weakness.consistent.with.a.polyradicu-
loneuropathy,. often. with. associated. cranial. nerve.
involvement.. . Motor. signs. and. symptoms. usually.
predominate.over.sensory.signs.and.symptoms...Loss.
of.tendon.reflexes.is.almost.ubiquitous...Major.compli-
cations. that. may. occur. include. respiratory. failure,.
autonomic. dysfunction. and. thromboembolism.. . The.
disease.is.monophasic,.reaching.its.nadir.usually.within.
2.weeks,.although.arbitrary.definition.accepts.a.limit.of.
�.weeks...A.plateau.phase.of.variable.duration.follows.
the.nadir.before.gradual.recovery...Although.recovery.is.
generally.good.or.complete.in.the.majority.of.patients,.
persistent.disability.has.been.reported.to.occur.in.about.
20%36,.and.death.in.�.to.1�%.of.patients37,.�1,.�2,.�6,.�9.
. It.is.now.generally.recognized.that.there.are.several.
subtypes. of. the. disease�.. .The. most. common. form,.
classic.GBS.(or.acute.inflammatory.demyelinating.poly-
neuropathy,.AIDP),.is.characterized.by.segmental.demy-
elination.in.peripheral.nerves...An.axonal.variant.without.
demyelination10,. 32,. either. in. the. form. of. acute. motor.
axonal.neuropathy.(AMAN).with.pure.motor.involvement.
or.acute.motor.and.sensory.axonal.neuropathy.(AMSAN).
with.mixed.sensorimotor.involvement,.has.been.distin-
guished.from.AIDP...The.Miller.Fisher.syndrome.variant.
is.defined.by.the.clinical.triad.of.extra-ocular.weakness,.
areflexia.and.ataxia...Other.much.less.common.variants.
have. also. been. related. to. GBS,. including. a. pharyngo-
cervico-brachial. variant,. pure. sensory. GBS. and. acute.
pandysautonomia.
. Significant. advances. have. been. made. in. under-
standing. the. immunopathogenesis. of. GBS.. .There. is.
evidence. of. a. primary. humoral. immune. reaction,.
involving.complement.activation,.targeted.at.peripheral.
nerve. components. in. Schwann. cell. membrane. or.
myelin,. and. in. the. axolemma,. with. the. target. sites.
correlating. with. AIDP. and. AMAN. respectively13,. 17,. 18...
High. titers. of. antibodies. to. gangliosides,. which. are.
common.components.of.Schwann.cell.and.neuronal.cell.
membranes,. have. been. associated. with. subtypes. of.
GBS,.eg...anti-GQ1b.ganglioside.IgG.with.MFS,.and.anti-
GDIa/anti-GM1.ganglioside.IgG.with.AMAN�2...Specific.
antecedent.infections,.namely.Campylobacter.jejuni.(C...
jejuni),.Mycoplasma.pneumoniae,.Epstein-Barr.virus.and.
23
GUILLAIN-BARRÉ SYNDROME
cytomegalovirus,. have. been. associated. with. GBS. in. a.
case.control.study27...Similarly,.C...jejuni.and.Haemophilus.
influenza. (H.. . influenza). have. been. associated. with.
MFS29.. . In. the. case. of. C.. . jejuni. infections,. the.
association.of.infection.with.GBS.was.further.correlated.
with. raised. anti-GM1b. and. anti-GalNac-GD1a. IgG.
antibodies...Ganglioside-like.epitopes.reactive.with.anti-
GM1.or.GQ1b.ganglioside.antibodies.have.been.shown.
to.exist.in.cell.wall.lipopolysaccharide.of.C...jejuni.and.H...
influenza.. . These. findings. support. the. hypothesis. of.
"molecular.mimicry".as.the.basis.of.the.immune.reaction.
in. GBS,. whereby. an. immune. reaction. directed. at.
specific. antigens.of. infectious. agents. cross-react.with.
components. of. Schwann. cell/myelin. or. axolemma. to.
result.in.a.specific.subtype.of.GBS.
. For. the. more. common. classic.AIDP. form. of. GBS,.
diagnosis.rests.primarily.on.a.consistent.clinical.picture.
that. is. supported. by. electrodiagnostic. evidence. of. an.
acquired,. generally. multifocal,. demyelinating. polyneu-
ropathy.. . Absent. demyelinating. and. prominent. axonal.
electrodiagnostic. findings. with. a. consistent. clinical.
picture.may.suggest.the.axonal.form.of.GBS...However,.
the.diagnosis.of. sporadic. cases.of.AMAN.or.AMSAN,.
outside.of.endemic.areas,.is.generally.more.problematic,.
requiring. exclusion. of. alternate. diagnoses. and. clinical.
follow. up.. .The. diagnosis. of. MFS. is. largely. based. on.
consistent.signs.and.symptoms...While.anti-ganglioside.
antibodies.generally.have.limited.diagnostic.application,.
specific. antibodies. can. be. useful,. especially. anti-GM1.
and. anti-GDIa. antibodies. in. AMAN,. and. anti-GQ1b.
antibodies. in. MFS. and. variants. of. MFS.. . CSF..
examination.to.look.for.cytologic-albumin.dissociation.is.
useful.mainly.to.exclude.alternative.diagnoses,.especially.
infections.
tREatMENt IN GBsThree.treatments.have.been.extensively.studied.in.GBS.
-.corticosteroid.therapy,.plasma.exchange.and.IVIG...Of.
these,.plasma.exchange.and.IVIG.have.been.shown.to.
be. effective,. while. repeated. studies. have. not. demon-
strated. a. beneficial. effect. from. steroid. therapy.. .Two.
other. treatments,. interferon-beta. and. immunoabsorp-
tion,. have. also. been. studied. in. GBS.. . Interferon-beta.
showed.no.benefit. in. a. small. randomized. trial38,.while.
immunoabsorption,.which.is.not.generally.available,.has.
not. revealed.clear.benefit. in. two.studies8,.19.. .They.will.
not.be.discussed.further.in.this.review.
CoRtICoStERoIDtHERAPyThe. first. randomised. controlled. trial. of. low. dose. oral.
prednisolone. showed. no. significant. benefit. and.
suggested. that. the. patients. receiving. prednisolone.
fared.worse21...The.latest.and.largest.of.the.studies1�,.a.
double.blind.and.randomised.study,.compared.IV.meth-
ylprednisolone. �00. mg. daily. +/-. PE. for. �. days. with.
placebo. +/-. PE.. . No. significant. difference. in. outcome.
between. the. treatment. groups. was. demonstrated. in.
this.study...A.Cochrane.review.of.six.randomized.trials.
involving.different.regimens.that.included.ACTH,.meth-
ylprednisolone.and.oral.prednisone.or.prednisolone,.and.
including.these.two.trials,.found.no.significant.difference.
in.outcome.between.the.patients. receiving.corticoste-
roid.and.control.patients2�.
PLASMAExCHANGEFollowing. the. encouraging. but. inconsistent. results. of.
several. small. studies,. a. large. open,. randomized. North.
American. trial. compared. PE. with. supportive. care. in. a.
large. number. of. GBS. patients. with. onset. within. �.
weeks.and. limitation.or. loss.of.ambulation��.. .The. trial.
showed. primary. and. secondary. outcome. measures.
were. significantly. better. in. treated. patients. than. in.
controls.. . Treated. patients. also. showed. significantly.
faster. recovery.of. function.. .These. findings.were. sub-
stantiated.by.a.large.French.study.which.showed.similar.
results11,.12.. .Following.these.reports.in.the.mid-1980's,.
PE.was. rapidly. adopted.as. the.standard. treatment. for.
GBS.with.significant.weakness.impairing.ambulation,.at.
least. until. the. advent. of. IVIG. trials. in. GBS.. . Meta-
analysis.by.a.Cochrane.systemic.review.of.six.PE.trials.
showed. results. consistent. with. these. two. leading.
studies�0...In.addition,.there.was.evidence.from.some.of.
these. studies. that. PE. treatment. reduced. the. cost. of.
treatment.for.GBS.compared.to.supportive.care.
IVIGCase. reports. that. IVIG. improved.patients.with. chronic.
inflammatory. demyelinating. polyneuropathy. led. to. its.
2�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
application.in.small.series.of.GBS.patients.followed.by.
several.large.randomised.trials...Analysis.of.IVIG.trials.in.
GBS.is.provided.by.reviews.from.the.Cochrane.Database.
of.Systemic.Reviews,.the.latest.versions23,.updating.an.
earlier. version22. and. a. review. from. the. Quality..
Standards. Subcommittee. of. the. American. Academy..
of.Neurology26.
a. Comparisonof IVIGwithplaceboor supportive
treatmentonly
No.trials.comparing. IVIG.with.placebo.were. identified...
Two. trials. comparing. IVIG. with. supportive. treatment.
alone1�,.30.and.three.related.studies.involving.retrospec-
tive.analysis.were.identified28,.�3,.��...However,.all.involved.
only.children,.with. few.participants.and/or.problematic.
methodology.. . Hence,. even. though. a. beneficial. effect.
was. indicated,. the. evidence. is. inadequate. and. cannot.
also. be. generalized. to. adults.. . These. studies. are..
further. reviewed. under. the. “IVIG. in. children. with..
GBS”.section.
b. ComparisonofIVIGwithPlasmaExchange(PE)
As.noted.above,.prior.to.the.conduction.of.randomised.
trials. of. IVIG,. PE. had. been. shown. to. be. beneficial. in.
GBS.. . Thus,. in. studying. the. use. of. IVIG. in. GBS,. it..
was. obligatory. to. compare. IVIG. with. PE. as. the.
established.treatment.
. Three. leading. class. I. randomised. controlled. trials.
compared.IVIG.with.PE6,.36,.�7...Patients.entering.the.trials.
had.similar,. though.not.precisely. the.same.degrees.of.
severity.-.either.with.difficulty.or. loss.of.ambulation.or.
inability. to.perform.manual.work.. .They.entered. these.
trials.early.in.the.disease,.within.2.weeks.of.onset...The.
results. of. all. three. trials. indicated. that. improvement.
from. IVIG. and. PE. was. equal. and. not. significantly.
different...Meta-analysis.of.two.of.the.trials22,.26.showed.
the. weighted. mean. difference. was. 0.11. more.
improvement.of.disability.grade.in.the.IVIG.group.than.
the.PE.group...The.other.trial,.which.was.not.included.in.
the.meta-analysis.because.of.unavailable.data,.showed.
a. mean. 1.2. grades. of. improvement. in. the. IVIG. group.
compared.with.1.0.grade.in.the.PE.group...Thus,.all.three.
trials.showed.a.trend.in.favor.of.IVIG.compared.to.PE,.
although.the.differences.were.not.significant.in.all...The.
updated. Cochrane. review23. identified. three. additional.
trials8,.3�,.�1.to.the.three.above,.but.one.of.these�1.was.not.
included.in.the.analysis.as.it.lacked.information.on.quality.
criteria. and. required. outcome. measures.. . In. another.
trial3�,.which.was.included.in.the.analysis,.the.method.of.
PE.included.ultrafiltration,.centrifugation.and.immunoab-
sorption...Meta-analysis.of.the.five.trials6,.8,.3�,.36,.�7.showed.
0.0�.disability.grade.more. improvement.with. IVIG. than.
with.PE,.i.e...a.similar.conclusion.of.equal.improvement.
in.IVIG.compared.to.PE.
. With.secondary.outcome.measures,.namely.time.to.
walk. unaided,. time. to. discontinuation. of. ventilation,.
proportion.deceased.or.severe.disabled.after.12.months,.
there.was.also.no.significant.differences.between.IVIG.
and. PE.. . Data. for. the. first. two. indices. were. only.
available.from.two.trials36,.�7,.and.for.the.third.index.from.
one. trial36.. . Among. five. of. the. trials. included. in. the.
updated. Cochrane. review,. there. were. more. adverse.
events. in. the. PE. group. than. the. IVIG. group. in. all,.
although. a. significant. difference. was. achieved. only. in.
one. trial�7.. . Meta-analysis. of. three. trials3�,. 36,. �7. found..
the. risk. of. patients. discontinuing. treatment. was..
0.11. less. in. the. IVIG. than. the. PE. group,. a. highly.
significant.difference...
c. IVIGinCombinationTreatments
i.. .Comparison of combined PE and IVIG with PE alone
and IVIG alone
One. blinded. randomised. trial. compared. combined. PE.
and. IVIG.treatment. (i.e.. .PE.followed.by. IVIG).with.PE.
alone.and.with.IVIG.alone36...No.significant.benefit.was.
demonstrated. for. the. combined. treatment. group.
compared. to. either. of. the. single. treatment. groups...
Although.there.was.a.trend.towards.more.improvement.
in.the.patients.receiving.both.treatments,.the.differences.
were.not.significant...More.complications.of.treatment.
were.reported.in.the.combined.treatment.group.
ii.. .Comparison of combined methylprednisolone and
IVIG with IVIG alone
A. recent. trial. compared. combined. IV. methylpredniso-
lone. and. IVIG. treatment. with. IVIG. alone. in. GBS,.
following. a. pilot. study. that. suggested. it. may. have. a.
2�
GUILLAIN-BARRÉ SYNDROME
beneficial.effect...However,.the.double-blind,.controlled.
randomised. trial. did. not. show. a. significant. difference.
between.the.two.treatments�8.
d. FurtherIssuesofIVIGtreatmentinGBS
i.. .Relapse, lack of response or worsening
following IVIG
About.10%.of.GBS.patients. treated.with. IVIG.demon-
strated.secondary.worsening.after.a.period.of.stabiliza-
tion.and. improvement.. .Such. relapses.appeared. to.be.
associated. with. a. more. prolonged. progression. of. the.
disease.. . They. responded. again. to. a. second. similar.
treatment�0.
. About.2�%.of.patients.will.fail.to.improve.immediately.
following.a.first.course.of.IVIG.and.may.even.continue.
to.deteriorate...The.value.of.a.second.course.of.IVIG.or.
a.course.of.PE.in.such.patients.has.not.been.established.
by.controlled.studies.
ii. IVIG in children with GBS
Children.were.excluded. from.most. trials. of. therapy. in.
GBS,.including.those.described.above.under.(b).and.(c)...
However,.there.are.several.studies.with.relatively.small.
numbers.of.children.that.compared.IVIG.with.supportive.
treatment1�,.28,.30,.�3,.��.. .Only.two.of.these.studies.were.
prospective. studies1�,. 30,. with. the. remaining. studies.
employing. retrospective. analysis.. . All. the. studies.
indicated. a. beneficial. effect. of. IVIG. compared. to. non-
treatment,.but.the.significance.of.their.findings.remains.
limited. by. the. small. number. of. study. subjects. or.
problems. with. methodology.. . The. updated. Cochrane.
review.of.IVIG.versus.PE23.identified.a.randomized.trial.
in.children�1.comparing. IVIG.plus.dexamethasone.with.
PE. plus. dexamethasone,. and. with. dexamethasone.
alone...As.mentioned.above,.the.review.did.not.include.
it. in. its. analysis. as. critical. data. was. not. available,..
a. limitation. that. also. prevents. further. comments. of..
this.trial.
iii.. .IVIG in mild GBS.
IVIG in GBS lasting longer than two weeks
No.randomised.trials.have.been.reported.on.the.use.of.IVIG.in.
mild.GBS.or.in.GBS.that.has.lasted.more.than.two.weeks.
iv. IVIG in GBS in pregnancy
There.are.only.case.reports.of.IVIG.use.in.GBS.occurring.
in.pregnancy...A.total.of.eight.reports.were.identified1,.7,.9,.
reporting.examples.of.rapid.recovery.as.well.as.continued.
progression. or. persistent. severe. disability. following.
IVIG.. . . One. case. of. neonatal. GBS. was. born. to. an.
affected. mother. who. received. IVIG31.. .The. baby,. who.
required.mechanical.ventilation,.responded.to.IVIG.with.
recovery. within. 2. weeks.. . No. complications. of. IVIG.
treatment.in.mother.or.baby.were.reported...There.are.
no.studies.comparing. the.use.of. IVIG.with.PE. in.GBS..
in.pregnancy.
v. IVIG in variants of GBS
The. trials. described. above. under. (b). and. (c). generally.
used.a.clinical.definition.of.GBS3,.�.for.case.inclusion.that.
did. not. specifically. distinguish. between. the. common.
demyelinating. form. of. GBS. and. its. variants,. including.
axonal.forms,.although.classic.MFS.without.significant.
weakness. would. have. been. excluded.. . No. controlled.
trials.are.reported.that.specifically.examined.the.use.of.
IVIG.in.AMAN,.MFS.or.dysautonomia.
. However,. in. the. trial. comparing. combined. PE. and.
IVIG.with.PE.or.IVIG.alone,.patients.were.classified.into.
sub-groups. by. nerve. conduction. criteria16.. . Outcome.
response.to.the.three.treatments.did.not.differ.among.
these.sub-groups,.which.included.demyelinating,.axonal.
and. pure. motor. variants,. and. those. with. inexcitable.
nerves.. . This. result. suggests. that. the. response. of.
axonal.variants.and.AMAN.to.IVIG.may.be.similar.to.the.
common.demyelinating.form.of.GBS...Interesting,.in.an.
animal. model. of. AMAN,. treatment. with. homologous.
IVIG.resulted.in.faster.recovery.compared.saline3�.
. Uncontrolled. studies. examining. IVIG. response. in.
small. numbers. of. MFS. patients. reported. beneficial.
results,.although.MFS.patients.in.these.studies.included.
those. with. motor. involvement2.. . As. MFS. with. no..
motor. involvement. is. generally. reported. to. have. a..
26
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
good. prognosis,. the. value. of. IVIG. in. such. cases..
remains.unresolved.
. Anecdotal.reports.of.good.response.of.acute.dysau-
tonomia.to.IVIG.are.documented20,.33.
EXpERt CONsENsUsa. IVIGuseinGBS
i.. .GBS with significant or severe involvement seen
within 2 weeks
IVIG.use.is.recommended.as.therapy.for.GBS.patients.
with. significant. involvement.. . For. example,. patients.
who.require.an.aid.to.walk,.those.with.impaired.bulbar.
or.ventilatory.function,.those.who.appear.to.be.rapidly.
deteriorating,. or. worse.. . Individuals. with. difficulties. in.
performing. activities. of. daily. living. should. also. be.
considered. for. IVIG. therapy.. . Treatment. should. be.
initiated.early,.i.e...within.2.weeks.of.onset...Considering.
its.relative.ease.of.administration,.lower.side.effects.and.
complications. and. similar. cost. when. compared. to. PE,.
IVIG.is.often.considered.the.therapy.of.first.choice.
ii.. .Mild GBS
GBS seen more than 2 weeks after onset
Although. little. or. no. evidence. is. available. for. IVIG.
therapy.in.mild.GBS.or.in.GBS.seen.more.than.2.weeks.
after.onset,.its.use.may.be.considered.according.to.an.
assessment.of.potential.benefits.from.treatment.versus.
clinical.risks,. i.e.. .cost.and.adverse.effects.of.IVIG.and.
the. subjective. clinical. assessment. of. progression. and.
disability.. . Mild. GBS. usually. recovers. well. without.
treatment,.although.the.time.to.full.functional.recovery.
may.be.an.important.factor...Treatment.with.IVIG.in.GBS.
beyond.two.weeks.of.onset.may.be.considered.if.dete-
rioration. continues. or. disability. is. severe,. even. if.
response.may.not.be.as.good...Benefit.from.IVIG.given.
>�.weeks.from.onset.of.symptoms.is.doubtful.
iii. Childhood GBS
The.effectiveness.of.IVIG.in.children.with.GBS.has.only.
been.shown.in.two.small.quasi-randomised.studies.and.
several. retrospective. studies.. . Nevertheless,. its. use.
should. be. considered. in. children. with. significant. or.
severe. involvement.. . Indeed,. for. many. pediatric.
practices,. IVIG. has. become. the. treatment. of. choice.
over. PE. in. childhood. GBS,. owing. particularly. to. its.
relative.ease.of.access.and.administration.
iv. GBS in pregnancy
The.value.of.IVIG.in.GBS.in.pregnancy.remains.unclear.
as.only.case.reports.are.available...However,.in.view.of.
its.proven.efficacy.in.adult.GBS,.its.good.safety.record.
in. pregnancy. and. its. ease. of. administration,. it. is.
reasonable. to. consider. IVIG. in. pregnant. women. with.
significant.or.severe.GBS.
v. GBS variants
AMAN/AMSAN
Miller.Fisher.Syndrome
Acute.pandysautonomia
While. evidence. of. benefit. from. controlled. trials. with.
IVIG. is. lacking.for.all. these.variants.of.GBS,. treatment.
with.IVIG.should.be.considered.in.these.variants.using.
the.same.clinical.criteria.as.described.above.of.severe.
or.significant.symptoms...In."pure".MFS.without.motor.
involvement,. the. use. of. IVIG. remains. unresolved. and.
controversial. in. view. of. the. generally. good..
prognosis.reported.
b.. .When to use other therapy instead of IVIG
inGBS
i.. .PE
As.IVIG.and.PE.have.shown.equal.efficacy,.the.preference.
of.one. treatment.over. the.other. is.generally.based.on.
issues.of.availability,.practicality,.convenience,.cost.and.
ease.or.safety.of.administration.
. In. practice,. the. relative. ease. and. safety. of. IVIG.
administration. compared. to. PE,. has. generally. made.
IVIG.the.preferred. treatment.. .However,. there.may.be.
situations.when.PE.is.preferred.or.indicated,.eg.:
1.. .Contraindication. to. IVIG. use,. eg.. . low. IgA,..
previous.allergy
2.. .Intolerance.or.serious.side.effects.of.IVIG.use
27
GUILLAIN-BARRÉ SYNDROME
3.. .Lack.of.availability.of.IVIG.with.PE.available
ii. Steroid
Steroids. should. not. be. used. in. GBS. and. are..
not.recommended..The.combination.of.methylpredniso-
lone.and.IVIG.is.also.not.recommended.
c. Recommendeddoseanddurationofinfusionof
IVIGinGBS
The.standard. total. dose. for. a. course.of. IVIG. is.2g/kg...
Conventionally,.this.is.given.as.0.�.g/kg/day.for.five.days,.
in.accordance.with.the.large.controlled.trials.comparing.
IVIG.with.PE...However,.many.centers.now.use.a.course.
of. 1. g/kg/day. over. two. days,. for. faster. and. more.
convenient.administration...A.study.in.children.comparing.
the. two. courses. showed. no. difference. in. recovery,.
although. secondary. transient. deterioration. in. disability.
scores. occurred. more. frequently. with. the. shorter.
course30...With.patients.at.risk.from.infusion.of.a.large.
hyperosmolar.volume,.eg...patients.with.cardiac.or.renal.
impairment,. care.should.be.exercised. in.using.shorter.
courses.of.infusion.
. A. small. trial. among. patients. requiring. ventilation.
suggested.that.a.six.day.IVIG.course.of.0.�g/kg/day.was.
more.effective. than. three.days39.. .While. this.suggests.
that.the.dose.should.not.be.lower.than.the.conventional.
2.gm.total.dose,.it.remains.unclear.if.a.higher.total.dose.
will.be.more.efficacious.
d. Recommended treatment for early relapse or
lackofresponse
A. second. course. of. IVIG. should. be. considered. in.
patients.who.show.relapse.following.initial.stabilization.
or.improvement.after.the.first.course.
. The.value.of.a.second.IVIG.course.in.patients.who.
fail.to.respond.to.the.first.course.is.doubtful...A.course.
of.PE.may.be.considered.in.these.cases.although.there.
is.no.clear.data.that.this.is.beneficial.
e. Combinationtherapy
Sequential.treatment.with.PE.followed.by.IVIG.does.not.
have. a. superior. effect. to. either. treatment. given. alone.
and.is.not.recommended.
REfERENCEs1.. .Agboola. O. and. Blott. M,. . Guillain. Barré. disease. in.
pregnancy. treated. with. intravenous. immunoglobu-
lin...J.Obstetrics.Gynaecology.2000;.20:�3�-�36.
2.. .Arakawa.Y,.Yoshimura. M,. Kobayashi. S,. Ichihashi. K,.
Miyao.M,.Momoi.MY.and.Yanagisawa.M...The.use.of.
intravenous.immunoglobulin.in.Miller.Fisher.syndrome...
Brain.&.Development.1993;.1�:.231-233.
3.. .Asbury. AK. and. Cornblath. DR,. . Assessment. of.
current. diagnostic. criteria. for. Guillain-Barré syndrome...Ann.Neurol.1990;.27(suppl):S21-S2�.
�.. .Asbury. AK.. . Diagnostic. considerations. in. Guillain-
Barré.syndrome...Ann.Neurol.1981;.9:.Suppl:.1-�.
�.. .Asbury. AK.. . New. concepts. of. Guillain-Barré.
syndrome...J.Child.Neurol.2000;.1�:.183-191.
6.. .Bril.V,.Use.WK,.Pearce.R,.Dhanani.A,.Sutton.D.and.
Kong.K...Pilot.trial.of.immunoglobulin.versus.plasma.
exchange. in.patients.with.Guillain-Barré.syndrome...
Neurology.1996;.�6:100-103.
7.. .Chan.LY,.Tsui.MH,.Leung.TN...Guillain-Barré.syndrome.
in. pregnancy.. . Acta. Obstet. Gynecol. Scand. 200�;.
83:319-32�.
8.. .Diener.H-C,.Haupt.WF,.Kloss.TM,.Rosenow.F,.Philipp.
T,. Koeppen. S.. . A. preliminary,. randomized. study.
comparing. intravenous. immunoglobulin,. plasma.
exchange,.and. immune.absorption. in.Guillain-Barré.
syndrome.. . European. Neurology. . 2001;. �6:. 107-
109...
9.. .Fait. G,. Gull. I,. Kupferminc. M,. Shenhav. M,. Gold. R,.
Jaffa. A. and. Lessing. JB.. . Intravenous. immune.
globulins.in.Guillain-Barré.syndrome.in.pregnancy...J.
Obstetrics.Gynaecology.1998;.18:78-79.
28
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
10...Feasby.TE,. Gilbert. JJ,. Brown.WF,. Bolton. CF,. Hahn.
AF,.Koopman.WF,.Zochodne.DW.. .An.acute.axonal.
form.of.Guillain-Barré.polyneuropathy.. .Brain.1986;.
109:.111�-1126.
11.. .French. Cooperative. Group. in. Plasma. Exchange. in.
Guillain-Barré. Syndrome.. . Efficiency. of. plasma.
exchange. in. Guillain-Barré. . syndrome:. role. of.
replacement.fluids...Ann.Neurol.1987;.22:.7�3-761.
12...French. Cooperative. Group. in. Plasma. Exchange. in.
Guillain-Barré. . Syndrome.. . Plasma. exchange. in.
Guillain-Barré. syndrome:. one. year. follow-up.. . Ann.
Neurol.1992;.32:.9�-97.
13...Griffin. JW,. Li. CY,. HoTW,. et. al.. . Guillain-Barré.
syndrome.in.northern.China...The.spectrum.of.neu-
ropathological. changes. in. clinically. defined. cases...
Brain.199�;.118:�77-�9�.
1�...Guillain-Barré. Syndrome. Steroid. Trial. . . Group...
Double-blind.trial.of.intravenous.methylprednisolone.
in.Guillain-Barré.syndrome.. .Lancet.1993;.3�1:�86-
�90.
1�...Gurses.N,.Uysal.S,.Cetinkaya.F,. Islek. I,.Kalayci.AG...
Intravenous. immunoglobulin. treatment. in. children.
with. Guillain-Barré. syndrome.. . Scand. J. Infect. Dis.
199�;.27:.2�1-2�3.
16...Madden.RDM,.Cornblath.DR,.Hughes.RAD,.Zielasek.
J,.Hartung.H-RToyka.KV,.Swan.AV,.and. the.Plasma.
Exchange/Snadoglobulin. Guillain-Barré. Syndrome.
Trial. Group.. . Electrophysiological. Classification. of.
Guillain-Barre. Syndrome:. Clinical. Associations. and.
Outcome...Ann.Neurol.1998;.��:780-788.
17.. .Hafer-Macko.C,.Hsieh.ST,.Li.CY,.et.al...Acute.motor.
axonal.neuropathy:.an.antibody-mediated.attack.on.
axolemma...Ann.Neurol.1996;.�0:.63�-6��.
18...Hafer-Macko.CE,.Sheikh.KA,.Li.CY,.et.al.. . Immune.
attack.on.the.Schwann.cell.surface.in.acute.inflam-
matory.demyelinating.polyneuropathy.. .Ann.Neurol.
1996;.39:.627-637.
19...Haupt.WF,. Rosenow. F,. van. der.Ven. C,. Borberg. H,.
Pawlik. G.. . Sequential. treatment. of. Guillain-Barré.
syndrome. with. extracorporeal. elimination. and.
intravenous. immunoglobulin.. . J. Neurol. Sci. 1996;.
137:1��-1�9.
20...Heafield.MT,.Gammage.MD,.Nightingale.S,.Williams.
AC.. . Idiopathic. dysautonomia. treated. intravenous.
gammaglobulin...Lancet.1996;.3�7:.28-29.
21.. .Hughes.RAC,.Newsom-Davis.JM,.Perkin.GD,.Pierce.
JM.. .Controlled. trial.of.prednisolone. in.acute.poly-
neuropathy...Lancet.1978;.2:7�0-7�3.
22...Hughes. RA,. Raphael. JC,. Swan. AV,. Doorn. PA...
Intravenous. immunoglobulin. for. Guillain-Barré.
syndrome...Cochrane.Database.Syst.Rev...2001;(2):
CD002063.
23...Hughes. RA,. Raphael. JC,. Swan. AV,. Doorn. PA...
Intravenous. immunoglobulin. for. Guillain-Barré.
syndrome...Cochrane.Database.Syst.Rev...200�;(1):
CD002063..and.2006;.(1):CD002063.
2�...Hughes.RAC,.Rees.JH...Clinical.and.epidemiological.
features. of. Guillain-Barré. syndrome.. . J. Infect. Dis.
1997;.176(suppl2):.S92-S98.
2�...Hughes.RAC,. van.der.Meche.FGA.. .Corticosteroid.
treatment. for. Guillain-Barré. syndrome.. . Cochrane.
Database.Syst.Rev.2000;(2):CD001��6.. .Update. in.
Cochrane.Database.Syst.Rev.2000;(3):CD001��6.
26...Hughes. RAC,.Wijdicks. EFM,. Barohn. R,. Benson. E,.
Cornblath. DR,. Hahn. AF,. Meythaler. JM,. Miller. RG,.
Sladky. JT. and. Stevens. JC.. . Practice. parameter:.
Immunotherapy. for. Guillain-Barré. syndrome.
Neurology.2003;.61:.736-7�0.
29
GUILLAIN-BARRÉ SYNDROME
27.. .Jacobs. BC,. Rothbarth. PH,. van. der. Meche. FG,.
Herbrink.P.Schmitz.PI,.de.Klerk.MA,.van.Doom.PA...
The. spectrum. of. antecedent. infections. in. Guillain-
Barré.syndrome...A.case.control.study.. .Neurology.
1998;.�1:.1110-111�.
28...Kanra.G,.Ozon.A,.Vaisar.J,.Castagna.L,.Secmeer.G,.
Topaloglu.H...Intravenous.immunoglobulin.treatment.
in. children. with. Guillain. Barré. syndrome.. . Eur. J.
Paediatr.Neurol.1997;.1:7-12.
29...Koga. M,. Gilbert. M,. Li. J,. Koike. S,. Takahashi. M,.
Furukawa.K,.Hirata.K,.Yuki.N...Antecedent.infections.
in. Fisher. syndrome:. a. common. pathogenesis. of.
molecular.mimicry...Neurology.200�;.6�:160�-1611.
30...Korinthenberg.R,.Schessl.J,.Kirschner.J,.Monting.JS...
Intravenously. administered. immunoglobulin. in. the.
treatment. of. childhood. Guillain-Barré. syndrome:. a.
randomized.trial...Pediatrics.200�;.116:8-1�.
31.. .Luijckx.GJ,.Vles.J,.de.Baets.M,.Buchwald.B,.Troost.
J...Guillain-Barré.syndrome.in.a.mother.and.newborn.
child...Lancet.1997;.3�9:27.
32...McKhann. GM,. Cornblath. DR,. Griffin. JW,. et. al...
Acute.motor.axonal.neuropathy:.a.frequent.cause.of.
acute. flaccid.paralysis. in.China.. .Ann.Neurol.1993;.
33:333-3�2.
33...Mericle.RA.and.Triggs.WJ...Treatment.of.acute.pan-
dyautonomia. with. intravenous. immunoglobulin.. . J.
Neurol.Neurosurg.Psychiatry.1997;.62:�29-�31.
3�...Nishimoto.Y,. Koga. M,. Kamijo. M,. Hirata. K,.Yuki. N...
Immunoglobulin. improves. a.model. of. acute.motor.
axonal. neuropathy. by. preventing. axonal. degenera-
tion...Neurology.200�;.62:.1939-19��.
3�...Nomura. T,. Hamaguchi. K,. Hosakawa. T,. Hattori. T,.
Satou.T,.Mannen.T,.et. al.. .A. randomized.controlled.
trial. comparing. intravenous. immunoglobulin. and.
plasmapheresis. in. Guillain-Barré. syndrome...
Neurological.Therapeutics.2001;.18:.69-81.
36...Plasma. Exchange/Sandoglobulin. Guillain-Barré.
Syndrome.Trial.Group.. .Randomised.trial.of.plasma.
exchange,. intravenous. immunoglobulin,. and.
combined. treatments. in. Guillain-Barré. syndrome...
Lancet.1997;.3�9:.22�-230.
37.. .Prevots. DR,. Sutler. RW.. . Assessment. of. Guillain-
Barré. syndrome. mortality. and. morbidity. in. the.
United.States:.implications.for.acute.flaccid.paralysis.
surveillance...J.Infect.Dis.1997;.17�(suppl.1):.S1�1-
S1��.
38...Pritchard.J,.Gray.IA,.Idrissoya.ZR,.Lecky.BR,.Sutton.
IJ,.Swan.AV,.Willison.HJ,.Winer.JB,.Hughes.RA...A.
randomized.controlled.trial.of.recombinant.interferon-
beta. 1a. in. Guillain-Barré. syndrome.. . Neurology.
2003;.61:1282-128�.
39...Raphael.JC,.Chevret.S,.Harboun.M,.Jars-Guincestre.
MC;. French. Guillain-Barré. Syndrome. Cooperative.
Group.. . Intravenous. immune. globulins. in. patients.
with.Guillain-Barre. syndrome.and.contraindications.
to.plasma.exchange:.3.days.versus.6.days...J.Neurol.
Neurosurg.Psychiatry.2001;.71:.23�-238.
�0...Raphael. J-C,. Chevret. S,. Hughes. RAC,. Annane. D...
Plasma. exchange. for. Guillain-Barré. syndrome.
(Cochrane.review)...Cochrane.Database.of.Systemic.
Reviews.2...Oxford:.Update.Software,.2001.
�1.. .Raphael. JC,. Masson. C,. Morice. V,. et. al.. . . Le.
syndrome.de.Guillain-Barre:.etude.retrospective.de.
233.observations.. .Sem.Hop.Paris.198�;.60:.2��3-
2��6.
�2...Rees. JH,. Thompson. RD,. Smeeton. NC,. Hughes.
RAC.. . An. epidemiological. study. of. Guillain-Barré.
syndrome.in.south.east.England...J.Neurol.Neurosurg.
Psychiatry.1988;.6�:.7�-77.
�3...Shahar. E. and. Leiderman. M.. . Outcome. of. severe.
Guillain-Barré. syndrome. in. children:. comparison.
between. untreated. cases. versus. gamma-globulin.
therapy...Clin.Neuropharmacol...2003;.26.(2):.8�-87.
30
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
��...Singhi. SC,. Jayshree. M,. Singhi. P. Banerjee. S,.
Prabhakar. S.. . Intravenous. immunoglobulin. in. very.
severe.childhood.Guillain-Barré.syndrome...AnnTrop.
Paediatr...1999;.19:.167-17�.
��...The. Guillain-Barré. Syndrome. Study. Group...
Plasmapheresis.and.acute.Guillain-Barré.syndrome...
Neurology.198�;.3�:.1096-110�.
�6...The.Italian.Guillain-Barré.Study.Group...The.prognosis.
and. main. prognostic. indicators. of. Guillain-Barré..
syndrome:. a. multicentre. prospective. study. of. 297.
patients...Brain.1996;.119:.20�3-2061.
�7.. .Van. der. Meche. FGA,. Schmitz. PIM. and. the. Dutch.
Guillain-Barré. Study. Group.. . A. randomized. trial.
comparing.intravenous.immune.globulin.and.plasma.
exchange.in.Guillain-Barré..syndrome...N.Engl.J.Med.
1992;.326:.1123-1129.
�8...Van. Koningsveld. R,. Schmitz. PIM,. van. der. Meche.
FGA,.Visser.LH,.Meulstee.J,. van.Doom.PA;.Dutch.
GBS. study. group.. . Effect. of. methylprednisolone.
when.added.to.standard.treatment.with.intravenous.
immunoglobulin. for. Guillain-Barré. syndrome:.
randomised.trial...Lancet.200�;363:192-196.
�9...Van.Koningsveld.R,.van.Doom.PA,.Schmitz.PI,.et.al...
Mild. forms. of. Guillain. Barré. syndrome. in. an. epi-
demiologic. survey. in. the. Netherlands.. . Neurology.
2000;.��:.620-62�.
�0...Visser. LH,. van. der. Meche. FG,. Meulstee. J,. van.
Doom.PA...Risk.factors.for.treatment.related.clinical.
fluctuations. in. Guillain-Barré. syndrome.. . Dutch.
Guillain-Barré. . study. group.. . J. Neurol. Neurosurg.
Psychiatry.1998;.6�:.2�2-2��.
�1.. .Wang.R,.Feng.A,.Sun.W,.Wen.Z...Intravenous.immu-
noglobulin.in.children.with.Guillain-Barré.syndrome...
Jounal. of. Applied. Clinical. Pediatrics. 2001;..
16:223-22�.
�2...Willison. HJ,. Yuki. N.. Peripheral. neuropathies. and.
antiglycolipid. antibodies.. Brain. 2002;. 12�:..
2�91-.262�.
31
CHRONIC INFLAMMATORYDEMYELINATING POLYNEUROPATHYINtROdUCtIONChronic.inflammatory.demyelinating.neuropathy.(CIDP).
is. an. acquired. sensorimotor. polyneuropathy. character-
ised. by. a. progressive. or. relapsing/remitting. course,.
evidence. of. demyelination. on. electrophysiological. or.
pathological. studies,. and. response. to. immunomodula-
tory.therapies...There.is.no.specific.diagnostic.test.but.
the. characteristic. clinical. and. laboratory. findings. help.
distinguish. this.disorder. from.other. immune.mediated.
neuropathic.syndromes.
dIaGNOsIsAccurate.diagnosis. is. the.critical.step. in.management...
Since. it. remains.the.major. treatable.neuropathy. in. the.
western.world.CIDP.should.be.considered.in.all.patients.
presenting.with.a.chronic.peripheral.neuropathy.and.in.
patients. presenting. with. Guillain-Barré. syndrome. of.
subacute.onset.or.when. recurrent.. .Diagnostic.criteria.
have.been.proposed.by.several.groups.which.describe.
characteristic.clinical,.electrophysiological.and.histologi-
cal. findings. and. other. causes. of. demyelinating.
neuropathy. that. should. be. excluded1-6.. . It. is. now.
recognized. that. CIDP. subtypes. or. variants. exist. and.
these. differing. phenotypes. may. relate. to. different.
pathogenic. mechanisms. and/or. host. genetic. factors...
Typical.CIDP.presents.with.a.chronically.progressive.or.
relapsing. and. remitting. symmetrical. mainly. motor.
neuropathy. with. proximal. and. distal. weakness. which.
develops.for.more.than.2.months...Cranial.nerves.may.
be.affected.but. less.commonly. than. in.GBS.and.deep.
tendon. reflexes. are. absent. or. reduced.. CIDP. variants.
include.patients.with
1.. Predominantly.distal.weakness-DADS.phenotype
2.. .Asymmetric. presentation-MADSAM. or. the. Lewis-
Sumner.syndrome
3.. Pure.motor.CIDP.
�.. Pure.sensory.CIDP.
�.. .Focal.presentation.i.e...one.or.more.nerves.or.a.focal.
group.of.nerves.
6.. CIDP.with.acute.onset.
7.. CIDP.with.CNS.involvement.6,7
Electrophysiological.criteria.for.demyelination.have.been.
much. debated. in. the. literature. since. if. too. restrictive.
patients.who.may.respond.to.therapy.could.be.denied.a.
therapeutic.trial2,3,6,8-10...The.EFN.and.PNS.Taskforce.have.
suggested.that.satisfactory.criteria.could.be.defined.by.
at.least.one.of.the.following.changes.in.2.nerves
1.. .At.least.�0%.prolongation.of.distal.motor.latency.or
2.. .At.least.30%.reduction.of.motor.conduction.velocity,.
or
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
32
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
3.. At.least.20%.prolongation.of.F-wave.latency.or
�.. .Absence.of.F-waves.in.2.nerves.+at.least.one.other.
demyelinating.parameter.in.at.least.one.other.nerve.
�.. Partial.motor.conduction.block.or
6.. Abnormal.temporal.dispersion.or
7.. .Distal.CMAP.duration.of.at.least.9ms.in.at.least.one.
nerve.+at.least.one.other.demyelinating.parameter.
in.at.least.one.other.nerve...
. In.practice.a.diagnosis.of.CIDP.may.be.made.when.
a.patient.presents.with.a.polyneuropathy.or.polyradicu-
loneuropathy.which.evolves.subacutely.over.more.than.
�.weeks.or.chronically.over.many.months.and.electro-
physiological. studies. show. evidence. of. (as. above).
demyelination..The.diagnosis.is.supported.by.the.finding.
of.elevated.CSF.protein.levels.without.a.rise.in.leukocyte.
count,.nerve.biopsy.findings.of.primary.demyelination,.
MRI. evidence. of. gadolinium. enhancement. and/or.
hypertrophy.of.nerve.roots.or.plexuses.or.improvement.
following.immunotherapy6.
. Nerve. biopsy. is. not. considered. mandatory. for.
diagnosis.by.most.groups11,12.but.it.is.a.useful.procedure.
when.doubt.concerning.diagnosis.remains...Since.cere-
brospinal. fluid. protein. is. increased. in. 80%. of. patients.
with.CIDP.its.measurement. is.another.helpful.but.non.
mandatory.consideration.in.diagnosis12.
. The.final.step.in.diagnosis.is.the.exclusion.of.other.
causes.of.demyelinating.neuropathy.
dIffERENtIaL dIaGNOsIs1.. .Hereditary. demyelinating. neuropathies. when. no.
family.history.available
2.. .Neuropathies.associated.with.malignancy.including.
POEMS.syndrome
3.. .IgM. monoclonal. gammopathy. with. antibodies..
to.MAG.
�.. .Metabolic. causes. of. demyelinating. neuropathy.
(diabetes,. uraemia,. hypothyroidism,. acromegaly)...
However.diabetes.and.CIDP.may.coexist.
�.. .Drug.induced.demyelinating.neuropathies.including.
amiodorone,.perhexiline.maleate,.n-hexane
6.. .Infective.disorders.including.HIV.and.Lyme.disease
7.. Recurrent.Guillain.Barré.syndrome...
8.. Multifocal.motor.neuropathy.with.conduction.block
NatURaL hIstORYThe. prevalence. of. CIDP. is. between. one. and. two. per.
hundred.thousand.of.population13,1�.
. The. clinical. course. and. response. to. therapy. is.
variable...Few.patients.have.relatively.minor.disease.and.
in.the.majority.treatment.is.necessary.to.prevent.severe.
disability.. . In. large.series.�%.to.17%.of.patients.have.
died.of.the.disease.usually.due.to.respiratory.failure.or.
pulmonary.embolism...�,1�-17
. The.prognosis.and.response.to.therapy.is.worse.in.
patients.over.6�.years18.
. CIDP.is.a.relatively.rare.disease.in.childhood...As.a.
result,. the. disease. course,. response. to. therapy. and.
prognosis. are. not. well. characterised.. . However. in. a.
number. of. series,. many. of. the. clinical. characteristics.
were.similar.to.those.found.in.adults.with.CIDP.
pathOGENEsIsCIDP. is. widely. accepted. as. an. autoimmune. disorder,.
based.upon.its.pathology,.similarity.to.the.animal.model.
experimental.autoimmune.neuritis.(EAN).and.its.chronic.
counterpart.chronic.relapsing.experimental.autoimmune.
neuritis. (CREAN). and. response. to. therapy19,. 20...
Pathological. studies. have. shown. perivascular. and.
endoneurial. mononuclear. cell. infiltrates. particularly.
within. spinal. nerve. roots,. ganglia. and. proximal. nerve.
trunks.. .These. infiltrates. are. comprised. of.T. cells. and.
macrophages. which. produce. a. number. of. cytokines.
including. interferon. gamma,. interleukin. 2,. tumour.
necrosis.factor.which.together.with.matrix.metallopro-
teinases. presumably. up. regulate. vascular. endothelial.
cell. adhesion. and. disrupt. the. blood. nerve. barrier20-22...
Studies.by.Yan.and.colleagues23.have.shown.antibodies.
to.the.PO.protein.of.myelin. in.a.significant.minority.of.
patients.with.CIDP.which. cause.conduction.block. and.
demyelination.in.rat.sciatic.nerve...Circulating.antibodies.
against.other.myelin.or.axonal.proteins.including.PMP22,.
P2. and. various. gangliosides. have. been. reported. but.
their.pathogenicity.has.not.been.proven.6,2�-27.
33
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
tREatMENtCoRtICoStERoIDSBeginning.with.the.renowned.work.of.Austin.28.many.non.
randomised.studies.have.shown.the.efficacy.of.corticoste-
roid.in.the.treatment.of.CIDP.16,29-31...In.these.studies.6�%.
to.9�%.of.patients. improved.with.steroid.therapy.. .Dyck.
and. colleagues. performed. a. randomised. controlled. trial.
comparing.prednisolone.commencing.at.120mg.daily.and.
tapering. over. 12. weeks. with. no. treatment. 32.. .This. trial.
showed. that. corticosteroids. significantly. reduced.
impairment.and.improved.measures.of.nerve.conduction...
The.absence.of.a.true.intention.to.treat.analysis.in.the.trial.
however.weakens.the.strength.of.the.evidence.obtained...
Recently.Hughes.et.al.33.compared.corticosteroid. to. IVIg.
and.found.that.in.the.short.term.these.treatments.were.of.
equivalent. efficacy.. . A. recent. study. looking. at. health-
related. quality. of. life. issues. found. that. patients. treated.
with. IVIg. in. comparison. to. corticosteroids. had. higher.
scores. but. the. difference. was. not. statistically.
significant3�.
. A.Cochrane. review3�. concluded. that. the. randomised.
controlled. study32. provided. weak. evidence. for. the. short.
term.efficacy.of.oral.steroids.in.CIDP...Different.regimes.for.
corticosteroid. therapy. are. used. in. different. centers. and.
there. is. no. consensus. regarding. dosage. nor. route. of.
administration6,36.. . Some. centres. begin. with. high. does.
intravenous.or.oral.therapy.1gm.daily.for.3.to.�.days.and.
then. continue. IV. therapy. at. increasing. intervals. of. time.
(weekly. &. then. monthly). or. convert. to. an. oral. dosage�...
Others.commence.with.oral.prednisone.in.a.dose.of.1.to.
1.�mg/kg/day. for. 6. to. 8. weeks. or. until. improvement. is.
maintained.. .The.dose. is. then.gradually. tapered.until. an.
effective. maintenance. dose. is. reached,. and. the.
maintenance.dose.is.often.given.on.alternate.days...These.
regimes.have.not.been.compared.in.appropriate.studies...
Pure.motor.CIDP.may.deteriorate.with.commencement.of.
corticosteroids.but.this.may.be.only.temporary.
. Although.corticosteroids.are.cheap.and.convenient.to.
administer3�. the. serious. complications. associated. with.
long.term.use.of.these.drugs.in.high.dosage.has.resulted.
in.a.trend.towards.using.IVIG.as.first.line.therapy.in.some.
centers...Osteoporosis.prophylaxis.should.be.started.with.
steroid.therapy.if.long.term.treatment.is.contemplated3�.
PLASMAExCHANGESeveral.uncontrolled.studies.have.reported.at.least.short.
term.benefit.from.plasma.exchange37-�1...Two.controlled.
trials. subsequently. confirmed. its. efficacy.. . Dyck. and.
colleagues�2.compared.twice.weekly.plasma.exchange.
(PE).or.sham.exchange.for.3.weeks.in.a.double.blind.trial.
and. showed. greater. improvement. in. disability. and.
motor. conduction. measurements. in. the. plasma.
exchange. treated. patients.. . Hahn. and. colleagues. �3.
performed. a. cross. over. trial. that. compared. PE. with.
sham.exchange;.patients.were.given.�.exchanges.in.the.
first.week,.three.in.the.second,.two.in.the.third.and.one.
in.the.fourth...The.PE.treated.patients.showed.significant.
improvements. in.disability.grip.strength.and.amplitude.
of.the.compound.muscle.action.potential.compared.to.
sham.exchange...A.Cochrane.review.concluded.that.PE.
provides. short-term. benefit. in. CIDP��.. . A. single. case.
study��.concluded. that. immunoabsorption. is. inferior. to.
PE.in.CIDP.
. Although.PE.is.efficacious.it.needs.to.be.repeated.at.
regular. intervals,.usually.about.�.weekly.. .Frequent.PE.
often.leads.to.problems.with.venous.access...Moreover,.
the. procedure. is. inconvenient,. available. only. in.
specialized.centres,.and.attended.by.various.complica-
tions.and.is.contraindicated.in.children.and.patients.with.
cardiovascular.instability.
INtRAVENouSIMMuNoGLoBuLINFour. randomised. placebo. controlled. trials. have. been.
performed.using. IVIg. in.CIDP.of.which.3.have. shown.
the.efficacy.of.this.treatment�3,.�6-�9...A.Cochrane.review,.
has. confirmed. the. favourable. effect. of. IVIg�0...
Improvement.after.IVIg.usually.begins.within.2.weeks,.
and.lasts.for.2.to.6.weeks.so.that.treatments.need.to.be.
repeated. for. maintained. improvement.. .This. need. for.
continued. therapy. represents. a. significant. problem.
since.IVIg.is.very.expensive...The.initial.dose.of.IVIg.is.
0.�g/kg. daily. for. �. days. and. the. maintenance. dose. is.
between.0.�g.and.2.0g/kg.given.over.one.to.two.days.
as. needed,. for. each. individual. patient. that. is. usually.
between. 2. and. 12. weeks�1-�3.. .There. is. considerable.
variation.between.patients.as.to.how.often.IVIg.needs.
to.be.given.but.most.patients.need.it.every.3-�.weeks.
to.maintain.the.benefit...Cross.over.trials.have.shown.no.
3�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
significant. short. term. difference. between. IVIg..
and. plasma. exchange��. or. between. IVIg. and..
oral.prednisone33...
IMMuNoSuPPRESSIVEAGENtSNo.controlled.trials.have.been.reported.for.any.immuno-
suppressive. agent. in. CIDP. . except. for. azathioprine,.
which.was.reported.to.show.no.benefit.when.added.to.
prednisone. in. 1�. patients��.. . However,. that. trial.
lacked. the. power. to. detect. any. but. very. large..
treatment.effects.
AzAtHIoPRINEAzathioprine.is.often.used.together.with.prednisone.to.
reduce. the. need. for. IVIg. or. PE. in. CIDP. patients. but.
there.is.very.little.hard.evidence.on.which.to.base.this.
practice.. .A.number.of.anecdotal.series. report.benefit.
but. the. numbers. in. each. are. small. and. the. studies.
uncontrolled�,�,31,�9.
MyCoPHENoLAtESeveral. uncontrolled. studies. of. small. numbers. of.
patients.have.examined.the.effect.of.Mycophenolate.in.
CIDP.. . Whereas. a. beneficial. effect. was. reported. by.
some�6,.no.benefit.was.reported.by.others�7...A.controlled.
trial.of.adequate.power.is.urgently.needed.
CyCLoPHoSPHAMIDEA.series.of.1�.patients.reported.by.Good.and.colleagues�8.
were. given. cyclophosphamide. by. IV. pulses. of. 1g/m2.
monthly.for.a.maximum.of.six.months...Twelve.patients.
were.said. to. improve.markedly,. three.did.not.and.one.
worsened...Despite.these.promising.results.most.neu-
rologists.are. reluctant. to.use.this.drug.because.of. the.
risk. of. serious. adverse. events. including. marrow.
suppression,. bladder. toxicity,. cancer,. infertility..
and.alopecia.
CyCLoSPoRINAThis.drug.which.acts.upon.T.cell.activation.and.cytokine.
production.has.been.reported.to.be.effective.in.treatment.
resistant.CIDP.in.anecdotal.series�9.60...The.recommended.
starting.dose.is.�mg/kg/day.and.the.maintenance.dose.
2-3mg/kg.. . Cyclosporin. A. levels. should. be. monitored.
carefully. as. well. as. creatinine. levels. and. creatinine.
clearance. measured,. if. there. is. any. rise. in. serum.
creatinine...Nephrotoxicity,.the.major.side.effect.is.dose.
dependent;. less. common. side. effects. include. hepato-
toxity,.anorexia,.gum.hypertrophy,.hirsuitism.and.neuro-
toxicity.
INtERfERoNAn. open. study. of. Interferon. alpha. showed. benefit. in.
about. �0%. of. treatment. resistant. patients. in. one.
study61...Interferon.beta.was.not.shown.to.be.effective.
in.a.controlled.study62...A.large.randomized.control.trial.
of. Interferon. beta. 1a. as. add-on. therapy. to. IVIg. is.
currently.in.progress.
sUGGEstEd appROaCh tO MaNaGEMENtINDuCtIoNofREMISSIoNFor.patients.who.merit.treatment,.i.e...those.with.more.
than.mild.symptoms,.consideration.should.be.given.to.
the.use.of. IVIg.or.corticosteroids. in. the. first. instance...
Cost,. convenience,. availability,. and. the. potential. for.
adverse.effects.will.dictate.the.choice.in.various.centers...
IVIg. would. be. the. first. line. treatment. for. pure. motor.
CIDP...If.these.therapies.are.not.effective.PE.should.be.
considered.. . Although. in. experienced. hands. PE. is.
relatively. safe. treatment. it. is. available. only. in. major.
centres.and.is.difficult.and.expensive.to.administer...
MAINtENANCEtREAtMENtThere. is.no.evidence. from.controlled. trials.concerning.
maintenance.therapy.since.all.trials.assessed.only.short.
term. benefit.. . Some. groups. continue. with. first. line.
therapy,. if. effective.. . An. attempt. is. made. to. find. the.
lowest.effective.maintenance.dose.of.IVIg,.PE.or.corti-
costeroid,. as. the. case. may. be.. . Others. introduce.
second. line.therapies.usually.a.combination.of.cortico-
steroid.and.immunosuppression,.in.an.attempt.to.lower.
the.dose.or.frequency.of.the.expensive.therapies,.IVIg.
or. PE,. in. those. patients. in. whom. high. maintenance.
doses.are.needed...However.there.is.no.evidence.base.
for.this.practice.
3�
. Occasional. patients. will. have. a. long. term. benefit.
from. a. single. treatment. course. of. IVIg,. but. most. will.
need. repeated. therapy. usually. at. an. interval. from.
between.2.and.6.weeks. to.maintain. the.benefit.. .The.
dose.per.course.needs.to.be.titrated.for.each.individual.
patient.If.IVIg.fails,.PE.may.be.tried...When.steroids.and.
immunosuppressive.agents.are.introduced.for.patients.
on.IVIg,.the.steroid.may.be.given.in.a.smaller.dose.say.
3�mg/day.and.the.dose.progressively.reduced.according.
to. clinical. improvement.. . Some. patients. can. be.
maintained. on. low. dose. steroid. and. immunosuppres-
sion.and.be.gradually.weaned.off. IVIg.or.PE. (Personal.
experience.JDP).
. In. those. few. unresponsive. patients. who. do. not.
respond.to.these.therapies,.cyclosporin.A.could.then.be.
used...If.alone.it.is.ineffective,.azathioprine.and.steroid.
could.be.added.in.a.transplant.like.regime.
. Most. would. agree. that. since. IVIg. is. an. expensive.
and. precious. resource. an. attempt. should. be. made. in.
each. patient. to. find. the. lowest. effective. maintenance.
dose.by. trial. reduction.of.dose.and.an. increase. in. the.
interval. between. treatments.. . Such. rationalization. is.
already. applied. to. PE. and. corticosteroid. therapy...
Moreover.it.would.seem.reasonable.that.for.continued.
access. to. IVIg,. treating. physicians. provide. to. the.
appropriate. authority. evidence. of. continued. efficacy,.
based. upon. objective. measures. of. muscle. strength.
and/or.nerve.conduction.studies.. .Continued.supply.of.
IVIg.may.be.contingent.upon.the.results.of.monitoring.
at. 6. monthly. intervals.. . Data. collection. of. this. type.
would.ensure.equitable.distribution.of.IVIg.and.provide.
an.extremely.useful.research.resource.
EXpERt CONsENsUsIn.summary.there.is.class.I.evidence.from.randomised.
controlled.studies.only.for.IVIg,.PE.and.corticosteroids...
First. line. therapy. in. any. given. area. will. depend. upon.
issues.of.economy,.availability.and.safety...However,.the.
evidence.concerning.the.efficacy.of.these.agents.is.only.
for.the.short.term...There.is.no.evidence.from.controlled.
studies.as.to.which.therapy.is.superior.in.the.long.term.
or.as.to.whether.the.addition.of.steroids.and.immuno-
suppression. can. lead. to. a. reduction. of. the. expensive.
treatments.over. time.. .Trials. addressing. this. issue. are.
needed.. .There. is. also. a. need. for. pharmacoeconomic.
and.safety.data.to.address.issues.of.quality.of. life.and.
cost.effectiveness.in.the.long.term.
REfERENCEs1.. .Research.criteria.for.diagnosis.of.chronic.inflamma-
tory. demyelinating. polyneuropathy. (CIDP).. . Report.
from. an. Ad. Hoc. Subcommittee. of. the. American.
Academy.of.Neurology.AIDS.Task.Force..Neurology...
1991;.�1:617-618.
2.. .Nicolas. G,. Maisonobe. T,. Le. Forestier. N,. et. al...
Proposed. revised. electrophysiological. criteria. for.
chronic. inflammatory. demyelinating. polyradiculo-
neuropathy.Muscle.Nerve...2002;.2�:26-30.
3.. .Van.den.Bergh.PY,.Pieret.F...Electrodiagnostic.criteria.
for. acute. and. chronic. inflammatory. demyelinating.
polyradiculoneuropathy. Muscle. Nerve.. . 200�;.
29:�6�-�7�.
�.. .McCombe. PA,. Pollard. JD,. McLeod. JG.. . Chronic.
inflammatory.demyelinating.polyradiculoneuropathy...
A.clinical.and.electrophysiological.study.of.92.cases.
Brain...1987;.110.(.Pt.6):1617-1630.
�.. .Barohn.RJ,.Kissel. JT,.Warmolts. JR,. et. al.. .Chronic.
inflammatory.demyelinating.polyradiculoneuropathy...
Clinical. characteristics,. course,. and. recommenda-
tions. for. diagnostic. criteria. Arch. Neurol.. . 1989;.
�6:878-88�.
6.. .Hughes.RA,.Bouche.P,.Cornblath.DR,.et.al...European.
Federation.of.Neurological.Societies/Peripheral.Nerve.
Society.guideline.on.management.of.chronic.inflam-
matory.demyelinating.polyradiculoneuropathy:.report.
of. a. joint. task. force. of. the. European. Federation. of.
Neurological. Societies. and. the. Peripheral. Nerve.
Society.Eur.J.Neurol...2006;.13:326-332.
7.. .van.Doorn.PA...Treatment.of.Guillain-Barré.syndrome.
and.CIDP.J.Peripher.Nerv.Syst...200�;.10:113-127.
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
36
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
8.. .Latov. N.. . Diagnosis. of. CIDP. Neurology.. . 2002;..
�9:S2-S6.
9.. .Magda. P,. Latov. N,. Brannagan. TH,. III,. et. al...
Comparison. of. electrodiagnostic. abnormalities. and.
criteria.in.a.cohort.of.patients.with.chronic.inflamma-
tory. demyelinating. polyneuropathy. Arch. Neurol...
2003;.60:17��-17�9.
10...Koller. H,. Kieseier. BC,. Jander. S,. et. al.. . Chronic.
inflammatory.demyelinating.polyneuropathy.N.Engl.
J.Med...200�;.3�2:13�3-13�6.
11.. .Molenaar. DS,. Vermeulen. M,. de. HR.. . Diagnostic.
value.of.sural.nerve.biopsy.in.chronic.inflammatory.
demyelinating. polyneuropathy. J. Neurol. Neurosurg.
Psychiatry...1998;.6�:8�-89.
12...Saperstein. DS,. Katz. JS,.Amato.AA,. et. al.. . Clinical.
spectrum. of. chronic. acquired. demyelinating. poly-
neuropathies.Muscle.Nerve...2001;.2�:311-32�.
13...Lunn. MP,. Manji. H,. Choudhary. PP,. et. al.. . Chronic.
inflammatory. demyelinating. polyradiculoneuropa-
thy:. a. prevalence. study. in. south. east. England.. . J.
Neurol.Neurosurg.Psychiatry...1999;.66:677-680
1�...McLeod.JG,.Pollard.JD,.Macaskill.P,.et.al...Prevalence.
of.chronic.inflammatory.demyelinating.polyneuropa-
thy. in. New. South. Wales,. Australia.. . Ann. Neurol...
1999;.�6:910-913.
1�...Dyck.PJ,.Lais.AC,.Ohta.M,.et.al..Chronic.inflammtory.
polyradiculoneuropathy.. Mayo. Clinic. Proceedings...
197�;.�0:621-6�1.
16...McCombe. PA,. Pollard. JD,. McLeod. JG.. . Chronic.
inflammatory.demyelinating.polyradiculoneuropathy...
A.clinical.and.electrophysiological.study.of.92.cases.
Brain...1987;.110.(.Pt.6):1617-1630.
17.. .Bouchard.C,.Lacroix.C,.Plante.V,.et.al..Clinicopathologic.
findings.and.prognosis.of.chronic.inflammatory.demye-
linating.polyneuropathy.Neurology...1999;.�2:�98-�03.
18...Hattori. N,. Misu. K,. Koike. H,. et. al.. . Age. of. onset.
influences.clinical. features.of.chronic. inflammatory.
demyelinating. polyneuropathy. J. Neurol. Sci.. . 2001;.
18�:�7-63.
19...Yan. WX,.Taylor. J,. Ndrias-Kauba. S,. et. al.. . Passive.
transfer. of. demyelination. by. serum. or. IgG. from.
chronic.inflammatory.demyelinating.polyneuropathy.
patients.Ann.Neurol...2000;.�7:76�-77�.
20...Toyka. KV,. Gold. R.. . The. pathogenesis. of. CIDP:.
rationale. for. treatment. with. immunomodulatory.
agents.Neurology...2003;.60:S2-S7.
21.. .Spies.JM,.Westland.KW,.Bonner.JG,.et.al...Intraneural.
activated. T. cells. cause. focal. breakdown. of. the.
blood-nerve.barrier.Brain..199�;.118.(.Pt.�):8�7-868.
22...Mathey.EK,.Pollard.JD,.Armati.PJ.. .TNF.alpha,. IFN.
gamma. and. IL-2. mRNA. expression. in. CIDP. sural.
nerve.biopsies.J.Neurol.Sci...1999;.163:�7-�2.
23...Yan.WX,.Archelos.JJ,.Hartung.HP,.et.al...P0.protein.
is.a.target.antigen.in.chronic.inflammatory.demyelin-
ating. polyradiculoneuropathy. Ann. Neurol.. . 2001;.
�0:286-292.
2�...Gabriel.CM,.Gregson.NA,.Hughes.RA..Anti-PMP22.
antibodies.in.patients.with.inflammatory.neuropathy.
J.Neuroimmunol...2000;.10�:139-1�6.
2�...Melendez-Vasquez.C,.Redford.J,.Choudhary.PP,.et.al...
Immunological. investigation.of.chronic. inflammatory.
demyelinating..J.Neuroimmunol...1997;.73:12�-13�.
26...Ritz. MF,. Lechner-Scott. J,. Scott. RJ,. et. al...
Characterisation. of. autoantibodies. to. peripheral.
myelin. protein. 22. in. patients. with. hereditary. and.
acquired. neuropathies. J. Neuroimmunol.. . 2000;.
10�:1��-163.
27....Hughes.RA,.Allen.D,.Makowska.A,.et.al...Pathogenesis.
of.chronic.inflammatory.demyelinating.polyradiculo-
neuropathy.J.Peripher.Nerv.Syst...2006;.11:30-�6.
37
28...Austin. JH.. . Recurrent. polyneuropathies. and. their.
corticosteroid. treatment;. with. five-year. observa-
tions.of.a.placebo-controlled.case.treated.with.corti-
cotrophin,.cortisone,.and.prednisone...Brain...19�8;.
81:1�7-192.
29...Thomas. PK,. Lascelles. RG,. Hallpike. JF,. et. al...
Recurrent.and.chronic. relapsing.Guillain-Barre.poly-
neuritis.Brain...1969;.92:�89-606.
30...Prineas.JW,.McLeod.JG...Chronic.relapsing.polyneu-
ritis.J.Neurol.Sci...1976;.27:�27-��8.
31.. .Dalakas. MC,. Engel. WK.. . Chronic. relapsing.
(dysimmune). polyneuropathy:. pathogenesis. and.
treatment.Ann.Neurol...1981;.9.Suppl:13�-1��.
32...Dyck. PJ,. O'Brien. PC,. Oviatt. KF,. et. al.. . Prednisone.
improves.chronic. inflammatory.demyelinating.poly-
radiculoneuropathy. more. than. no. treatment. Ann.
Neurol...1982;.11:136-1�1.
33...Hughes.R,.Bensa.S,.Willison.H,.et.al...Randomized.
controlled.trial.of.intravenous.immunoglobulin.versus.
oral.prednisolone.in.chronic.inflammatory.demyelin-
ating. polyradiculoneuropathy. Ann. Neurol.. . 2001;.
�0:19�-201.
3�...McCrone.P,.Chisholm.D,.Knapp.M,.et.al.. .Cost-utility.
analysis.of.intravenous.immunoglobulin.and.predniso-
lone. for. chronic. inflammatory. demyelinating. polyra-
diculoneuropathy.Eur.J.Neurol...2003;.10:687-69�.
3�...Mehndiratta. MM,.Hughes.RA.. .Corticosteroids. for.
chronic. inflammatory. demyelinating. polyradiculo-
neuropathy. Cochrane. Database. Syst. Rev.. . 2002;.
CD002062.
36...Bromberg.MB,.Carter.O...Corticosteroid.use.in.the.
treatment. of. neuromuscular. disorders:. empirical.
and. evidence-based. data. Muscle. Nerve.. . 200�;.
30:20-37.
37.. .Levy.RL,.Newkirk.R,.Ochoa.J...Treatment.of.chronic.
relapsing. Guillain-Barré. syndrome. by. plasma.
exchange.Lancet...1979;.2:7�1.
38...Server.AC,.Lefkowith.J,.Braine.H,.et.al.. .Treatment.
of. chronic. relapsing. inflammatory. polyradiculoneu-
ropathy. by. plasma. exchange. Ann. Neurol.. . 1979;..
6:2�8-261.
39...Gross. ML,.Thomas. PK.. .The. treatment. of. chronic.
relapsing.and.chronic.progressive. idiopathic. inflam-
matory.polyneuropathy.by.plasma.exchange.J.Neurol.
Sci...1981;.�2:69-78.
�0...Pollard.JD,.McLeod.JG,.Gatenby.P,.et.al...Prediction.
of.response.to.plasma.exchange.in.chronic.relapsing.
polyneuropathy.. .A.clinico-pathological.correlation.J.
Neurol.Sci...1983;.�8:269-287.
�1.. .Wrobel. CJ,.Watson. D.. . Plasmapheresis. in. chronic.
demyelinating.polyneuropathy.N.Engl.J.Med...1992;.
326:1089-1090.
�2...Dyck.PJ,.Daube.J,.O'Brien.P,.et.al...Plasma.exchange.
in.chronic.inflammatory.demyelinating.polyradiculo-
neuropathy.N.Engl.J.Med...1986;.31�:�61-�6�.
�3...Hahn.AF,.Bolton.CF,.Pillay.N,.et.al...Plasma-exchange.
therapy.in.chronic.inflammatory.demyelinating.poly-
neuropathy...A.double-blind,.sham-controlled,.cross-
over.study.Brain...1996;.119.(.Pt.�):10��-1066.
��...Mehndiratta. MM,. Hughes. RA,.Agarwal. P.. . Plasma.
exchange. for. chronic. inflammatory. demyelinating.
polyradiculoneuropathy. Cochrane. Database. Syst.
Rev...200�;CD003906.
��...Hadden. RD,. Bensa. S,. Lunn. MP,. et. al...
Immunoadsorption.inferior.to.plasma.exchange.in.a.
patient. with. chronic. inflammatory. demyelinating.
polyradiculoneuropathy. J. Neurol. Neurosurg.
Psychiatry...2002;.72:6��-6�6.
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
38
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
�6...van.Doorn.PA,.Brand.A,.Strengers.PF,.et.al.. .High-
dose. intravenous. immunoglobulin. treatment. in.
chronic. inflammatory. demyelinating. polyneuropa-
thy:. a. double-blind,. placebo-controlled,. crossover.
study.Neurology...1990;.�0:209-212.
�7.. .Thompson. N,. Choudhary. P,. Hughes. RA,. et. al.. . A.
novel.trial.design.to.study.the.effect.of.intravenous.
immunoglobulin. in. chronic. inflammatory. demyelin-
ating. polyradiculoneuropathy. J. Neurol.. . 1996;.
2�3:280-28�.
�8...Mendell. JR,. Barohn. RJ,. Freimer. ML,. et. al...
Randomized. controlled. trial. of. IVIg. in. untreated.
chronic. inflammatory. demyelinating. polyradiculo-
neuropathy.Neurology...2001;.�6:���-��9.
�9...Hahn.AF,.Bolton.CF,.Zochodne.D,.et.al...Intravenous.
immunoglobulin. treatment. in. chronic. inflammatory.
demyelinating. polyneuropathy.. . A. double-blind,.
placebo-controlled,. cross-over. study. Brain.. . 1996;.
119.(.Pt.�):1067-1077.
�0...van.Schaik.IN,.Winer.JB,.de.Haan.R,.et.al...Intravenous.
immunoglobulin.for.chronic.inflammatory.demyelin-
ating. polyradiculoneuropathy:. a. systematic. review.
Lancet.Neurol..2002;.1:�91-�98.
�1.. .Choudhary.PP,.Hughes.RA...Long-term.treatment.of.
chronic. inflammatory. demyelinating. polyradiculo-
neuropathy. with. plasma. exchange. or. intravenous.
immunoglobulin.QJM...199�;.88:�93-�02.
�2...van.Doorn.PA,.Vermeulen.M,.Brand.A,.et.al...Intravenous.
immunoglobulin. treatment. in. patients. with. chronic.
inflammatory. demyelinating. polyneuropathy.. . Clinical.
and. laboratory. characteristics. associated. with.
improvement.Arch.Neurol...1991;.�8:217-220.
�3...Wiles. CM,. Brown. P,. Chapel. H,. et. al.. . Intravenous.
immunoglobulin.in.neurological.disease:.a.specialist.
review. J. Neurol. Neurosurg. Psychiatry.. . 2002;.
72:��0-��8.
��...Dyck. PJ,. Litchy. WJ,. Kratz. KM,. et. al.. . A. plasma.
exchange. versus. immune. globulin. infusion. trial. in.
chronic. inflammatory. demyelinating. polyradiculo-
neuropathy.Ann.Neurol...199�;.36:838-8��.
��...Dyck. PJ,. O'Brien. P,. Swanson. C,. et. al.. . Combined.
azathioprine.and.prednisone. in.chronic. inflammato-
ry-demyelinating.polyneuropathy.Neurology.. . 198�;.
3�:1173-1176.
�6...Mowzoon.N,.Sussman.A,.Bradley,.WG...Mycophenolate.
(CellCept). treatment. of. myasthenia. gravis,. chronic.
inflammatory. polyneuropathy. and. inclusion. body.
myositis.J.Neurol.Sci...2001;.18�:119-122.
�7.. .Umapathi. T,. Hughes. RA,. Nobile-Orazio. E,. et. al...
Immunosuppressive.treatment.for.multifocal.motor.
neuropathy. Cochrane. Database. Syst. Rev...
2002;CD003217.
�8...Good. JL,. Chehrenama. M,. Mayer. RF,. et. al.. . Pulse.
cyclophosphamide. therapy. in.chronic. inflammatory.
demyelinating. polyneuropathy. Neurology.. . 1998;.
�1:173�-1738.
�9...Hodgkinson.SJ,.Pollard.JD,.McLeod.JG...Cyclosporin.
A.in.the.treatment.of.chronic.demyelinating.polyra-
diculoneuropathy. J. Neurol. Neurosurg. Psychiatry...
1990;.�3:327-330.
60...Barnett.MH,.Pollard.JD,.Davies.L,.et.al...Cyclosporin.
A. in. resistant. chronic. inflammatory. demyelinating.
polyradiculoneuropathy. Muscle. Nerve.. . 1998;.
21:���-�60.
61.. .Gorson.KC,.Ropper.AH,.Clark.BD,.et.al.. .Treatment.
of.chronic.inflammatory.demyelinating.polyneuropa-
thy.with.interferon-alpha.2a.Neurology...1998;.�0:8�-
87.
62...Hadden.RD,.Sharrack.B,.Bensa.S,.et.al...Randomized.
trial. of. interferon. beta-1a. in. chronic. inflammatory.
demyelinating. polyradiculoneuropath. Neurology...
1999;.�3:�7-61.
39
MULTIFOCAL MOTOR NEUROPATHYdEfINItIONMultifocal.Motor.Neuropathy.(MMN).is.a.relatively.rare.
disorder. characterized. by. slowly. progressive,.
asymmetric,. predominately. distal. limb. weakness.
without.sensory.impairment...Weakness.often.begins.in.
the. arms. and. the. combination. of. weakness,. wasting.
cramps.and. fasciculations.may.suggest.a.diagnosis.of.
Motor.Neuron.Disease.. .However,.clinical.examination.
may.demonstrate.that.the.pattern.of.weakness.follows.
the.distribution.of.individual.nerves.rather.than.a.spinal.
segmental.pattern1,2...Upper.motor.neuron.signs.do.not.
occur. in.MMN.nor.marked.bulbar. involvement.. .These.
features.and.an.increased.CSF.protein.level.above.1g/L.
may.be. regarded.as.exclusion. criteria. (EFNS.and.PNS.
Taskforce.2006)
dIaGNOsIsThe. hallmark. of. this. condition. is. persistent. localized.
motor.conduction.block...Block.may.occur.at.any.level.of.
the.peripheral.nerve.but.there.is.a.predilection.for.distal.
segments. of. mixed. nerves. particularly. the. forearm.
segments.of.the.median.and.ulnar.nerves3...Conduction.
velocity.through.the.blocked.segment.is.often.markedly.
slowed. and. the. proximal. compound. muscle. action.
potential.dispersed�,�...Block.is.persistent.for.prolonged.
periods,.months.or.years...Changes.of.acute.or.chronic.
denervation.are.found.on.EMG.of.affected.muscles...It.
should.be.noted.however.that.conduction.block.is.easy.
to. misdiagnose;. many. chronic. denervating. conditions.
can.result.in.significant.reductions.in.CMAP.amplitudes.
due.to.conduction.delays.and.motor.unit.remodelling6,7.
It. is. recommended. that. the. “inching”. technique. be.
used. to. define. an. abrupt. change. in. distal. CMAP.
amplitude�...When.the.distal.CMAP.is.less.than.1mV.the.
diagnosis. of. conduction. block. is. more. difficult. and.
Pfeiffer. et. al. have. proposed. that. a. distal. to. proximal.
CMAP. ratio. under. these. circumstances. should. be. at.
least. 7�%. whereas. �0%. would. be. appropriate. when.
the.distal.CMAP.is.over.1mV...Another.technical.problem.
associated.with.misdiagnosis.of.CB.is.failure.of.supra-
maximal.stimulation.
. However.Pakiam.and.Parry8.have.described.patients.
with.typical.MMN.in.whom.CB.was.not.demonstrated.
hence. they. and. other. workers9,. 1. have. suggested. that.
failure.to.satisfy.strict.electrophysiological.criteria.should.
not. preclude. a. trial. of. therapy. in. otherwise. typical.
cases.. . Recently. activity. dependent. conduction. block.
(ADCB),. defined. as. transient. CB. induced. by. brief.
exercise. has. been. reported. in. MMN. and. this. may. be.
demonstrated.by.the.magnetic.fatigue.test10...Moreover.
MULTIFOCAL MOTOR NEUROPATHY
�0
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
ADCB. may. account. for. the. failure. to. demonstrate.
routine. CB. in. some. typical. cases.. .The. same. authors.
reported.that.the.most.sensitive.indicator.of.MMN.was.
prolongation. of. the. duration. from. the. onset. to. the.
positive.peak.of.the.CMAP...In.MMN,.nerve.conduction.
studies. outside. areas. of. conduction. block. should..
be.normal3.
. High.levels.of.IgM.anti.GM-1.antibodies.have.been.
reported. in. 18. -. 8�%. of. patients11-13. Series. reviews.
suggest. about. �0%. of. typical. cases. are. positive. for.
these.antibodies.and. the.association.does.suggest.an.
autoimmune.basis.to.this.disease1�...However.the.role.
of. antiganglioside. antibodies. in. MMN. remains. to..
be.defined...
. Hence. the. diagnosis. is. usually. made. in. a. patient.
with.the.appropriate.clinical.features.and.electrophysio-
logical. evidence. of. localized. conduction. block.. . The.
presence.of.anti.GM-1.antibodies.provides.confirmatory.
evidence. but. cannot. be. considered. essential. for. the.
diagnosis...Likewise.CB.is.regarded.as.the.gold.standard.
for.diagnosis,.but. typical.cases. that.do.not. fulfill. strict.
criteria.may.merit.a.treatment.trial...
pathOGENEsIsThe. pathogenesis. of. MMN. remains. unknown.. . The.
presence.of.anti.GM-1.antibodies.and.response.to.IVIg.
and. immunosuppression. is. suggestive. of. an. immune.
aetiology;.however.the.relationship.of.GM-1.antibodies.
to. the. pathogenesis. is. uncertain.. . Kiernan. and.
colleagues1�. have. shown. hyperpolarization. of. nerve.
distal.to.the.site.of.conduction.block.and.have.postulated.
depolarization.at.the.site.due.to.inactivation.of.Na+/K+.
pumps. possible. resulting. from. GM-1. antibodies...
However. the. application. of. these. antibodies. to. single.
nerve. fibres. has. produced. both. negative. and. positive.
results.. . Conflicting. results. have. also. been. obtained.
with. intraneural. injections16-19.. . Kiernan. et. al1�. have.
further. postulated. that. extensive. depolarization. at. the.
site.of.conduction.block.will.result. in.the.accumulation.
of.Na+.intracellularly...The.combination.of.depolarization.
and. reduced. transmebrane. Na+. gradient. will. lead. to.
intracellular. Ca2+. accumulation. and. hence. axonal.
degeneration.. .These. postulates. are. highly. consistent.
with. the. pathological. findings. described. by.Taylor. and.
colleagues20.. . Moreover. Van. Asseldonk. et. al.21. has.
shown.electrophysiologically.that.axonal.loss.rather.than.
conduction.block.or.demelinative.slowing.of.conduction.
was. the. most. significant. determinant..
of.weakness.
NatURaL hIstORYMMN. is. a. slowly. progressive. disorder. which. may.
ultimately. result. in. severe. wasting. and. disability...
Although. patients. may. improve. with. therapy. and. this.
improvement. is. maintained. long. term,. a. majority. will.
ultimately.worsen.despite.increasing.IVIg.dosage22...This.
reduced.efficacy.of.treatment.and.concomitant.deterio-
ration. correlates. with. reduced. distal. CMAP. amplitude.
presumably. because. of. progressive. axonal. degenera-
tion22...In.the.largest.reported.group.of.patients.with.this.
disorder.none.of. �6.patients. improved. spontaneously,.
however. there. were. no. patients. who. died. with. the.
disorder20.. .As.noted.below,.this.progressive.deteriora-
tion.may.relate.to.question.of.dosage23-2�...
pathOLOGYIn.two.earlier.studies.in.which.tissue.was.removed.from.
identified.sites.of.conduction.block.the.changes.of.thinly.
myelinated. and. demyelinated. axons. and. small. onion.
bulbs. were. found26,27.. . However. in. a. recent. study. of.
fascicular. nerve. biopsies. in. seven. patients,.Taylor. and.
colleagues20. found. multifocal. fibre. degeneration,. and.
loss.with.prominent.regenerating.clusters,.at.the.site.of.
block.. . Although. an. increase. in. remyelinated. fibre.
profiles. was. seen. axonal. pathology. predominated...
These.findings.are.consistent.with.the.clinical. findings.
of.muscle.weakness.and.atrophy.
tREatMENtINtRAVENouSIMMuNoGLoBuLINFour. randomised. controlled. studies. and. several. open.
studies.have. shown. that. IVIg. is. effective. treatment. in.
MMN12,28-3�.. . However. in. the. vast. majority. of. patients.
maintenance. therapy. is. needed3�,. 36-38.. . Occasional.
patients. receive. long. lasting. benefit. from. the. initial.
therapy.but.most.patients.need.repeated.maintenance.
therapy. at. varying. intervals. from. one. to. eight.
weeks28,36,39,�0.. . Some. authorities. give. maintenance.
�1
treatment. at. clinical. worsening,. although. others.
recommend. anticipating. "end. of. dose". effect. by.
shortening. the. interval. between. infusions. to. weekly.
doses. if. necessary. in. some. cases22,38.. . In. most. long.
term.studies.although.patients.clearly.improve.following.
IVIg,. some. slowly. deteriorate. despite. continued.
therapy22,28.37.38...In.the.first.few.years.of.treatment,.the.
reduced.response.to.IVIg.may.be.restored.by.increasing.
IVIg.dose,.but.later.this.increase.in.dose.is.only.partially.
effective22...In.one.recent.long.term.follow.up.study.ten.
patients. given. high. dose. maintenance. IVIg. improved.
over. time. and. showed. a. decrease. in. the. number. of.
conduction.blocks.and.the.degree.of.axonal.degenera-
tion23.. . A. previous. study. has. correlated. clinical.
improvement.with.reduction.of.conduction.block.in.neu-
rophysiological. studies30,. but. another. long. term. study.
reported. that. conduction. block. improved. in. some.
nerves.but.become.apparent.in.others.during.treatment.
with.IVIg38...A.report.of.progressive.axonal.loss.despite.
therapy22. is. consistent. with. those. studies. showing.
continued. clinical. deterioration22,28,38,�0. but. may. reflect.
inadequate.dosage.
DoSAGETreatment.is.usually.initiated.by.giving.2g/Kg.of.IVIg.over.
1-�. days.. . Maintenance. doses. vary. and. should. be.
adjusted.to.the.individual.response...Typical.maintenance.
regimes.are.1g/Kg.every.2. to.�.weeks.or.2g/Kg.every.
�-8.weeks2�...Although.several.studies.have.suggested.
that. patients. slowly. worsen. over. time. despite. IVIg.
treatments22,28,38,�0,. the. long. term. follow. up. study. by.
Cros.and.Drake2�.in.which.patients.given.high.dose.IVIg.
improved. over. time. suggest. that. some. previous.
maintenance. regimes. may. have. used. inadequate.
dosages...Confirmation.of.this.report.and.the.efficacy.of.
higher. doses. are. clearly. needed.. . However. clearly. an.
attempt.should.be.made.to.define.the.lowest.effective.
dose. of. IVIg. for. each. patient. and. to. monitor. the.
therapeutic. efficacy. by. objective. measures. of. muscle.
strength.. . Attempts. have. been. made. to. reduce. the.
maintenance. dose. of. IVIg. by. the. use. of. immunosup-
pressive. agents. such. as. Chlorambucil,. azathioprine. or.
cyclophosphamide. and. by. the. use. of. interferon-beta.
1a22,33,36,�1...However.there.are.no.controlled.trials.of.any.
immunosuppressive. agent. in. MMN. alone. or. in.
combination. with. IVIg�2.. . Because. of. the. well. known.
adverse. effects. of. cyclophosphamide. its. use. in. MMN.
should.be.considered.only.in.severely.affected.cases.
IMMuNoSuPPRESSIVEAGENtSSeveral.uncontrolled.studies.have.reported.a.beneficial.
response.to.cyclophosphamide32,�3-��...Cyclophosphamide.
may.be.given.orally.or. intravenously.alone.or.following.
plasma.exchange22,.36,.�6...Although.over.70%.of.patients.
reported.appear. to.have.benefited.from.cyclophospha-
mide.the.lack.of.controlled.studies.and.its.adverse.effect.
profile.have.limited.its.use.in.MMN.
otHERtHERAPIESPatients. with. MMN. may. worsen. following. treatment.
with.corticosteroids�7.and.plasma.exchange�8.and.their.
use.is.not.indicated...Improvement.has.been.described.
in. small. numbers. of. patients. following. interferon-beta.
1a.therapy�9...Benefit.has.also.been.reported.in.a.small.
group.of.patients. following. the.use.of. the.B.cell. (anti-
CD20).monoclonal.antibody,.Rituximab�0-�2.
sUMMaRYBecause.of.its.proven.efficacy.and.relative.safety.profile,.
IVIg.is.currently.first-line.therapy.for.MMN...However.it.
will.presumably.need.to.be.continued.lifelong...There.is.
no.class.1.evidence.for.any.other.therapy.either.alone.or.
in.combination.with.IVIg.or.PE...There.is.no.universally.
accepted.dosage.regime.for.IVIg.but.since.it.is.a.scarce.
and.expensive.commodity,.physicians.should.attempt.to.
define.the.minimum.effective.dose.for.each.patient.
EXpERt CONsENsUsIVIg. is. the. first-line. therapy. for. multifocal. motor.
neuropathy.. .Treatment. is. usually. continued. over. the.
long. term. but. the. minimum. effective. dose. for. each.
patient.should.be.sought.
MULTIFOCAL MOTOR NEUROPATHY
�2
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
REfERENCEs1.. .Nobile-Orazio. E,. Cappellari. A,. Meucci. N,. et. al...
Multifocal. motor. neuropathy:. clinical. and. immuno-
logical.features.and.response.to.IVIg.in.relation.to.the.
presence.and.degree.of.motor.conduction.block.. .J.
Neurol.Neurosurg.Psychiatry...2002;.72:761-766.
2.. .Nobile-Orazio.E,.Casellato.C,.Di.Troia.A...Neuropathies.
associated.with.IgG.and.IgA.monoclonal.gammopathy..
Rev.Neurol.(Paris)...2002;.1�8:979-987.
3.. .Taylor.BV,.Willison.HJ...Multifocal.Motor.Neuropathy.
and.Conduction.Block.ed.,.200�:2277-2298
�.. .Parry. GJ.. . Motor. neuropathy. with. multifocal.
conduction. block.. . Semin. Neurol.. . 1993;. 13:269-
27�.
�.. .Krarup.C,.Stewart.JD,.Sumner.AJ,.et.al...A.syndrome.
of.asymmetric.limb.weakness.with.motor.conduction.
block...Neurology...1990;.�0:118-127.
6.. .Rhee. EK,. England. JD,. Sumner. AJ.. . A. computer.
simulation.of.conduction.block:.effects.produced.by.
actual. block. versus. interphase. cancellation.. . Ann.
Neurol...1990;.28:1�6-1�6.
7.. .Pfeiffer. G,.Wicklein. EM,.Wittig. K.. . Sensitivity. and.
specificity.of.different.conduction.block.criteria...Clin.
Neurophysiol...2000;.111:1388-139�.
8.. .Pakiam.AS,.Parry.GJ...Multifocal.motor.neuropathy.
without. overt. conduction. block.. . Muscle. Nerve...
1998;.21:2�3-2��.
9.. .Katz. JS,. Saperstein. DS,. Gronseth. G,. et. al.. . Distal.
acquired. demyelinating. symmetric. neuropathy...
Neurology...2000;.��:61�-620.
10...Nodera. H,. Bostock. H,. Izumi. Y,. et. al.. . Activity-
dependent. conduction. block. in. multifocal. motor.
neuropathy:. magnetic. fatigue. test.. . Neurology...
2006;.67:280-287.
11.. .Kornberg.AJ,.Pestronk.A,.Bieser.K,.et.al...The.clinical.
correlates. of. high-titer. IgG. anti-GM1. antibodies...
Ann.Neurol...199�;.3�:23�-237.
12...Bouche.P,.Moulonguet.A,.Younes-Chennoufi.AB,.et.
al.. . Multifocal. motor. neuropathy. with. conduction.
block:.a.study.of.2�.patients.. .J.Neurol.Neurosurg.
Psychiatry...199�;.�9:38-��.
13...Pestronk. A,. Li. F,. Griffin. J,. et. al.. . Polyneuropathy.
syndromes. associated. with. serum. antibodies. to.
sulfatide. and. myelin-associated. glycoprotein...
Neurology...1991;.�1:3�7-362.
1�...Willison. HJ.. .The. immunobiology. of. Guillain-Barré.
syndromes.. . J. Peripher. Nerv. Syst.. . 200�;. 10:9�-
112.
1�...Kiernan.MC,.Guglielmi.JM,.Kaji.R,.et.al.. .Evidence.
for.axonal.membrane.hyperpolarization.in.multifocal.
motor. neuropathy. with. conduction. block.. . Brain...
2002;.12�:66�-67�.
16...Hirota.N,.Kaji.R,.Bostock.H,.et.al...The.physiological.
effect.of.anti-GM1.antibodies.on.saltatory.conduction.
and.transmembrane.currents.in.single.motor.axons...
Brain...1997;.120.(.Pt.12):21�9-2169.
17.. .Takigawa.T,.Yasuda.H,.Kikkawa.R,.et.al.. .Antibodies.
against.GM1.ganglioside.affect.K+.and.Na+.currents.
in.isolated.rat.myelinated.nerve.fibers...Ann.Neurol...
199�;.37:�36-��2.
18...Santoro.M,.Uncini.A,.Corbo.M,.et.al...Experimental.
conduction.block. induced.by.serum. from.a.patient.
with. anti-GM1. antibodies.. . Ann. Neurol.. . 1992;.
31:38�-390.
19...Harvey.GK,.Gold.R,.Hartung.HP,.et.al.. .Non-neural-
specific.T.lymphocytes.can.orchestrate.inflammato-
ry. peripheral. neuropathy.. . Brain.. . 199�;. 118. (. Pt.
�):1263-1272.
�3
20...Taylor. BV,. Dyck. PJ,. Engelstad. J,. et. al.. . Multifocal.
motor.neuropathy:.pathologic.alterations.at.the.site.
of. conduction. block.. . J. Neuropathol. Exp. Neurol...
200�;.63:129-137.
21.. .Van.Asseldonk.JT,.Van.den.Berg.LH,.Kalmijn.S,.et.al...
Axon.loss.is.an.important.determinant.of.weakness.
in.multifocal.motor.neuropathy...J.Neurol.Neurosurg.
Psychiatry...2006;.77:7�3-7�7.
22...Terenghi.F,.Cappellari.A,.Bersano.A,.et.al...How.long.
is. IVIg. effective. in. multifocal. motor. neuropathy?...
Neurology...200�;.62:666-668.
23...Vucic.S,.Black.KR,.Chong.PS,.et.al...Multifocal.motor.
neuropathy:.decrease.in.conduction.blocks.and.rein-
nervation. with. long-term. IVIg.. . Neurology.. . 200�;.
63:126�-1269.
2�...van. Schaik. IN,. Bouche. P,. Illa. I,. et. al.. . European.
Federation. of. Neurological. Societies/Peripheral.
Nerve. Society. guideline. on. management. of.
multifocal.motor.neuropathy.. .Eur.J.Neurol.. .2006;.
13:802-808.
2�...Cross. D,. Drake. E.. . Multifocal. motot. neuropathies.
with. conduction. block;. long. term. follow. up. of. ten.
patients.treated.with.IVIg...Rev.Neurol.(Paris)...2006;.
162S1:3��6-3��0.
26...Auer.RN,.Bell.RB,.Lee.MA...Neuropathy.with.onion.
bulb. formations. and. pure. motor. manifestations...
Can.J.Neurol.Sci...1989;.16:19�-197.
27.. .Kaji.R,.Oka.N,.Tsuji.T,.et.al...Pathological.findings.at.
the. site. of. conduction. block. in. multifocal. motor.
neuropathy...Ann.Neurol...1993;.33:1�2-1�8.
28...Azulay.JP,.Rihet.P,.Pouget.J,.et.al...Long.term.follow.
up.of.multifocal.motor.neuropathy.with.conduction.
block. under. treatment.. J. Neurol. Neurosurg.
Psychiatry...1997;.62:391-39�.
29...Van. den. Berg. LH,. Kerkhoff. H,. Oey. PL,. et. al...
Treatment.of.multifocal.motor.neuropathy.with.high.
dose.intravenous.immunoglobulins:.a.double.blind,.
placebo. controlled. study.. . J. Neurol. Neurosurg.
Psychiatry...199�;.�9:2�8-2�2.
30...Federico.P,.Zochodne.DW,.Hahn.AF,.et.al...Multifocal.
motor. neuropathy. improved. by. IVIg:. randomized,.
double-blind,.placebo-controlled.study.. .Neurology...
2000;.��:12�6-1262.
31.. .Leger.JM,.Chassande.B,.Musset.L,.et.al...Intravenous.
immunoglobulin. therapy. in. multifocal. motor.
neuropathy:. a. double-blind,. placebo-controlled.
study...Brain...2001;.12�:1��-1�3.
32...Chaudhry. V,. Corse. AM,. Cornblath. DR,. et. al...
Multifocal. motor. neuropathy:. response. to. human.
immune.globulin...Ann.Neurol...1993;.33:237-2�2.
33...Nobile-Orazio.E,.Meucci.N,.Barbieri.S,.et.al...High-
dose. intravenous. immunoglobulin. therapy. in.
multifocal. motor. neuropathy.. . Neurology.. . 1993;.
�3:�37-���.
3�...Comi. G,. Amadio. S,. Galardi. G,. et. al.. . Clinical. and.
neurophysiological.assessment.of. immunoglobulin.
therapy. in. five. patients. with. multifocal. motor.
neuropathy...J.Neurol.Neurosurg.Psychiatry...199�;.
�7.Suppl:3�-37.
3�...Azulay. JP,. Blin. O,. Pouget. J,. et. al.. . Intravenous.
immunoglobulin. treatment. in. patients. with. motor.
neuron. syndromes. associated. with. anti-GM1.
antibodies:.a.double-blind,.placebo-controlled.study...
Neurology...199�;.��:�29-�32.
36...Meucci.N,.Cappellari.A,.Barbieri.S,.et.al...Long.term.
effect. of. intravenous. immunoglobulins. and. oral.
cyclophosphamide. in.multifocal.motor.neuropathy...
J.Neurol.Neurosurg.Psychiatry...1997;.63:76�-769.
MULTIFOCAL MOTOR NEUROPATHY
��
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
37.. .Van. den. Berg. LH,. Franssen. H,. Wokke. JH...
Improvement.of.multifocal.motor.neuropathy.during.
long-term. weekly. treatment. with. human. immuno-
globulin...Neurology...199�;.��:987-988.
38...Van.den.Berg-Vos.RM,.Franssen.H,.Wokke.JH,.et.al...
Multifocal.motor.neuropathy:. long-term.clinical.and.
electrophysiological. assessment. of. intravenous.
immunoglobulin. maintenance. treatment.. . Brain...
2002;.12�:187�-1886.
39...van.Doorn.PA,.van.der.Meche.FG.. . IVIg. treatment.
improves.multifocal.motor.neuropathy:.easy.to.start.
but. difficult. to. stop.. . Neurology.. . 2000;. ��:12�6-
12�7.
�0...Van.den.Berg.LH,.Franssen.H,.Wokke.JH...The.long-
term.effect.of.intravenous.immunoglobulin.treatment.
in.multifocal.motor.neuropathy...Brain...1998;.121.(.
Pt.3):�21-�28.
�1.. .Van.den.Berg-Vos.RM,.Franssen.H,.Wokke.JH,.et.al...
Multifocal.motor.neuropathy:.diagnostic.criteria.that.
predict.the.response.to.immunoglobulin.treatment...
Ann.Neurol...2000;.�8:919-926.
�2...Umapathi. T,. Hughes. RA,. Nobile-Orazio. E,. et. al...
Immunosuppressive.treatment.for.multifocal.motor.
neuropathy.. . Cochrane. Database. Syst. Rev...
2002;CD003217.
�3...Feldman. EL,. Bromberg. MB,. Albers. JW,. et. al...
Immunosuppressive. treatment. in. multifocal. motor.
neuropathy...Ann.Neurol...1991;.30:397-�01.
��...Pestronk.A,.Cornblath.DR,.Ilyas.AA,.et.al...A.treatable.
multifocal.motor.neuropathy.with.antibodies.to.GM1.
ganglioside...Ann.Neurol...1988;.2�:73-78.
��...Tan.E,.Lynn.DJ,.Amato.AA,.et.al...Immunosuppressive.
treatment.of.motor.neuron.syndromes...Attempts.to.
distinguish.a.treatable.disorder...Arch.Neurol...199�;.
�1:19�-200.
�6...Pestronk. A,. Lopate. G,. Kornberg. AJ,. et. al.. . Distal.
lower.motor.neuron.syndrome.with.high-titer.serum.
IgM. anti-GM1. antibodies:. improvement. following.
immunotherapy.with.monthly.plasma.exchange.and.
intravenous. cyclophosphamide.. . Neurology.. . 199�;.
��:2027-2031.
�7.. .Donaghy.M,.Mills.KR,.Boniface.SJ,.et.al...Pure.motor.
demyelinating.neuropathy:.deterioration.after.steroid.
treatment.and.improvement.with.intravenous.immu-
noglobulin.. . J.Neurol.Neurosurg.Psychiatry.. . 199�;.
�7:778-783.
�8...Carpo.M,.Cappellari.A,.Mora.G,.et.al...Deterioration.
of. multifocal. motor. neuropathy. after. plasma.
exchange...Neurology...1998;.�0:1�80-1�82.
�9...Martina.IS,.van.Doorn.PA,.Schmitz.PI,.et.al...Chronic.
motor. neuropathies:. response. to. interferon-beta1a.
after. failure. of. conventional. therapies.. . J. Neurol.
Neurosurg.Psychiatry...1999;.66:197-201.
�0...Levine.TD,. Pestronk.A.. . IgM. antibody-related. poly-
neuropathies:. B-cell. depletion. chemotherapy. using.
Rituximab...Neurology...1999;.�2:1701-170�.
�1.. .Pestronk.A,.Florence.J,.Miller.T,.et.al...Treatment.of.
IgM. antibody. associated. polyneuropathies. using.
rituximab.. . J. Neurol. Neurosurg. Psychiatry.. . 2003;.
7�:�8�-�89.
�2...Ruegg. SJ,. Fuhr. P,. Steck. AJ.. . Rituximab. stabilizes.
multifocal. motor. neuropathy. increasingly. less.
responsive. to. IVIg.. . Neurology.. . 200�;. 63:2178-
2179.
��
IGM PARAPROTEINEMIC NEUROPATHIESINtROdUCtION The.association.of.paraproteins.with.peripheral.neuropa-
thies. was. first. described. with. multiple. myeloma. and.
subsequently. with. Waldenström’s. macroglobulinemia...
In.current.practice.these.days,.searching.for.the.presence.
of. monoclonal. proteins. has. become. an. important. and.
essential. step. in. evaluating. patients. with. chronic.
peripheral.neuropathy.(PN).of.unknown.etiology.
dEfINItIONNeuropathies.associated.with.the.presence.of.excessive.
amounts. of. abnormal. immunoglobulin. are. collectively.
referred. to. as. paraproteinemic. neuropathies. (PpN)...
Paraproteins.are.usually.a.product.of.a.single.clone.of.
plasma.cells.-.monoclonal.(M-proteins./.M-spike).
GENERaL INfORMatIONIt.is.estimated.that.10%.of.idiopathic.polyneuropathies.
are.paraproteinemic.neuropathies...These.neuropathies.
form.a.heterogenous.group.of.disorders.not.only.from.
the. clinical. presentation. and. electrophysiological.
features.but.also.with.regard.to.the.class.of.circulating.
immunoglobulins,. immunoreactivity. to. myelin.
compounds,. pathogenicity. of. the. paraproteins. and.
responsiveness.to.immunosuppressive.treatment...
. In. 1978. Kyle. first. proposed. the. term. ‘Monoclonal.
Gammopathy. of. Undetermined. Significance’. (MGUS).
and.today,.this.group.forms.two-thirds.of.paraproteinemic.
neuropathies...The.features.of.this.condition.are.a.serum.
protein. level.of.<3.g/dL,.fewer.than.�%.plasma.cells. in.
the. bone. marrow,. no. proteinuria,. normal. haematology.
and.the.absence.of.systemic.symptoms./.signs...
. Kelly.et.al. in.1981,. reported.an. incidence.of.1%.in.
adults. older. than. �0. years. and. it. appears. that. the.
prevalence.increases.with.age:.3.–.10.%.of.those.older.
than. 70. years. of. age,. dependent. on. the. technique. of.
detection.of.paraproteins...In.1998,.Ropper.and.Gorson.
pointed.out.that.though.initially.thought.benign,.20%.of.
non-malignant. cases. do. progress. to. malignancy6...
Ponsford. et. al. reported. in. 2000. that. at. the. time. of.
diagnosis,.less.than.one-third.of.monoclonal.gammopa-
thies. were. associated. with. malignant. lymphoprolifera-
tive.diseases1�.
pathOGENEsIsPathogenetically,.damage.to.nerve.tissue.by.paraproteins.
is.thought.to.occur.by.the.following.mechanisms1�:.-
•..Directly,.if.having.properties.of.antibodies.specific.for.
a.myelin.or.axonal.component.–.gangliosides,.sulfated.
glycosphingolipids.&.glycoprotein.antigens
IGM PARAPROTEINEMIC NEUROPATHIES
�6
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
•..Amyloid. by-product. deposition. (causing..
non-specific.damage)
•..Local. ischemia.due.to.serum.hyperviscosity. (causing.
non-specific.damage)
The.role.of.these.aberrant.proteins.in.the.pathogenesis.
of.peripheral.neuropathy.remains.partially.clarified.and.is.
perhaps.best. evidenced. in.most. of. the.PN-associated.
with. an. IgM. monoclonal. gammopathy.. . On. the. other.
hand,. most. IgG. or. IgA. monoclonal. gammopathies. of.
unknown. significance. (MGUS). and. POEMS. (polyneu-
ropathy,. organomegaly,. endocrinopathy,. M. band. and.
skin.changes).syndrome.have.an.uncertain.causal.rela-
tionship.with.neuropathies...
CLINICaL pREsENtatIONParaproteinemic. neuropathies. may. precede. systemic.
disorders.or.be. the.principal.presenting.manifestation...
The. table. below. outlines. some. of. the. more. common.
associations.with.the.type.of.immunoglobulin.detected.
and.polyneuropathy.seen:-
Clinically,.PpN.tends.to.affect.men.more.than.�0.years.
of.age.and.slowly.progresses.over.a.period.of.months...
Patients.may.report.any.of.the.following:-
•..Foot.numbness,.paresthesias,. imbalance,.gait.ataxia,.
dysesthesias.or.lancinating.pains
•..Weakness.of.distal. leg.muscles.and.variable.atrophy,.
as.illness.advances
IgMneuropathies.appear.mostly.demyelinating,.more.
severe.&.more.frequent.(60%).compared.to.IgG.(30%).
or. IgA. (10%). neuropathies6. which. present. with. a.
variable.picture.of.demyelinating,.axonal.or.mixed.neu-
ropathies.. . IgM. demyelinating. neuropathies. form. a.
distinct.subset.with.the.following.features:-
•..Characterized. by. slowly. progressive,. mainly. distal,.
symmetrical,.sensorimotor.neuropathy.or.predominant.
sensory.ataxia.associated.with.postural.tremors.in.the.
upper.limbs.(the.result.of.large.fibre.dysfunction).and.
late.development.of.distal.limb.weakness.
SyStEMICDISoRDER tyPEofIMMuNoGLoBuLIN& tyPEofPoLyNEuRoPAtHy LIGHtCHAINCLASS
Multiple.myeloma. 10%.show.IgM./.IgG-κ. Axonal
Waldenström’s.macroglobulinemia. IgM-κ. Demyelinating
Osteosclerotic.myeloma. 8�%.IgG./.IgA-λ. Demyelinating
Primary.NF-amyloidosis. IgG/IgA-.λ.;.initial.feature.in.1�%. Axonal
Cryoglobulinemia. IgM.or.IgG. Axonal
POEMS.syndrome. IgG/IgA-.λ. Mixed.demyelinating.&.axonal.picture
CANOMAD.syndrome. IgM. Mixed.demyelinating.&.axonal.picture
�7
•..More.than.�0%.are.associated.with.antibodies.against.
myelin-associated.glycoprotein.(MAG).and.sphingogly-
colipids. and. are. more. commonly. associated. with.
kappa.than.lambda.light.chains
•..IgM.neuropathies.associated.with.anti-GM1.antibodies.
show.a.pure. lower.motor.neuron.clinical.presentation.
with. multifocal. motor. conduction. block. while. those.
associated. with. sulfatide. or. chondroitin. sulphate.
demonstrate.a.predominant.sensory.neuropathy.
•..Nerve.conduction.studies.shows.sensory. fibres. that.
are. severely. affected. with. conduction. velocity..
slowing. (without. block). that. is. more. diffuse. and.
distally.predominant
•..Less. responsive. to. conventional..
immunosuppressive.therapy
In.Chronic.Inflammatory.Demyelinating.Polyneuropathy.
(CIDP),. 20. -. 2�%. of. patients. may. also. demonstrate.
presence. of. paraproteins. (IgG. or. IgA).. .This. group. of.
patients. usually. has. an. indolent. course,. predominant.
sensory.symptoms.and.shows. less. response. to.usual.
treatment.modalities.of.CIDP.than.those.without.para-
proteins.. . Electrophysiologically,. focal. blocks. of.
conduction.in.motor.nerves.may.be.detected...
INVEstIGatIONsThe.important.principle.in.investigating.paraproteinemic.
patients.is.to.differentiate.the.malignant.from.the.non-
malignant.causes.of.monoclonal.gammopathy...
. Patients. are. usually. screened. for. M-protein. and. if.
detected,. then. immunoelectrophoresis. or. the. more.
sensitive.immunofixation.is.used.to.identify.the.immu-
noglobulin. type. and. light. chain. class.. . M-proteins. are.
usually.measured.annually...
. Work-up. includes. urine. for. Bence-Jones. protein,.
radiological. skeletal. survey. to. detect. lytic. or. sclerotic.
bone. lesions. and. a. full. blood. count,. serum. calcium,.
renal. profile,. liver. function,. lactate. dehydrogenase,.
rheumatoid.factor,.serum.cryoglobulins.with.erythrocyte.
sedimentation.rate...It.is.equally.important.to.distinguish.
the.type.of.neuropathy.as.either.axonal.or.demyelinating.
by. conducting. nerve. conduction. studies. (NCS).. .This.
type.of.diagnostic.testing.not.only.guides.further.work-
up. but. also. provides. a. correlation. with. patient’s.
symptoms.for.prognosis.and.symptom.clarification...The.
most.compelling.reason.for.ordering.a.nerve.biopsy.will.
be.to.rule.out.amyloid.deposition...
OBJECtIVEsTo. examine. the. existing. evidence. regarding. the. use. of.
intravenous.immune.globulin.(IVIG).and.its.efficacy.in.the.
management.in.IgM.paraproteinemic.neuropathies.
. In. reviewing. the. literature,. only. limited. published.
data. exists. regarding. the. efficacy. of. various. immuno-
suppressive.regimes.. .Most.case.series.are.small. (1.–.
��.patients).and.include.diverse.groups.of.patients.with.
conventional.immunotherapies...Peer-reviewed.publica-
tions.were. identified. through.MEDLINE. (1990.–.2007).
and. the. Cochrane. Collaboration.. . Criteria. used. for.
selection. of. studies. included. clinical. pertinence. and.
publication.being.in.the.English.Language.
IVIG IN IGM paRapROtEINEMIC NEUROpathIEsIn.an.open.study.in.1990,Cooketal1.reported.that.two.
patients,.who.had.had.a.3-year.history.of.demyelinating.
PN.associated.with. IgM.monoclonal.gammopathy.and.
been. treated. with. steroids. and. immunosuppressants,.
were. seen. to. show.a. fairly. rapid. clinical. improvement.
after.monthly.high-dose.IVIG.infusion...This.was.evident.
within. �. -10. days. after. the. infusion. and. the. beneficial.
effect. lasted. 3. –. 6. weeks.. . Retreatment. resulted. in.
improvement. after. each. consecutive. infusion....
[Level.V.evidence]
. In. 1994, Léger et al2. in. an. open-label. IVIG. study,.
reported. six. out. of. 13. patients. (�6%),. who. demon-
strated. a. slight. clinical. improvement. after. IVIG. but.
appeared.to.worsen.several.months.later.despite.further.
similar. treatment.. .There. was. however. no. observable.
change.in.immunoglobulin.titres.or.electrophysiological.
improvement...[Level.III-3.evidence]
. Dalakas et al3. in. 1996,. conducted. a. randomized,.
double-blind,. placebo-controlled. cross-over. study. of.
IVIG. in. 11. patients. with. demyelinating. polyneuropathy.
associated. with. monoclonal. IgM. antibodies.. . IVIG. or.
placebo. was. administered. monthly. for. 3. months.
followed. by. a. washout. period. before. crossing. over. to.
the. alternate. therapy.. . Response. was. measured. by.
evaluating.muscle.strength,.sensation.and.neuromuscu-
lar. symptoms. at. baseline,. three. months. and. at.
IGM PARAPROTEINEMIC NEUROPATHIES
�8
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
treatment’s.end...Only.2.out.of.11.patients.demonstrat-
ed. improvement. in. muscle. strength. initially. but. this.
improvement.declined.after.placebo...One.other.patient.
showed. only. sensory. scores. improvement.. . Antibody.
titres.to.myelin-associated.glycoprotein.(MAG).were.not.
observed.to.change.significantly...The.conclusions.at.the.
end. of. this. study. were. that. IVIG. had. only. a. modest.
benefit.of.not.more.than.18%.in.their.group.of.patients...
Interestingly,. the. few. patients. who. had. responded.
showed. the. lowest. strength. of. reactivity. to. MAG. by.
enzyme-linked.immunosorbent.assay.(ELISA)...[Level.II.
evidence]
. Also. in. 1996, Ellie et al�. in. an. open-label. study.
treated.17.patients.with.IVIG...While.76%.showed.some.
degree.of.response,.only.�.out.of.the.original.17.patients.
(2�%).had.sustained,.objective.improvement.based.on.
a.clinical.scale...Level.III-3.evidence]
. Gorsonetal20.in1997.studied.the.effects.of.plasma.
exchange.(PE),.IVIG.and.prednisolone.in.1�.patients.of.
which.12.were.IgM.MGUS...All.seven.patients.with.PE.
improved.while.only.two.out.of.six.patients.in.the.IVIG.
arm.showed.similar.improvement..[Level.IV.evidence]
. In. 1997, Mariette et al�. of. the. IgM-associated.
Polyneuropathy. Study. Group. in. France. reported. the.
results. of. a. 12. month,. prospective,. multi-centre,.
randomized,. open. (non-blinded). clinical. trial. comparing.
IVIG. (@.2g/kg.and. then.1g/kg.every. three.weeks). and.
recombinant. interferon. (IFN. -α. subcutaneously. 3. MU/
m².three.times.a.week).in.20.patients...At.six.months,.
only.one.out.of.10. (10%).patients.enrolled. in. the. IVIG.
arm. had. a. clinical. neurological. disability. score.
improvement.of.more. than.20%.whereas.eight.out.of.
10. (80%). in. the. IFN-α. had.such.an. improvement. (P.=..
0.00�).. .Sustained. improvement. in. the.disability.score.
after. 12. months. was. seen. in. the. latter. arm. and. was.
mainly. attributed. to. an. improvement. in. the. sensory.
component.. .The. anti-MAG. antibody. activity. was. still.
detectable.in.serum.samples.from.all.patients...However,.
a. subsequent. placebo-controlled. study. of. IFN. -. α.
conducted. by. the. same. group. of. investigators,..
found. no. benefit. from. interferon. treatment....
[Level.II.evidence]
. A.case.report.by.Ponsfordetalin2000.of.2.patients.
with. chronic. sensory. ataxia. and. anti-disialosyl. IgM.
antibodies,. showed. evidence. that. electrophysiologically.
demonstrated. demyelination. appeared. to. correlate. to.
treatment.responsiveness.to.IVIG...[Level.V.evidence]
. Comi et al13 in 2002 from Milan. published. the.
results. of. a. multi-centre,. randomized,. double-blind,.
placebo-controlled.cross-over.trial.of.IVIG.(2g/kg.over.2�.
–. �8. hours). in. 22. IgM. demyelinating. polyneuropathy.
patients.. . In. their. study,. there. was. some. short. term.
benefit.of.IVIG.seen.in.about.half.of.the.patients.while.
a. modest. but. statistically. significant. benefit. was.
recorded.in.secondary.endpoints.(Rankin.scale.scores,.
sensory. symptoms. score. &. time. to. walk. 10m)....
[Level.II.evidence]
sUMMaRY 1.. .IgM. neuropathies,. with. or. without. reactivity. to.
myelin-associated. glycoprotein. (MAG,). are. more.
refractory. despite. combinations. of. PE,. IVIG,.
alkylating. agents. and. corticosteroids.. . In. those.
patients.who.progress.very.slowly.and.are.without.
significant.disability,. they.may.be.managed.conser-
vatively.and.treated.only.symptomatically.for.pares-
thesiae. and. tremors.. . However,. for. patients. with.
rapid. progression. or. demonstrating. significant.
disability,.the.use.of.IVIG.or.for.that.matter,.plasma.
exchange. is. marginal,. variable. and. unproven,. as. is.
evidenced. in. the. review. of. the. existing. literature...
Newer. options. of. immunosuppressants. may. hold.
the. key. to. more. effective. therapy. for. those. with.
moderately.severe.disease...
2.. .Those. IgG & IgA monoclonal gammopathies.
fulfilling. criteria. for. demyelinating. neuropathy. are.
best. treated. like. idiopathic.CIDP.with.conventional.
immunomodulating. therapies. such. as. corticoste-
roids,.plasma.exchange.and. IVIG.. . (Please. refer. to.
section.on.CIDP)
�9
3.. .In. those. patients. where. PpN are detected with
multiplemyeloma,amyloidosisorWaldenström’s
macroglobulinemia,.treatment.should.be.directed.
at. the. underlying. disease.. . Most. disappointingly,.
these. neuropathies. often. remain. recalcitrant. to.
treatment...IVIG.is.not.indicated.here.
�.. .For.those.paraproteinemic.neuropathies.associated.
with.Type.II./.III.Cryoglobulinemia.due.to.Hepatitis.C.
virus.infection,.it.is.recommended.that.they.receive.
interferon. -. α. (with. or. without. ribavirin). for..
6.–.12.months
OthER IMMUNOsUppREsaNts BEING CONsIdEREdIn.recent.times,.the.following.drugs.have.been.tested.as.
alternative. treatment. options. for. refractory. cases. but.
their.efficacy.remains.open.to.debate:-
•..Mycophenolatemofetil. (MMF).–.Showed.a.modest.
(20%).benefit.as.adjuvant.therapy.primarily.by.reducing.
steroid. requirements. or. the. frequency. of. IVIG.
infusions16...MMF.was.administered.as.1g.orally.twice.
per.day.
•. .Rituximab.–.Humanized.monoclonal.antibody.against.
CD20. antigen. has. been. used. especially. for.
Waldenström’s.macroglobulinemia.with.IgM-related.
neuropathies. that. show. moderate. to. severe.
disability...Weekly.infusions.of.37�mg/m2.were.used.
for.�.weeks...However,.clinicians.need.to.be.aware.
that. sudden. increases. in. IgM. and. viscosity. levels.
are.possible.and.mandate.close.monitoring
•. .Fludarabine. –. fluorinated. purine. analogue. shows.
promising.results.in.various.low.grade.lymphoprolif-
erative. conditions. including. IgM-secreting. plasma.
cell. dyscrasias.. . Intravenous. (IV). Fludarabine. was.
given.at.2�mg/m2.daily.for.�.days.every.�.–.6.weeks.
for.6.months.7...
•. .Cladribine. –. a. purine. nucleoside. analogue;. in.
combination. with. IVIG. infusion. has. been. used. 1�...
While. the. M-protein. levels. reduced,. IVIG. was.
required.to.maintain.the.clinical.remission...
EXpERt CONsENsUs At. present,. no. clear. consensus. exists. for. the. optimal.
management. of. neuropathy. associated. with. MGUS.
patients.including.those.with.or.without.anti-MAG.para-
proteinemic.antibody.activity...
. While. there. appears. to. be. a. fairly. good. record. of.
safety. with. the. use. of. IVIG,. its. benefits. in. the.
management. of. IgM. paraproteinemic. neuropathies. as.
evidenced. by. the. existing. published. trials. and. case.
studies.are.not.statistically.significant.and.at.best,.may.
be.categorized.as.variable,.marginal.and.transient...
. In.view.of.the.slow.progression.of.this.group.of.para-
proteinemic.neuropathies,.only.patients.with.disabling.or.
rapid.progression.may.merit.consideration.of.IVIG.therapy.
although. its. efficacy. remains. to. be. validated. through.
larger.multi-centre.trials.of.longer.durations...
REfERENCEs: 1.. .Cook. D,. Dalakas. M,. Galdi. A,. et. al.. . High. dose.
intravenous. immunoglobulin. in. the. treatment. of.
demyelinating. neuropathy. associated. with.
monoclonal. gammopathy.. . Neurology. 1990;..
�0:212-2�1.
2.. .Léger. JM,. Ben. Younces-Chennoufi. A,. Chassande.
B,et. al.. . Human. immunoglobulin. treatment. of.
multifocal.neuropathy.and.polyneuropathy.associated.
with.monoclonal.gammopathy...J.Neurol.Neurosurg.
Psychiatry.199�;.�7(Suppl):�6-�9.
3.. .Dalakas. MC,. Quarles. RH,. Farrer. RC,. et. al.. . A.
controlled. study. of. intravenous. immunoglobulin. in.
demyelinating. neuropathy. with. IgM. gammopathy...
Ann.Neurol.1996;.�0(�):792-79�.
�.. .Ellie.E,.Vital.A,.Steck.A,.et.al...Neuropathy.associated.
with. “benign”. anti-myelin-associated. glycoprotein.
IgM. gammopathy:. Clinical,. immunological,. neuro-
physiological,.pathological.findings.and.response.to.
treatment.in.33.cases...J.Neurol.1996;.2�3:3�-�3.
IGM PARAPROTEINEMIC NEUROPATHIES
�0
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
�.. .Mariette. X,. Chastang. C,. Clavelou. P,. et. al.. . A.
randomized.trial.comparing.interferon.(IFN).–.α.and.
intravenous. immunoglobulin. in. polyneuropathy.
associated.with.monoclonal.IgM...J.Neurol.Neurosurg.
Psychiatry.1997;.63:28-3�.
6.. .Ropper. &. Gorson.. . Neuropathies. associated. with.
Paraproteinemia...NEJM.1998;.338(22):.1601.–.1607.
7.. .Wilson. HC,. Lunn. MPT,. Schey. S. &. Hughes. RAC...
Successful. treatment. of. IgM. paraproteinemic.
neuropathy. with. fludarabine.. . J. Neurol. Neurosurg.
Psychiatry.1999;66:�7�.-.�80.
8.. .Levine.TD.&.Pestronk.A...IgM.antibody-related.poly-
neuropathies:. B-cell. depletion. chemotherapy. using.
Rituximab...Neurology.1999;�2:1701.–.170�.
9.. .Nobile-Orazio. E,. Meucci. N,. Baldini. L,. Di. Troia. A,.
Scarlato. G.. . Long-term. prognosis. of. neuropathy.
associated. with. anti-MAG. IgM. M-proteins. and. its.
relationship.to.immune.therapies...Brain.2000;123:710.
–.717.
10...Kissel. JT,. Mendell. JR.. . Neuropathies. Associated.
with. Monoclonal. Gammopathies.. . Diagnosis. and.
Management. of. Peripheral. Nerve. Disorders. 2001.
Oxford.University.Press,.Inc.:272.-.291.
11.. .Saperstein. DS,. Amato. AA,. Katz. JS,. Barohn. RJ...
Immune-Mediated.Polyneuropathies...Neuromuscular.
Diseases.2001.Butterworth-Heinemann:.1�7.–.167.
12...Wicklund. MP. &. Kissel. JT.. . Paraproteinemic.
Neuropathy...Current.treatment.Options.in.Neurology.
2001;.3.:1�7.-.1�6.
13...Comi.et.al...for.the.Inflammatory.Neuropathy.Cause.
and. Treatment. Group.. . A. randomized. trail. of.
intravenous. immunoglobulin. in. IgM. paraproteins.
associated.demyelinating.neuropathy...J...Neurology.
2002;.2�9:.1370.–.1377.
1�...Ghosh.A,.Littlewood.T.&.Donaghy.M...Cladribine.in.
the.treatment.of. IgM.paraproteinemic.neuropathy...
Neurology.2002;�9:1290.–.1291.
1�...Pletz. MWR,. Duda. PW,. Kappos. L. &. Steck. AJ...
Immune-mediated. neuropathies:. etiology. and.
pathogenic. relationship. to.again.processes.. .J.. .of.
Neuroimmunology.2003;137:1-11..
16...Gorson. KC,. Amato. A. &. Ropper. AH.. . Efficacy. of.
mycophenolate. mofetil. in. patients. with. chronic.
immune.demyelinating.polyneuropathy...Neurology.
200�;.63:71�.–.717.
17.. .Monaco.S,.Turri.E,.Zanusso.G,.Maistrello.B...Treatment.
of. inflammatory.and.paraproteinemic.neuropathies...
Curr.Drug.Targets. Immune.Endocr.Metabol.Disord...
200�.Jun;.�.(2):1�1.–.1�8...Review.
18...P.Kumar,.A.Verma,.D.Kishore,.LD.Parhi,.D.Joshi,.S.
Misra.. . Polyneuropathy. with. Osteosclerotic.
Myeloma.–.POEMS.Syndrome.JAPI..Dec.200�;.Vol...
�2:.997-998.
19...Joint.Task.Force.of.the.EFNS.and.PNS...Guideline.on.
management. of. paraproteinemic. demyelinating.
neuropathies.. . J. Peripher. Nerv. Syst.. . 2006. Mar;..
11.(1):.9.–.19.
20...Gorson.KC,.Allam.G,.Ropper.AH.. .Chronic. inflam-
matory. demyelinating. polyneuropathy:. clinical.
features.and.response.to.treatment.in.67.consecutive.
patients.with.and.without.a.monoclonal.gammopathy...
Neurology.1997;�8:.321-8.
21.. .The.Cochrane.Collaboration:.Immunotherapy.for.IgM.
anti-myelin-associated. glycoprotein. paraproteins-
associated.peripheral.neuropathy.(Review).2007.
�1
BRACHIAL AND LUMBOSACRAL PLEXOPATHIESNEURaLGIC aMYOtROphY/BRaChIaL NEURItIsBACkGRouNDNeuralgic. amyotrophy. is. a. disorder. characterized. by.
attacks.of.pain.associated.with.patchy.weakness.of.the.
upper. limbs.. . Other. terms. used. synonymously. for. this.
disorder. include. brachial. neuritis,. brachial. plexus.
neuropathy. or. neuritis. and. the. Parsonage-Turner.
syndrome.. . Typically,. the. onset. is. acute,. with. severe.
neuropathic.pain.followed.by.weakness.and.sensory.loss,.
and.later.by.muscle.atrophy...The.severe.pain.is.continu-
ously.present.and.may.last.several.weeks...The.weakness,.
wasting.and.sensory.loss.are.often.very.patchy.in.distri-
bution,. suggesting. multifocal. lesions. at. root,. plexus. or.
peripheral.nerve. level(s).. .While.practically.any.site.may.
be.involved,.the.typical.sites.suggested.include.the.upper.
and. middle. trunks,. and. the. anterior. interosseus. nerve,.
long.thoracic.and.suprascapular.nerves...
. An. antecendent. event,. including. infection,. surgery,.
peripartum,. minor. trauma. or. exercise,. immunization. or.
serum.sickness,.is.reported.in.about.half.the.cases...Only.
one.arm.is.involved.in.the.majority,.but.in.a.quarter,.both.
arms.are.involved...While.the.disorder.is.usually.seen.in.
adults,. it. may. occur. in. childhood.. .The. course. of. the.
illness.can.be.quite.variable.with.recovery.times.ranging.
from.a.few.weeks.to.no.recovery.for.years...Overall,.it.has.
been. reported. that. 80-90%. of. patients. have. functional.
recover.after.2-3.years,.but. recent. reports.suggest. this.
may. be. over-optimistic,. with. a. large. patient. series.
reporting.a.majority.of.patients.with.persistent.pain.and.
residual.paresis.and.a.quarter.unable.to.work.after.3.or.
more.years.
. Neuralgic. amyotrophy. is. typically. sporadic. with. a.
reported. incidence. of. 2-3/100,000. per. year.. . A. rare.
hereditary. form. with. autosomal. dominant. inheritance.
exists,.known.as.hereditary.neuralgic.amyotrophy.(HNA)...
Mutations. in. the. SEPT9. gene. were. recently. linked. to.
some.HNA.families...Clinically,.HNA.differs.from.sporadic.
neuralgic. amyotrophy. in. several. aspects.. . Recurrent.
attacks.occur.very.frequently.in.HNA,.although.they.also.
occur. in. NA.. . HNA. patient. may. display. unusual. clinical.
features,. incuding. short. stature,. hypertelorism,. cleft.
palate. and. unusual. skin. folds.. . Cumulative. residual.
disability.follow.repeated.attacks...Like.sporadic.neuralgic.
amyotrophy,.HNA.attacks.are.also.associated.with.similar.
antecedent. events.. . HNA. is. distinct. with. hereditary.
neuropathy. with. liability. to. pressure. palsies. (HNPP),.
which.has.dominant.inheritance.and.is.linked.to.deletion.
of. the. PMP22. gene,. but. which. may. also. present. with.
attacks. resembling. neuralgic. amyotrophy,. except. that.
these.attacks.are.painless.
BRACHIAL AND LUMBOSACRAL PLEXOPATHIES
�2
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
pathOGENEtIC MEChaNIsMs IN NEURaLGIC aMYOtROphYTwo. pathological. studies. of. brachial. plexus. biopsies.
involving. a. total. of. 6. cases. of. neuralgic. amyotrophy,.
presumably. the. non-hereditary. form,. reported. similar.
findings.indicative.of.an.inflammatory.immune.process,.
with.the.presence.of.multifocal.mononuclear.infiltrates.
involving.T. lymphocytes. at. endoneurial,. epineurial. and.
perivascular.sites,.together.with.axonal.degeneration...A.
report.of.upper.limb.peripheral.nerve.biopsies.in.�.HNA.
cases. also. found. epineurial. perivascular. inflammatory.
infiltration.with.vessel.wall.disruption...
tREatMENt Of NEURaLGIC aMYOtROphYCoNVENtIoNALtHERAPyConventional. treatment. of. neuralgic. amyotrophy. has.
generally.been.conservative,.based.on.the.understand-
ing. of. a. relatively. benign. prognosis.. . Patients. have.
generally. been. offered. symptomatic. treatments,.
especially.pain.relief.during.the.acute.phase,.with.reha-
bilitative. measures. and. physical. therapy. to. facilitate.
recovery...Analgesia.offered.should.be.adequate.as.the.
pain. of. neuralgic. amyotrophy. is. usually. severe. and.
disturbing.. . However,. more. recent. patient. series.
suggesting.higher.morbidity.and.disability.may.call.this.
conservative.approach.into.question.
IMMUNE MOdULatING thERapY IN NEURaLGIC aMYOtROphY, INCLUdING IVIGWith. pathological. reports. indicating. an. inflammatory,.
likely. autoimmune,. process,. it. would. appear. that.
immune.modulating.therapy. is.appropriate. in.neuralgic.
amyotrophy.. . However,. to. date,. there. are. only. a. few.
uncontrolled. case. series. reported. involving. different.
immune.modulating.therapies...Suarez.et.al.believed.the.
use. of. prednisolone,. methylprednisolone. and. plasma.
exchange.may.have.benefited.three.of.their.four.patients.
with.neuralgic.amyotrophy...Klein.et.al.treated.four.HNA.
patients,.reporting.dramatic.improvement.in.two.treated.
with. IV. methlprednisolone,. while. the. effect. was.
uncertain.in.two.who.received.oral.prednisone.
. There. are. only. four. single. case. reports. of. IVIG.
treatment.in.neuralgic.amyotrophy,.though.all.suggested.
beneficial.effect.. .Of. these,. the.patient.of.Amato.et.al.
having.conduction.block.and.no.pain.may.not.be.distin-
guished.from.HNPP.with.plexopathy,.while.the.patient.
of. Inoue. et. al. unusually. had. combined. idiopathic. and.
relapsing.brachial.and.lumbosacral.plexopathy...Ardilino.
et.al.reported.a.13.yr.old.patient.with.HNA.in.whom.IVIG.
dramatically.reversed.a.severe.episode.
dIaBEtIC LUMBOsaCRaL pLEXOpathYDiabetic. lumbosacral.plexopathy. is.a.distinct.complica-
tion. of. diabetes. mellitus. characterized. by. subacute,.
painful,.asymmetrical.lower.limb.weakness.and.wasting...
It.occurs.more.commonly.in.older.patients.with.type.II.
diabetic.mellitus,.and.may.be.the.first.manifestation.of.
diabetes.. .The.onset. is.heralded.by.severe.pain. in. the.
lower.back.and.proximal. lower. limbs,.often.associated.
with. sudden. severe. weight. loss.. .This. is. followed. by.
weakness. and. subsequent. wasting. of. predominantly.
proximal.lower.limb.muscles,.with.asymmetrical,.often.
bilateral.and.multifocal.distribution.. .Sensory. loss.may.
be. present. and. variable.. .The. multifocal. localization. of.
signs. and. symptoms. often. suggests. involvement. at.
root,. plexus. and/or. peripheral. nerves.. .The. process. is.
generally.self.limited,.progressing.over.weeks.or.months.
before.stabilizing.with.slow.recovery.though.incomplete.
recovery.with.residual.weakness.is.not.uncommon...The.
disorder.is.also.referred.to.by.several.synonyms.including.
diabetic. lumbosacral. amyotrophy,. diabetic. lumbosacral.
polyradiculo-neuropathy. or. radiculoplexus. neuropathy,.
proximal. diabetic. neuropathy. and. the. Bruns-.
Garland.syndrome.
IdIOpathIC LUMBOsaCRaL pLEXOpathYA.syndrome.similar.to.diabetic.lumbosacral.plexopathy,.
but. unassociated. with. diabetes. mellitus. is. also.
recognized.and.referred.to.as.idiopathic,.primary.or.non-
diabetic. lumbosacral. plexopathy. or. non-diabetic.
lumbosacral. radiculoplexus. neuropathy.. . Otherwise,.
idiopathic.lumbosacral.plexopathy.shares.similar.features.
with.diabetic.lumbosacral.plexopathy,.including.acute.or.
subacute.onset.in.later.life,.prominent.pain.followed.by.
proximal. and. asymmetrical. lower. limb. weakness. and.
wasting.. . The. outcome. is. also. generally. favourable.
although. extended. morbidity. with. significant. residual.
weakness.and.wasting.may.occur.
�3
pathOGENEtIC MEChaNIsMs Of dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathYPathological.studies.of.a.large.series.of.distal.cutaneous.
nerve. biopsies. in. patients. with. diabetic. lumbosacral.
plexopathy. revealed.evidence.of. ischemic. injury. linked.
to. microscopic. vasculitis. as. evidenced. by. epineurial.
perivascular. mononuclear. inflammation,. vessel. wall.
inflammation,. occasionally. with. necrosis,. and. signs. of.
previous. bleeding. involving. small. arterioles,. venules..
or.capillaries...
. Similar.pathological.abnormalities.were.described.in.
idiopathic. lumbosacral. plexopathy. in. distal. cutaneous.
nerve. biopsies. suggesting. a. microvasculitis.. . A. study.
comparing. pathology. in. distal. cutaneous. nerves. of.
diabetic.and.idiopathic.lumbosacral.plexopathy.patients.
concluded. that. the.pathological. alterations.were. indis-
tinguishable,. raising. the. question. whether. the. two.
disorders.have.a.similar.pathogenetic.mechanism.
thERapY IN dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathYAlthough.controlled.trials.with.IVIG.and.methylpredniso-
lone.have.been.reported.to.be. in.progress.for.diabetic.
lumbosacral.plexopathy,.there.are.currently.no.published.
reports.of.such. trials.. .There.are.only.several.single.or.
small.case.series.reporting.the.use.of.prednisone,.IVIG,.
plasma. exchange,. and. cyclophosphamide,. sometimes.
in.combination.. .These. reports. in.general. suggested.a.
beneficial. effect,. with. faster. and. more. marked.
improvement,. from. immune. modulation. therapy.
compared.to.before.therapy...However,.there.is.a.report.
of.failure.of.immunotherapy.in.3.cases,.with.2.patients.
progressing.despite. IVIG.and.1.patient.developing. the.
disorder.while.on.immunosuppressives,.including.cyclo-
sporine.
. There. are. also. no. reports. of. controlled. trials. in.
idiopathic. lumbosacral. plexopathy,. only. single.or. small.
series. case. reports. of. outcome. following. immune.
modulating.therapies.. .Prednisone.use.was.associated.
with.improvement.in.�.of.6.patients,.while.all.11.patients.
given. IV. methylprednisolone. were. reported. to. show.
improvement. of. pain. and. weakness. that. was. better.
than.expected...Up.to.five.single.case.reports.or.small.
case.series. reported.beneficial.effects. from.IVIG.. .The.
largest.of. these.series. reported.five.patients. in.whom.
response.to.IVIG.was.suggested.by.the.temporal.rela-
tionship. of. improvement. to. IVIG. administration. and.
response.to.repeat.treatment.following.deterioration...
EXpERt CONsENsUs There. is. only. anecdotal. and. uncontrolled. evidence.
supporting. a. beneficial. effect. of. IVIG. in. neuralgic.
amyotrophy,.and. in.diabetic.and. idiopathic. lumbosacral.
plexopathy.. . As. such,. a. general. recommendation. for.
IVIG.as.first. line.therapy.in.these.conditions.cannot.be.
made...However,.the.use.of.IVIG.may.be.considered.in.
severely.affected.cases.with.marked.disability.or.debility.
on.a.“trial.of.therapy”.basis...Controlled.clinical.trials.of.
IVIG. are. warranted. in. all. three. disorders. neuralgic.
amyotrophy. to. resolve. the. issue. of. its. value. in. these.
disorders...These.trials.should.also.consider.comparison.
of. IVIG. with. other. immune. modulating. therapies,. in.
particular. with. methylprednisolone,. and. should.
distinguish. between. the. hereditary. and. the. non-
hereditary.forms.of.neuralgic.amyotrophy....
REfERENCEs1.. .Ardolino.G,.Barbieri.S,.Priori.A...High.dose.intravenous.
immune. globulin. in. the. treatment. of. hereditary.
recurrent. brachial. plexus. neuropathy.. . J. Neurol.
Neuorsurg.Psychiat.2003;.7�:��0-��1.
2.. .Cusimano.MD,.Bilbao.JM,.Cohen.SM...Hypertrophic.
brachial.plexus.neuritis:.A.pathological.study.of.two.
cases...Ann.Neurol.1988;.2�:61�-622.
3.. .Dyck. PJB,. Engelstad. J,. Norell. J,. Dyck. PJ...
Microvasculitis.in.non-diabetic.lumbosacral.radiculo-
plexus.neuropathy.(LSRPN):.Similarity.to.the.diabetic.
variety. (DLSRPN).. . J. Peripheral. Nervous. System.
2001...6:
�.. .Dyck.PJB,.Norell.JE,.Dyck.PJ.. .Microvasculitis.and.
ischemia. in. diabetic. lumbosacral. radiculoplexus.
neuropathy...Neurology.1999;.�3:2113-2121.
BRACHIAL AND LUMBOSACRAL PLEXOPATHIES
��
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
�.. .Dyck.PJ,.Windebank.AJ...Diabetic.and.non-diabetic.
lumbosacral. radiculoplexus. neuropathies:. new.
insights.into.pathophysiology.and.treatment...Muscle.
Nerve.2002...2�:�77-�91.
6.. .Filho.FJA,.Nathan.BM,.Palmert.MR,.Katirji.B...Diabetic.
amyotrophy. in. an. adolescent. responsive. to.
intravenous. immunoglobulin.. .Muscle.Nerve.200�...
32:818-820.
7.. .Hollinger. P,. Sturzenegger. M.. . Chronic. progressive.
primary. lumbosacral. plexus. neuritis:. MRI. findings.
and.response.to.immunoglobulin.therapy...J.Neurol.
2000...2�7:1�3-1��.
8.. .Inoue. C,. Hayashi. A,.Yoshizawa.T,. Sato. A,. Shoji. S...
Efect. of. intravenous. immunoglobulin. therapy. in. a.
case.of.idiopathic.recurrent.brachial.and.lumbosacral.
plexopathy...Rinsho.Shinkeigaku.1999...39:661-661.
9.. .Kawagashira.Y,.Watanabe.H,.Oki.Y,.Iijima.M,.Koike.H,.
Hattori.N,.Katsuno.M,.Tanaka.F,.Sobue.G...Intravenous.
immunoglobulin. therapy. markedly. ameliorates.
muscle. weakness. and. severe. pain. in. proximal.
diabetic.neuropathy...J.Neurol.Neurosurg.Psychiatry.
2007...78:899-901.
10...Klein. CJ,. Dyck. PJB,. Friedenberg. SM,. Burns. TM,.
Windebank. AJ,. Dyck. PJ.. . Inflammation. and.
neuropathic. attacks. in. hereditary. brachial. plexus.
neuropathy.. . J. Neurol. Neurosurg. Psychiatry. 2002...
73:��-�0.
11.. .Llewelyn. JG,. Thomas. PK,. King. RHM.. . Epineurial.
microvasculitis. in. proximal. diabetic. neuropathy.. . J.
Neurol.1998...2��:1�9-16�.
12...Park. DH,. Park.YK,. Kim. JH.. . Intravenous. immuno-
globulin. therapy. for. idiopathic. postoperative.
lumbosacral. plexopathy.. . J. Clin. Neurosci.. . 200�...
12:313-31�.
13...Said.G,.Goulon-Goeau.C,.Lacroix.C,.Moulonguet.A...
Nerve.biopsy.findings.in.different.patterns.of.proximal.
diabetic.neuropathy...Ann.Neurol.199�...3�:��9-�69.
1�...Suarez.GA,.Giannini.C,.Bosch.EP,.Barohn.RJ,.Wodak.
J,.Ebeling.P,.Anderson.R,.McKeever.PE,.Bromberg.
MB,.Dyck.PJ...Immune.brachial.plexus.neuropathy:.
suggestive. evidence. for. an. inflammatory-immune.
pathogenesis...Neurology.1996...�6:��9-�61.
1�...Triggs.WJ,.Young.MS,.Eskin.T,.Valenstein.E...Treatment.
of.idiopathic.lumbosacral.plexopathy.with.intravenous.
immunoglobulin...Muscle.Nerve.1997...20:2��-2�6.
16...van.Alfen.N,.van.Engelen.BG...The.clinical.spectrum.
of.neuralgic.amyotrophy.in.2�6.cases...Brain.2006...
129:�38-��0.
17.. .Verma. A,. Bradley. WG.. . High. dose. intravenous.
immunoglobulin. therapy. in. chronic. progressive.
lumbosacral.plexopathy.. .Neurology.199�.. .��:2�8-
2�0.
18...Zochodne.DW,.Isaac.D,.Jones.C...Failure.of. immu-
notherapy. to. prevent,. arrest. or. reverse. diabetic.
lumbosacral. plexopathy. Acta. Neurol. Scand. 2003..
107:299-301.
��
MYASTHENIA GRAVISCLINICaL INfORMatIONMyasthenia. gravis. (MG). is. an. autoimmune. disease.
associated.with.the.presence.of.antibodies.to.the.ace-
tylcholine. receptors. (AChR). at. the. neuromuscular.
junction..However,.these.antibodies.cannot.be.detected.
in.up.to.20%.of.patients.with.generalized.MG.(serone-
gative. MG)1.. Recently,. antibodies. to. muscle-specific.
tyrosine.kinase. (MuSK),.a.surface.membrane. receptor.
essential. for. the. development. of. the. neuromuscular.
junction.(by.mediating.agrin-induced.clustering.of.AChR.
during. synapse. formation2),. were. found. in. 70%. of. 2�.
seronegative.generalized.MG.patients.in.one.series.and.
37.�%.of.32.such.patients.in.another.series3,.�...Antibodies.
to. MuSK. have. also. been. studied. in. some. Asian.
populations. with. variable. findings. being. detected. in.
2.�%.of.�3.mainland.Chinese,.�%.of.26.Taiwan.Chinese,.
26.7%.of.Korean.and.�1%.of.17.Japanese.seronegative.
generalized.MG.patients�-8.
. Clinical. features. are. characterised. by. fluctuating.
weakness.and.fatigability.of.voluntary.muscles,.namely.
levator.palpebrae,.extraocular,.bulbar,.limb.and.respiratory.
muscles.. . Patients. usually. present. with. unilateral. or.
bilateral. drooping. of. eyelid. (ptosis),. double. vision.
(diplopia),. difficulty. in. swallowing. (dysphagia). and.
proximal. muscle. weakness.. .Weakness. of. respiratory.
muscles.can.result.in.respiratory.failure.in.severe.cases.
or. in. acute. severe. exacerbations. (myasthenic. crisis)...
This. is. life-threatening. and. requires. mechanical.
ventilation..Although.clinical.characteristics.of.seronega-
tive.MG.(SNMG).are.similar.to.those.of.seropositive.MG.
(SPMG),.subsets.of.SNMG.patients.have.predominant.
oculobulbar.weakness.and.poor.response.to.therapy9,.10...
These. features. are. seen. in. MuSK. antibody. positive.
SNMG.patients.(who.are.often.female).contrasting.with.
MuSK.antibody.negative.SNMG.patients.who.are.more.
likely.to.have.generalized.weakness.and.better.response.
to.treatment11,.12.
. The.pathogenesis.of.MG.involves.an.immune.attack.
directed. against. AChR. of. skeletal. muscles. by. the.
antibodies.to.AChR.resulting.in.an.increase.in.degradation.
of. AChR13.. . Complement-mediated. processes. cause.
destruction. of. the.AChR. and. lysis. of. the. postsynaptic.
junctional.folds..Antibodies.also.impair.AChR.function.by.
blocking.binding.of.ACh.to.their.receptors1�...The.factors.
involved.in.the.initiation.or.induction.of.autoimmune.MG.
are. unknown.. . However,. MG. is. associated. with. other.
immune. system. abnormalities. particularly. prominent.
being.abnormalities.in.the.thymus.gland...Approximately.
1�%.of.patients.have.thymoma.and.another.60%.have.
thymic.hyperplasia...There.is.also.a.marked.increase.in.
MYASTHENIA GRAVIS
�6
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
other.autoantibodies.and.autoimmune.diseases1�,e.g.,.
systemic. lupus.erythematosus16-18,.hypothyroidism.and.
hyperthyroidism16,. 19,. 20,. autoimmune. thrombocytopenic.
purpura. and. autoimmune. hemolytic. anemia21,.
scleroderma22,. multiple. sclerosis23,. 2�,. neuromyotonia2�,.
26. and. Lambert-Eaton. myasthenic. syndrome27-29..
Congenital.myasthenic.syndromes.(CMS).are. inherited.
disorders. of. neuromuscular. transmission. that. do. not.
have.an.underlying.autoimmune.mechanism...They.are.
a.heterogeneous.group.of.disorders.caused.by.a.variety.
of. genetic. defects. and. are. rare. compared. with.
autoimmune. forms. of. myasthenia30-32.. . The. gradual.
evolution.of.myasthenia.has.been.linked.to.a.number.of.
drugs,.especially.D-penicillamine.
. Diagnosis.can.usually.be.made.from.the.characteris-
tic. clinical. features.. .This. can. be. confirmed. by. one. or.
more. of. the. following. tests:. bed-side. injection. of.
edrophonium. hydrochloride. (Tensilon. test)33. or.
neostigmine,.ice.pack.test3�-36,.repetitive.nerve.stimulation.
test.(RNST)37,.38,.single-fiber.electromyography.(SFEMG)38,.
39. and. serum. AChR. antibodies�0.. . Five. to. ten. mg. of.
edrophonium,.a.short-acting.cholinesterase. inhibitor,. is.
slowly.administered.intravenously.and.the.effect.can.be.
observed.within.30.seconds.to.1.minute.. .The.striking.
response. can.usually. be.observed. as. improvement.of.
eye.opening.(less.weakness.of.levator.palpebrae.or.less.
ptosis). and. improvement. of. strength. of. paretic.
extraocular. muscles. lasting. up. to. �. minutes. whereas.
observed.strength.of.limb.muscles.is.largely.dependent.
on.patient's.effort.and.is.less.reliable..If.edrophonium.is.
not. available,. neostigmine,. a. longer-acting. cholinester-
ase.inhibitor,.can.be.given.at.a.dose.of.0.�.mg..intrave-
nously. or. 1.0. mg. intramuscularly.. .Atropine. should. be.
given. at. the. dose. of. 0.6. mg. prior. to. neostigmine. to.
counter. muscarinic. side. effects.. . The. effect. can. be.
observed. after. several. minutes.. Since. the. effect. of.
neostigmine. lasts. rather. long,. respiratory. function.can.
also.be.assessed.in.severe.cases...However,.this.test.is.
neither. absolutely. sensitive. nor. specific. for. MG. and.
patients. with. weakness. from. other. diseases,. e.g.,.
Lambert-Eaton. myasthenic. syndrome,. motor. neuron.
disease.and.mitochondrial.myopathy,.etc.,.can.also.give.
positive.response.at.times...Therefore,.this.test.alone.is.
not. diagnostic. of. MG.. In. ice. pack. test,. an. ice. pack. is.
placed. over. the. ptotic. eyelid. for. 2. minutes. and. the.
response.is.then.assessed.by.observing.whether.ptosis.
improves.. It. was. reported. to. be. both. sensitive. and.
specific. for. the. diagnosis. of. MG3�-36,. �1.. . RNST. is. the.
most. commonly. used. electrophysiological. test. being.
quite.sensitive.and.easily.performed...It.is.best.recorded.
in. proximal. limb. or. facial. muscles,. i.e.,. anconeus,.
trapezius,.orbicularis.oculi.and.nasalis.with.low.frequency.
(3Hz).stimulation.on.respective.nerves..A.decrement.of.
10%.or.more.is.considered.abnormal.and.suggestive.of.
abnormal.neuromuscular. transmission.. .SFEMG. is. the.
most.sensitive.test.in.the.diagnosis.of.MG39,.�2.but.it.is.
more. difficult. to. perform. and. needs. expertise. of. the.
electromyographer...Extensor.digitorum.communis.and.
orbicularis. oculi. are. the. two. most. commonly. used.
muscles.. . SFEMG. or. concentric. needle. electrode. is.
positioned.to.record.action.potentials.from.two.muscle.
fibers. in. one. voluntarily. or. electrically. activated. motor.
unit...A.variation.in.the.time.intervals.between.each.pair.
of. the.action.potentials. is.called.neuromuscular. 'jitter'...
When. neuromuscular. transmission. is. disturbed,. the.
variation.in.the.time.intervals.(jitter).is.increased.because.
it. takes. longer. for. the. endplate. potential. to. reach. the.
threshold. for. action.potential. generation.and. this. time.
varies39.. . Reference. values. for. jitter. measured. during.
voluntary. activation. have. been. determined. for. many.
muscles�3...Antibodies.to.the.AChR.is.generally.regarded.
as.the.most.specific.diagnostic.marker.for.MG.and.are.
present.in.about.8�%.of.the.cases.as.measured.by.the.
conventional. radioimmunoprecipitation. assay�0,. ��...
Normal. AChR. antibody. concentrations. do. not. exclude.
the.diagnosis..
. There.is.evidence.that.the.natural.history.of.MG.is.
characterized.by.exacerbations.and.remissions.similar.to.
those. seen. in.other. autoimmune.diseases.. .The.most.
striking. initiating. factor. of. exacerbation. has. been.
infection.. . Respiratory. failure. is. the. most. common.
cause. of. death.. . Advance. technology. in. artificial.
ventilation.has.significantly.contributed.to.the.decreased.
mortality. from. �0%. to. �%��.. Similarly,. improved.
antibiotics.have.also.reduced.mortality.from.respiratory.
and. other. infections. in. patients. with. severe. exacerba-
tions...The.clinical.features.of.drug-induced.myasthenic.
syndrome. are. similar. to. idiopathic. MG. and. serum.
�7
antibodies.to.AChR.may.be.detected..Gradual.recovery.
is.common.upon.withdrawal.of.the.drug...However,.full.
recovery. after. drug. withdrawal. does. not. occur. in. all.
patients.and.MG.may.persist.with.a.need.for.immuno-
suppressive. therapy.. . In.such.cases,. it.may.be.argued.
that.the.drug.unmasked.a.pre-existing.immune-mediated.
disorder.of.the.neuromuscular.junction�6.
. Available. therapies. include. symptomatic. treatment.
with. cholinesterase. inhibitors. such. as. pyridostigmine,.
specific. treatment.with. immunosuppressive.drugs.par-
ticularly.corticosteroids.and.thymectomy..Pyridostigmine.
is.usually.effective.early.in.the.disease.course.or.for.mild.
cases.. .There. is. often. a. marked. improvement. at. the.
beginning. of. the. treatment. but. the. effect. tends. to.
lessen.over.time.and.increasing.doses.are.required.for.
the.same.result.. .The.more.effective. treatment. is. that.
which.directly. targets. the.autoimmune.response.. .The.
strategy.of.treatment.is.to.first.induce.a.remission.and.
then. to. maintain. the. remission. (complete. or. nearly.
complete.absence.of.symptoms)�7...This.can.be.achieved.
by. thymectomy.or. immunosuppressive.drugs..Despite.
the. absence. of. randomized. well-controlled. studies,.
thymectomy.in.MG.patients.with.and.without.thymoma.
is. widely. practised.. . From. the. report. of. the. Quality.
Standards.Subcommittee.of.the.American.Academy.of.
Neurology,.it.is.asserted.that.thymectomy.increases.the.
probability. of. remission. or. improvement. and. that.
patients.with.generalized.MG.and.AChR.antibodies.are.
the.group.most.probably. to.benefit�8,.�9.. .The.effect.of.
thymectomy. may. be. felt. within. months. after. the.
operation.but.is.often.not.apparent.until.after.1.year.and.
the.full.effect.may.not.be.achieved.for.up.to.�.years�0,.�1...
The. indication. for. thymectomy. in. SNMG. patients. is.
controversial.. .Two. retrospective. studies. showed. that.
the.response.to.thymectomy.was.similar.in.SPMG.and.
SNMG. patients. whereas. other. studies. revealed. that..
SNMG. patients. with. anti-MuSK. antibodies. have. no.
benefit. from. thymectomy�,. 11.. . In. MG. patient. with. a.
thymoma,. thymectomy. is. indicated. irrespective.of. the.
severity.of.MG..
. Corticosteroids. are. the. mainstay. of. immunosup-
pressive.treatment.for.MG.in.spite.of.their.side.effects�2...
In. observational. studies,. remission. or. marked.
improvement. was. seen. in. the. majority. of. patients.
treated. with. prednisolone�3.. . Limited. evidence. from.
randomised. controlled. trials. suggests. that. corticoste-
roid. treatment. offers. significant. short-term. benefit. in.
myasthenia.gravis.compared.with.placebo��...Azathioprine.
is.also.useful.alone.to.induce.a.remission.but.it.has.slow.
onset.of.action.and.can.take.3-12.months.to.have.any.
effect.. . Limited. evidence. from. randomised. controlled.
trials.does.not.show.any.difference.in.efficacy.between.
corticosteroids.and.azathioprine��.. . It.was.mostly.used.
in. conjunction. with. corticosteroids��-�7.. A. randomized.
double-blind.trial.has.demonstrated.that.the.addition.of.
azathioprine. to.prednisolone. lowered. the.maintenance.
dose. of. prednisolone. and. was. associated. with. longer.
remission. and. fewer. treatment. failures�8.. . In. patients.
failing.to.respond.to.azathioprine.or.who.are. intolerant.
of.it.may.try.other.drugs..Cyclosporine.was.shown.to.be.
effective. in. a. randomized. controlled. trial. but. adverse.
effects.caused.one-third.of.the.patients.to.discontinue.
the. medication�9.. . One. retrospective. study. also.
supported.the.beneficial.effect.of.cyclosporine.in.MG60..
Cyclophosphamide. (CP). is. another. useful. drug61,. 62.
which. can. be. administered. orally. and. intravenously..
Monthly.intravenous.pulse.CP.was.used.in.a.randomized.
double-blind. trial. in. patients. with. severe. disease.
responding. poorly. to. corticosteroids.. Significant.
improvement.was.reported.in.the.CP.group.and.cortico-
steroid.dose.could.be.tapered63...Mycophenolate.mofetil.
(MyM),.a.new.immunosuppressive.agent,. is.safe,.well.
tolerated. and. associated. with. objective. evidence. of.
clinical.improvement.in.approximately.three-quarters.of.
treated.patients6�-67...In.one.retrospective.review,.it.was.
effective.as.an.adjunctive.and.steroid-sparing.agent.and.
as.the.initial.or.sole.form.of.immunotherapy.but.it.was.
not.as.effective. in. 'refractory'.patients.of.whom.fewer.
than.half.improved...In.this.study,.patients.who.improved.
with.MyM.treatment.had.the.onset.of.objective.benefit.
on. average. 10.7. weeks. from. the. time. of. treatment.
initiation.ranging.from.as.early.as.�.weeks.to.as.late.as.
�0.weeks.with.maximal.benefit.occurring.at.a.mean.of.
26.weeks..The.main.advantage.of.MyM.appeared.to.be.
its.tolerability.and.safety.profile66...However,.randomized.
controlled.trials.(RCT).are.needed.to.confirm.its.efficacy...
Tacrolimus.is.a.new.drug.which.has.recently.been.used.
in. MG.. Case. reports. and. open. clinical. trials. showed.
MYASTHENIA GRAVIS
�8
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
improvement. in. various. proportions. of. the. treated.
patients. without. serious. side. effects68-73.. . From. the.
available.information,.it.can.be.concluded.that.tacrolimus.
may.be.useful. in. the. treatment.of.MG.and.can.safely.
serve. as. an. adjunct. to. steroid. therapy. but. RCTs. are.
needed.to.support.its.efficacy.
. In. severe. disease. or. acute. severe. exacerbations,.
plasma.exchange.(PE).and.intravenous.immunoglobulin.
(IVIG).are.two.treatments.with.rapid.onset.of.effect..PE.
and. IVIG. may. be. helpful. in. preparing. patients. with.
moderate. to. severe. symptoms. for. thymectomy.. The.
rationale. for. PE. is. that. the. bulk. removal. of. antibody.
would.reduce.the.autoimmune.attack.at.the.neuromus-
cular. junction.. . The. therapeutic. function. of. IVIG. is.
complex.. Its. main. effects. include. elimination. of.
pathogens.by.natural.and.immune.antibodies,.provision.
of.anti-idiotypic.antibodies.which.may.bind.pathogenic.
autoantibodies. thereby. preventing. binding. of. them. to.
autoantigens,. inhibition.of.T-cell. and.B-cell.proliferation.
thereby.suppressing.autoantibody.production,.inhibition.
of. the. compliment. cascade. and. neutralization. of.
cytokines.by.anti-cytokine.autoantibodies7�...As.regards.
PE,.there.are.no.adequate.randomized.controlled.trials.
but. many. case. series. reported. short-term. benefit.
especially.in.myasthenic.crisis7�...A.randomized.controlled.
trial.showed.PE.and.IVIG.to.be.of.equal.benefit76...In.a.
retrospective. case. study. of. myasthenic. crisis,. PE.
resulted. in. a. significantly. better. ventilatory. outcome.
than. IVIG. treatment77.. Another. randomized. controlled.
trial. comparing. the.efficacy.of.PE.and. IVIG. in.patients.
with. moderate. to. severe. stable. MG,. there. was. no.
significant.difference.between.the.two.treatments.but.
the. improvement.was.faster.after.PE.than.after. IVIG78...
Occasionally,.patients.who.fail. to.respond.to. IVIG.may.
improve.after.PE79...The.recommended.protocols.are.to.
remove.one.plasma.volume.daily. or. on. alternate.days.
for. �. treatments. or. one. and. a. half. plasma. volume. on.
alternate.days.for.3.treatments.. .The.standard.dose.of.
IVIG. is.2.g/kg.over.2-�.days. (usually.0.�.g/kg/day.for.�.
consecutive.days)...Recently,.one.randomized.controlled.
trial.showed.that.IVIG.at.the.dose.of.1.g/kg.for.1.day.and.
1.g/kg/day.for.2.days.were.equally.effective80.
OBJECtIVEsTo.examine.the.efficacy.of.IVIG.in.the.treatment.of.MG:
1.. Acute.exacerbation.and.myasthenic.crisis
2.. MG.with.worsening.weakness
3.. Moderate.to.severe.stable.MG
INtRaVENOUs IMMUNOGLOBULIN fOR MG EXaCERBatIONs aNd MYasthENIC CRIsIsIVIGVERSuSPEEfficacy.of.IVIG.has.been.established.for.the.treatment.
of.myasthenic.crisis...There.has.been.RCT.by.Gajdos.et.
al. comparing. IVIG. with. PE. and. comparing. 2. doses. of.
IVIG.. . In. the. PE. group,. patients. received. 3. PE. of. 1.�.
plasma.volume.every.other.day..The. IVIG.group.had.2.
arms:.in.one.arm,.patients.received.IVIG.0.�.g/kg/day.for.
3.days.and.in.the.other.arm,.patients.received.0.�.g/kg/
day.for.�.days..If.the.patients.had.been.on.immunosup-
pressive. treatment. before. randomization,. those. drugs.
were.continued.without.any.change.in.dosage..Eighty-
seven. participants. were. included:. �1. in. the. PE. group.
and.�6.in.the.IVIG.group.(23.each.in.the.3-day.and.�-day.
groups).. . There. was. no. difference. in. the. efficacy.
between. PE. and. IVIG. groups. nor. between. the. 3-day.
(total.1.2.g/kg).and.�-day.(total.2.g/kg).IVIG.groups..In.the.
PE.group,.19.�%.developed.adverse.effects.consisting.
of. hemolysis,. hematoma,. catheter-related. venous.
thrombosis,.fever,.nausea,.hypotension.and.tachycardia..
In. the. IVIG. group,. one. patient. (2.2%). had. headache..
Adverse.events.led.to.discontinuation.of.PE.in.2.partici-
pants. (femoral. venous. thrombosis. and. retroperitoneal.
hematoma)76.
. A. retrospective.multicenter. case.study.by.Qureshi.
et. al. compared. the. efficacy. of. PE. and. IVIG. in. ��.
episodes.of.myasthenic.crisis...Participants.were.treated.
with.�.or.6.PE.or.with.IVIG.0.�.g/kg/day.for.�.days...One.
week.after.initiation.of.treatment,.there.was.significant.
improvement.in.both.groups...Ventilatory.status.at.two.
weeks. and. outcome. at. one. month. were. significantly.
better.in.the.PE.group.but.total.hospital.stay.was.longer.
in.the.PE.group...Complication.rate.was.higher.with.PE.
group.(13.VS.�.complications)...However,.this.study.was.
retrospective. and. there. was. a. hospital. bias. toward.
selection.of.a.particular.treatment77.
�9
IVIGVERSuSMEtHyLPREDNISoLoNEThere.has.been.one.RCT.by.Schuchardt.(Schuchardt.et.
al,.2002.unpublished.data).comparing.IVIG.to.oral.meth-
ylprednisolone...Participants.were.randomized.to.receive.
either. IVIG.30.g/day. for.�.days.and.placebo. tablets.or.
methylprednisolone. tablets. 1. mg/kg/day. increased. to.
1.�. mg/kg/day. on. day. 7. and. infusion. of. 1. %. human.
albumin..Thirty-three.patients.were. included.with.1�. in.
the.IVIG.group.and.18.in.the.methylprednisolone.group...
There.was.no.significant.difference.of.efficacy.between.
these. 2. groups.. Adverse. events. in. the. IVIG. group.
included. headache,. hypertension,. allergic. reaction. and.
chill.and.those.in.the.methylprednisolone.group.included.
mild. hyperglycemia,. hypertension. and. agitation.. .The.
weak. point. of. this. RCT. is. that. it. did. not. recruit. the.
number.of.participants.required.and.so.was.underpow-
ered.in.relation.to.the.study.objectives.
HIGHDoSEVERSuSLoWDoSEIVIGOne. randomized. double-blind. placebo-controlled.
multicenter.trial.by.Gajdos.et.al.was.aimed.to.determine.
the.optimal.dose.of.IVIG.for.treating.MG.exacerbation...
This.study.was.designed.to.demonstrate.superiority.of.
the.2.g/kg.dose.over.the.1.g/kg.dose.of.IVIG...Participants.
were.randomly.assigned.to.receive.1.g/kg.of.IVIG.on.day.
1. and. placebo. on. day. 2. (group. 1). versus. 1. g/kg. on. 2.
consecutive.days.(group.2)..One.hundred.and.seventy-
three.patients.aged.1�-8�.years.with.acute.MG.exacer-
bation.were.included...Improvement.in.the.myasthenic.
muscular. score. was. measured. after..
2.weeks...There.was.no.significant.superiority.of.2.g/kg.
over.1.g/kg.of.IVIG80.
INtRaVENOUs IMMUNOGLOBULIN fOR MG WIth WORsENING WEaKNEssIVIGVERSuSPLACEBoA.recent.randomized,.placebo-controlled,.masked.study.
by.Zinman.et.al.was.aimed.to.determine.the.effective-
ness. of. IVIG. in. the. treatment. of. MG. patients. with.
worsening. weakness.. . Fifty-one. such. patients. were.
randomized. to. infusion. with. 2. g/kg. of. IVIG. or. an.
equivalent. volume. of. IV. �%. dextrose. in. water. over. 2.
days.. . The. Quantitative. Myasthenia. Gravis. Score. for.
Disease.Severity.(QMGSDS).was.calculated.by.a.masked.
observer.at.baseline.and.days.1�.and.28.. . In. the. IVIG.
group,.there.was.significant.improvement.in.QMGSDS.
as.compared.to.placebo.at.day.1�.and.persisted.at.day.
28...The.greatest.improvement.occurred.in.patients.with.
more. severe. disease.. . There. were. no. serious. side.
effects.with.headache.being.the.most.frequent.one81.
INtRaVENOUs IMMUNOGLOBULIN fOR MOdERatE tO sEVERE staBLE MGIVIGVERSuSPEThere. has. been. one. RCT. by. Ronager. et. al. comparing.
the.efficacy.of.IVIG.and.PE.in.patients.with.moderate.to.
severe. stable. MG. in. a. controlled. cross-over. study...
Participants. were. randomly. assigned. to. receive. either.
IVIG.0.�.g/kg/day.for.�.days.and.�.PE.every.other.day.16.
weeks. later. or. firstly. �. PE. and. IVIG. 16. weeks. later..
Twelve. participants. were. included.. . There. was. no.
significant.difference.between.the.two.treatments.after..
�.weeks.but.the.improvement.had.a.more.rapid.onset.
after. PE. than. after. IVIG.. . Adverse. events. from. PE.
included.hypotension,.vomiting,.deep.venous.thrombosis.
and. arterial. bleeding.. . Adverse. effects. of. IVIG. were.
fever,. headache,. nausea. and. vomiting78.. .The. pitfall. of.
this. study. is. the. insufficient. number. of. participants.
included.
IVIGVERSuSPLACEBoOne.RCT.by.Wolfe.et.al.compared.IVIG.with.�%.albumin.
as. placebo.. . Fifteen. participants. were. included,. six.
being.in.the.IVIG.arm.and.nine.in.the.placebo.arm...They.
were. randomized. to. receive. either. IVIG. 1. g/kg. or. �%.
albumin.on.days.one.and.two...A.1.g/kg.IVIG.or.placebo.
was. repeated. on. day. 22.. . There. was. no. significant.
difference. in. the. quantified. myasthenia. gravis. score.
from.day.0.to.day.�2.between.the.2.groups..However,.
this.study.was.underpowered82.
IVIGASMAINtENANCEtHERAPyTwo.open-label.trials.by.Achiron.et.al.and.Hilkevich.et.al.
treating.10.and.11.patients.with.severe.generalized.MG.
respectively.with. IVIG.at.an. initial.dose.of.2.g/kg.over..
�.days.followed.by.maintenance.doses.of.0.�.g/kg.every.
�-6.weeks...All.patients.improved.at.1-2.years.and.doses.
of. prednisolone. could. be. reduced83,. 8�.. . However,. it. is.
MYASTHENIA GRAVIS
60
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
difficult. to. deduce. from. these. uncontrolled. studies.
whether.there.is.a.drug.sparing.effect.
sUMMaRY There.is.good.evidence.that.IVIG.is.as.effective.as.PE.for.
the. treatment. of. myasthenia. gravis. exacerbations. and.
myasthenic. crisis..There. is. no. significant. difference. in.
efficacy.between.1.g/kg.and.2.g/kg.of. IVIG.. In.chronic.
MG,. there. is. no. sufficient. evidence. from. RCT. to.
determine.whether.IVIG.is.efficacious.. .More.research.
is.needed.to.determine.whether.IVIG.reduces.the.need.
for.steroids.as.suggested.by.two.case.series8�...There.is.
evidence. from. one. RCT. that. IVIG. is. effective. in. MG.
patients. with. worsening. weakness.. . The. greatest.
improvement. occurred. in. patients. with. more. sever.
disease81.
Dosage:. There. are. various. recommended. doses. and.
durations
•. .0.�.g/kg/day.for.3-�.days.(a.total.dose.of.1.2.g/kg.is.
as.effective.as.2.g/kg)
•. .1.g/kg/day.for.1-2.days.(a.total.dose.of.1.g/kg.is.as.
effective.as.2.g/kg)
REPoRtED ADVERSE EffECtS:. headache,. hypertension,.
allergic. reaction,. fever,. chill,. nausea. and. vomiting,.
aseptic. meningitis,. renal. tubular. acidosis,. hemolysis,.
serum.viscosity.and.thromboembolic.events.
EXpERt CONsENsUs1.. .IVIG.is.recommended.for.myasthenia.gravis.exacer-
bations,.myasthenic.crisis.and.patients.with.severe.
weakness.poorly.controlled.with.other.agents.or.in.
lieu.of.PE.
2.. .A.dose.of.IVIG.of.1.g/kg.for.1.day.can.be.used.in.the.
treatment.of.MG.exacerbations.
REfERENCEs1.. .Mossman.S,.Vincent.A,.Newsom-Davis.J..Myasthenia.
gravis. without. acetylcholine-receptor. antibody:. a.
distinct.disease.entity..Lancet.1986;1(8�73):116-9.
2.. .Liyanage.Y,.Hoch.W,.Beeson.D,.Vincent.A..The.agrin/
muscle-specific. kinase. pathway:. new. targets. for.
autoimmune.and.genetic.disorders.at.the.neuromus-
cular.junction..Muscle.Nerve.2002;2�(1):�-16.
3.. .Hoch.W,.McConville.J,.Helms.S,.Newsom-Davis.J,.
Melms.A,.Vincent.A..Auto-antibodies.to.the.receptor.
tyrosine. kinase. MuSK. in. patients. with. myasthenia.
gravis. without. acetylcholine. receptor. antibodies..
Nat.Med.2001;7(3):36�-8.
�.. .Sanders.DB,.El-Salem.K,.Massey.JM,.McConville.J,.
Vincent.A..Clinical.aspects.of.MuSK.antibody.positive.
seronegative.MG..Neurology.2003;60(12):1978-80.
�.. .Zhang.X,.Yang.M,.Xu.J,.Zhang.M,.Lang.B,.Wang.W,.
et. al.. Clinical. and. serological. study. of. myasthenia.
gravis.in.HuBei.Province,.China..J.Neurol.Neurosurg.
Psychiatry.2007;78(�):386-90.
6.. .Yeh. JH,. Chen. WH,. Chiu. HC,. Vincent. A.. Low.
frequency.of.MuSK.antibody.in.generalized.serone-
gative.myasthenia.gravis.among.Chinese..Neurology.
200�;62(11):2131-2.
7.. .Lee.JY,.Sung.JJ,.Cho.JY,.Oh.DH,.Kim.HJ,.Park.JH,.
et. al.. MuSK. antibody-positive,. seronegative.
myasthenia. gravis. in. Korea.. J. Clin. Neurosci.
2006;13(3):3�3-�.
8.. .Ohta.K,.Shigemoto.K,.Kubo.S,.Maruyama.N,.Abe.Y,.
Ueda. N,. et. al.. MuSK. antibodies. in. AChR. Ab-sero-
positive. MG. vs. AChR. Ab-seronegative. MG..
Neurology.200�;62(11):2132-3.
9.. .Birmanns. B,. Brenner. T,. Abramsky. O,. Steiner. I..
Seronegative. myasthenia. gravis:. clinical. features,.
response.to.therapy.and.synthesis.of.acetylcholine.
receptor. antibodies. in. vitro.. J. Neurol. Sci.
1991;102(2):18�-9.
61
10...Evoli. A,. Batocchi. AP,. Lo. Monaco. M,. Servidei. S,.
Padua.L,.Majolini.L,.et.al..Clinical.heterogeneity.of.
seronegative. myasthenia. gravis.. Neuromuscul.
Disord.1996;6(3):1��-61.
11.. .Evoli.A,.Tonali.PA,.Padua.L,.Monaco.ML,.Scuderi.F,.
Batocchi.AP,.et.al..Clinical.correlates.with.anti-MuSK.
antibodies. in. generalized. seronegative. myasthenia.
gravis..Brain.2003;126(Pt.10):230�-11.
12...Vincent. A,. McConville. J,. Farrugia. ME,. Newsom-
Davis. J.. Seronegative. myasthenia. gravis.. Semin.
Neurol.200�;2�(1):12�-33.
13...Drachman. DB,. Angus. CW,. Adams. RN,. Michelson.
JD,. Hoffman. GJ.. Myasthenic. antibodies. cross-link.
acetylcholine.receptors.to.accelerate.degradation..N.
Engl.J.Med.1978;298(20):1116-22.
1�...Drachman. DB,. Adams. RN,. Josifek. LF,. Self. SG..
Functional.activities.of.autoantibodies.to.acetylcho-
line.receptors.and.the.clinical.severity.of.myasthenia.
gravis..N.Engl.J.Med.1982;307(13):769-7�.
1�...Wolf.SM,.Rowland.LP,.Schotland.DL,.McKinney.AS,.
Hoefer. PF,. Aranow. H,. Jr.. Myasthenia. as. an.
autoimmune.disease:.clinical.aspects..Ann.N.Y.Acad.
Sci.1966;13�(1):�17-3�.
16...Zonana.MF,.Reyes.E,.Weisman.AK..Coexistence.of.
four.autoimmune.diseases.in.one.patient:.the.kalei-
doscope. of. autoimmunity.. J. Clin. Rheumatol.
2002;8(6):322-�.
17.. .Sthoeger.Z,.Neiman.A,.Elbirt.D,.Zinger.H,.Magen.E,.
Burstein.R,.et.al..High.prevalence.of.systemic.lupus.
erythematosus. in.78.myasthenia.gravis.patients:. a.
clinical. and. serologic. study.. Am. J. Med. Sci.
2006;331(1):�-9.
18...Iwadate. H,. Kobayashi. H,. Shio. K,. Noguchi. E,.
Watanabe.K,.Sasajima.T,. et. al..A. case.of. systemic.
lupus. erythematosus. complicated. by. pure. red. cell.
aplasia. and. idiopathic. portal. hypertension. after.
thymectomy..Mod.Rheumatol.2006;16(2):109-12.
19...Ratanakorn. D,. Vejjajiva. A.. Long-term. follow-up. of.
myasthenia. gravis. patients. with. hyperthyroidism..
Acta.Neurol.Scand.2002;106(2):93-8.
20...Toth. C,. McDonald. D,. Oger. J,. Brownell. K..
Acetylcholine. receptor. antibodies. in. myasthenia.
gravis. are. associated. with. greater. risk. of. diabetes.
and. thyroid. disease.. Acta. Neurol. Scand.
2006;11�(2):12�-32.
21.. .Wakata.N,.Kiyozuka.T,.Konno.S,.Nakazora.H,.Nomoto.
N,.Sugimoto.H,.et.al..Autoimmune.thrombocytope-
nic. purpura,. autoimmune. hemolytic. anemia. and.
gastric.cancer.appeared.in.a.patient.with.myasthenia.
gravis..Intern.Med.2006;��(7):�79-81.
22...Zivkovic.SA,.Medsger.TA,.Jr..Myasthenia.gravis.and.
scleroderma:.Two.cases.and.a.review.of.the.literature..
Clin.Neurol.Neurosurg.2007;109(�):388-91.
23...Furukawa. Y,. Yoshikawa. H,. Yachie. A,. Yamada. M..
Neuromyelitis. optica. associated. with. myasthenia.
gravis:. characteristic. phenotype. in. Japanese.
population..Eur.J.Neurol.2006;13(6):6��-8.
2�...Kister.I,.Gulati.S,.Boz.C,.Bergamaschi.R,.Piccolo.G,.
Oger.J,.et.al..Neuromyelitis.optica. in.patients.with.
myasthenia. gravis. who. underwent. thymectomy..
Arch.Neurol.2006;63(6):8�1-6.
2�...Fukushima.K,.Sato.T,.Mitsuhashi.S,.Kaneko.K,.Yazaki.
M,.Matsuda.M,.et.al.. Isaacs'.syndrome.associated.
with. myasthenia. gravis,. showing. remission. after.
cytoreductive. surgery. of. pleural. recurrence. of.
thymoma..Neuromuscul.Disord.2006;16(11):763-�.
MYASTHENIA GRAVIS
62
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
26...Antelli.A,.Spengos.K,.Zambelis.T,.Pandis.D,.Tsivgoulis.
G,. Zis.V.. Neuromyotonia. and. myasthenia. gravis. in.
the.absence.of.thymoma..Eur.J.Neurol.2006;13(7):
e�.
27.. .Oh. SJ,. Sher. E.. MG. and. LEMS. overlap. syndrome:.
case. report. with. electrophysiological. and. immuno-
logical. evidence.. Clin. Neurophysiol. 200�;116(�):.
1167-71.
28...Roohi.F,.Smith.PR,.Bergman.M,.Baig.MA,.Sclar.G..A.
diagnostic. and. management. dilemma:. combined.
paraneoplastic. myasthenia. gravis. and. Lambert-
Eaton. myasthenic. syndrome. presenting. as. acute.
respiratory.failure..Neurologist.2006;12(6):322-6.
29...Sha.SJ,.Layzer.RB..Myasthenia.gravis.and.Lambert-
Eaton. myasthenic. syndrome. in. the. same. patient..
Muscle.Nerve.2007.
30...Engel.AG..The.investigation.of.congenital.myasthenic.
syndromes..Ann.N.Y.Acad.Sci.1993;681:�2�-3�.
31.. .Beeson.D,.Palace.J,.Vincent.A..Congenital.myasthenic.
syndromes..Curr.Opin.Neurol.1997;10(�):�02-7.
32...Newsom-Davis.J,.Beeson,.D..Myasthenia.gravis.and.
myasthenic. syndrome:. autoimmune. and. genetic.
disorders..In:.Karpati.G,.Hilton-Jones,.D,.Griggs,.RC,.
editor.. Disorders. of. voluntary. muscle.. 7th. ed..
Cambridge:. Cambridge. University. Press;. 2001.. p..
660-7�.
33...Daroff. RB.. The. office. Tensilon. test. for. ocular.
myasthenia.gravis..Arch.Neurol.1986;�3(8):8�3-�.
3�...Sethi. KD,. Rivner. MH,. Swift.TR.. Ice. pack. test. for.
myasthenia.gravis..Neurology.1987;37(8):1383-�.
3�...Kubis.KC,.Danesh-Meyer.HV,.Savino.PJ,.Sergott.RC..
The. ice. test. versus. the. rest. test. in. myasthenia.
gravis..Ophthalmology.2000;107(11):199�-8.
36...Czaplinski. A,. Steck. AJ,. Fuhr. P.. Ice. pack. test. for.
myasthenia. gravis..A. simple,. noninvasive. and. safe.
diagnostic.method..J.Neurol.2003;2�0(7):883-�.
37.. .Kimura.J..Principles.of.nerve.conduction.studies..In:.
Kimura. J,. editor.. Electrodiagnosis. of. diseases. of.
nerve. and. muscle.. Philadelphia:. FA. Davis;. 1989...
p..78-101.
38...Literature. review. of. the. usefulness. of. repetitive.
nerve.stimulation.and.single.fiber.EMG.in.the.elec-
trodiagnostic.evaluation.of.patients.with.suspected.
myasthenia. gravis. or. Lambert-Eaton. myasthenic.
syndrome..Muscle.Nerve.2001;2�(9):1239-�7.
39...Sanders. DB,. Stalberg. EV.. AAEM. minimonograph.
#2�:. single-fiber. electromyography.. Muscle. Nerve.
1996;19(9):1069-83.
�0...Vincent.A,.Newsom-Davis.J..Acetylcholine.receptor.
antibody.as.a.diagnostic.test.for.myasthenia.gravis:.
results. in.1�3.validated.cases.and.2967.diagnostic.
assays.. J. Neurol. Neurosurg. Psychiatry.
198�;�8(12):12�6-�2.
�1.. .Larner. AJ.. The. place. of. the. ice. pack. test. in. the.
diagnosis. of. myasthenia. gravis.. Int. J. Clin. Pract.
200�;�8(9):887-8.
�2...Oh.SJ,.Kim.DE,.Kuruoglu.R,.Bradley.RJ,.Dwyer.D..
Diagnostic. sensitivity. of. the. laboratory. tests. in.
myasthenia.gravis..Muscle.Nerve.1992;1�(6):720-�.
�3...Single. fiber. EMG. reference. values:. a. collaborative.
effort.. Ad. Hoc. Committee. of. the. AAEM. Special.
Interest.Group.on.Single.Fiber.EMG..Muscle.Nerve.
1992;1�(2):1�1-61.
��...Vincent. A,. McConville. J,. Farrugia. ME,. Bowen. J,.
Plested. P,.Tang.T,. et. al.. Antibodies. in. myasthenia.
gravis. and. related. disorders.. Ann. N. Y. Acad. Sci.
2003;998:32�-3�.
63
��...Grob.D,.Brunner.NG,.Namba.T..The.natural.course.of.
myasthenia. gravis. and. effect. of. therapeutic.
measures..Ann.N.Y.Acad.Sci.1981;377:6�2-69.
�6...Argov.Z,.Kaminski,.H,.Al-Mudallal,.A,.Ruff,.RL..Toxic.
and.iatrogenic.myopathies.and.neuromuscular.trans-
mission. disorders.. In:. Karpati. G,. Hilton-Jones,. D,.
Griggs,. RC,. editor.. Disorders. of. voluntary. muscle..
7th. ed.. Cambridge:. Cambridge. University. Press;.
2001..p..677-88.
�7.. .Richman. DP,.Agius. MA..Treatment. of. autoimmune.
myasthenia.gravis..Neurology.2003;61(12):16�2-61.
�8...Gronseth. GS,. Barohn. RJ.. Practice. parameter:.
thymectomy.for.autoimmune.myasthenia.gravis.(an.
evidence-based. review):. report. of. the. Quality.
Standards.Subcommittee.of.the.American.Academy.
of.Neurology..Neurology.2000;��(1):7-1�.
�9...Gronseth. GS,. Barohn. RJ.. Thymectomy. for.
Myasthenia. Gravis.. Curr. Treat. Options. Neurol.
2002;�(3):203-209.
�0...Buckingham.JM,.Howard.FM,.Jr.,.Bernatz.PE,.Payne.
WS,.Harrison.EG,.Jr.,.O'Brien.PC,.et.al..The.value.of.
thymectomy. in. myasthenia. gravis:. a. computer-
assisted. matched. study.. Ann. Surg. 1976;18�(�):.
��3-8.
�1.. .Perlo. VP,. Poskanzer. DC,. Schwab. RS,. Viets. HR,.
Osserman. KE,. Genkins. G.. Myasthenia. gravis:.
evaluation.of.treatment.in.1,3��.patients..Neurology.
1966;16(�):�31-9.
�2...Bedlack. RS,. Sanders. DB.. Steroid. treatment. for.
myasthenia.gravis:.steroids.have.an.important.role..
Muscle.Nerve.2002;2�(1):117-21.
�3...Pascuzzi.RM,.Coslett.HB,.Johns.TR..Long-term.cor-
ticosteroid.treatment.of.myasthenia.gravis:.report.of.
116.patients..Ann.Neurol.198�;1�(3):291-8.
��...Schneider-Gold.C,.Gajdos.P,.Toyka.KV,.Hohlfeld.RR..
Corticosteroids. for. myasthenia. gravis.. Cochrane.
Database.Syst.Rev.200�(2):CD002828.
��...Witte.AS,.Cornblath.DR,.Parry.GJ,.Lisak.RP,.Schatz.
NJ.. Azathioprine. in. the. treatment. of. myasthenia.
gravis..Ann.Neurol.198�;1�(6):602-�.
�6...Kuks.JB,.Djojoatmodjo.S,.Oosterhuis.HJ..Azathioprine.
in. myasthenia. gravis:. observations. in. �1. patients.
and. a. review. of. literature.. Neuromuscul. Disord.
1991;1(6):�23-31.
�7.. .Bromberg.MB,.Wald.JJ,.Forshew.DA,.Feldman.EL,.
Albers. JW.. Randomized. trial. of. azathioprine. or.
prednisone.for.initial.immunosuppressive.treatment.
of. myasthenia. gravis.. J. Neurol. Sci. 1997;1�0(1):�9-
62.
�8...Palace.J,.Newsom-Davis.J,.Lecky.B..A.randomized.
double-blind.trial.of.prednisolone.alone.or.with.aza-
thioprine. in. myasthenia. gravis.. Myasthenia. Gravis.
Study.Group..Neurology.1998;�0(6):1778-83.
�9...Tindall.RS,.Phillips.JT,.Rollins.JA,.Wells.L,.Hall.K..A.
clinical.therapeutic.trial.of.cyclosporine.in.myasthenia.
gravis..Ann.N.Y.Acad.Sci.1993;681:�39-�1.
60...Ciafaloni. E,. Nikhar. NK,. Massey. JM,. Sanders. DB..
Retrospective.analysis.of.the.use.of.cyclosporine.in.
myasthenia.gravis..Neurology.2000;��(3):��8-�0.
61.. .Perez. MC,. Buot. WL,. Mercado-Danguilan. C,.
Bagabaldo. ZG,. Renales. LD.. Stable. remissions. in.
myasthenia.gravis..Neurology.1981;31(1):32-7.
62...Niakan. E,. Harati.Y,. Rolak. LA.. Immunosuppressive.
drug. therapy. in. myasthenia. gravis.. Arch. Neurol.
1986;�3(2):1��-6.
63...De.Feo.LG,.Schottlender.J,.Martelli.NA,.Molfino.NA..
Use. of. intravenous. pulsed. cyclophosphamide. in.
severe,. generalized. myasthenia. gravis.. Muscle.
Nerve.2002;26(1):31-6.
MYASTHENIA GRAVIS
6�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
6�...Chaudhry.V,. Cornblath. DR,. Griffin. JW,. O'Brien. R,.
Drachman. DB.. Mycophenolate. mofetil:. a. safe. and.
promising. immunosuppressant. in. neuromuscular.
diseases..Neurology.2001;�6(1):9�-6.
6�...Ciafaloni.E,.Massey.JM,.Tucker-Lipscomb.B,.Sanders.
DB..Mycophenolate.mofetil.for.myasthenia.gravis:.an.
open-label.pilot.study..Neurology.2001;�6(1):97-9.
66...Meriggioli. MN,. Ciafaloni. E,. Al-Hayk. KA,. Rowin. J,.
Tucker-Lipscomb.B,.Massey.JM,.et.al..Mycophenolate.
mofetil.for.myasthenia.gravis:.an.analysis.of.efficacy,.
safety,. and. tolerability.. Neurology. 2003;61(10):.
1�38-�0.
67.. .Meriggioli.MN,.Rowin.J,.Richman.JG,.Leurgans.S..
Mycophenolate. mofetil. for. myasthenia. gravis:. a.
double-blind,.placebo-controlled.pilot.study..Ann.N.Y.
Acad.Sci.2003;998:�9�-9.
68...Wakata. N,. Saito. T,. Tanaka. S,. Hirano. T,. Oka. K..
Tacrolimus.hydrate.(FK�06):.therapeutic.effects.and.
selection. of. responders. in. the. treatment. of.
myasthenia. gravis.. Clin. Neurol. Neurosurg.
2003;106(1):�-8.
69...Konishi.T,.Yoshiyama.Y,.Takamori.M,.Yagi.K,.Mukai.E,.
Saida. T.. Clinical. study. of. FK�06. in. patients. with.
myasthenia.gravis..Muscle.Nerve.2003;28(�):�70-�.
70...Kawaguchi.N,.Yoshiyama.Y,.Nemoto.Y,.Munakata.S,.
Fukutake.T,.Hattori.T..Low-dose.tacrolimus.treatment.
in.thymectomised.and.steroid-dependent.myasthenia.
gravis..Curr.Med.Res.Opin.200�;20(8):1269-73.
71.. .Nagane. Y,. Utsugisawa. K,. Obara. D,. Kondoh. R,.
Terayama. Y.. Efficacy. of. low-dose. FK�06. in. the.
treatment.of.Myasthenia.gravis--a. randomized.pilot.
study..Eur.Neurol.200�;�3(3):1�6-�0.
72...Konishi.T,.Yoshiyama.Y,.Takamori. M,. Saida.T.. Long-
term. treatment. of. generalised. myasthenia. gravis.
with. FK�06. (tacrolimus).. J. Neurol. Neurosurg.
Psychiatry.200�;76(3):��8-�0.
73...Tada.M,.Shimohata.T,.Oyake.M,.Igarashi.S,.Onodera.
O,. Naruse. S,. et. al.. Long-term. therapeutic. efficacy.
and. safety. of. low-dose. tacrolimus. (FK�06). for.
myasthenia.gravis..J.Neurol.Sci.2006;2�7(1):17-20.
7�.. .Simon. HU,. Spath. PJ.. IVIG--mechanisms. of. action..
Allergy.2003;�8(7):��3-�2.
7�...Gajdos.P,.Chevret.S,.Toyka.K..Plasma.exchange.for.
myasthenia. gravis.. Cochrane. Database. Syst. Rev.
2002(�):CD00227�.
76...Gajdos.P,.Chevret.S,.Clair.B,.Tranchant.C,.Chastang.
C.. Clinical. trial. of. plasma. exchange. and. high-dose.
intravenous. immunoglobulin. in. myasthenia. gravis..
Myasthenia.Gravis.Clinical.Study.Group..Ann.Neurol.
1997;�1(6):789-96.
77.. .Qureshi.AI,.Choudhry.MA,.Akbar.MS,.Mohammad.Y,.
Chua.HC,.Yahia.AM,.et.al..Plasma.exchange.versus.
intravenous.immunoglobulin.treatment.in.myasthenic.
crisis..Neurology.1999;�2(3):629-32.
78...Ronager. J,. Ravnborg. M,. Hermansen. I,.Vorstrup. S..
Immunoglobulin.treatment.versus.plasma.exchange.
in. patients. with. chronic. moderate. to. severe.
myasthenia.gravis..Artif.Organs.2001;2�(12):967-73.
79...Newsom-Davis.J..Therapy.in.myasthenia.gravis.and.
Lambert-Eaton.myasthenic.syndrome..Semin.Neurol.
2003;23(2):191-8.
80...Gajdos.P,.Tranchant.C,.Clair.B,.Bolgert.F,.Eymard.B,.
Stojkovic.T,. et. al.. Treatment. of. myasthenia. gravis.
exacerbation. with. intravenous. immunoglobulin:. a.
randomized. double-blind. clinical. trial.. Arch. Neurol.
200�;62(11):1689-93.
6�
81.. .Zinman. L,. Ng. E,. Bril. V.. IV. immunoglobulin. in.
patients. with. myasthenia. gravis:. a. randomized.
controlled.trial..Neurology.2007;68(11):837-�1.
82...Wolfe.GI,.Barohn.RJ,.Foster.BM,.Jackson.CE,.Kissel.
JT,. Day. JW,. et. al.. Randomized,. controlled. trial. of.
intravenous. immunoglobulin. in. myasthenia. gravis..
Muscle.Nerve.2002;26(�):��9-�2.
83...Achiron. A,. Barak. Y,. Miron. S,. Sarova-Pinhas. I..
Immunoglobulin.treatment.in.refractory.Myasthenia.
gravis..Muscle.Nerve.2000;23(�):��1-�.
8�...Hilkevich.O,.Drory.VE,.Chapman.J,.Korczyn.AD..The.
use.of.intravenous.immunoglobulin.as.maintenance.
therapy.in.myasthenia.gravis..Clin.Neuropharmacol.
2001;2�(3):173-6.
8�...Gajdos.P,.Chevret.S,.Toyka.K..Intravenous.immuno-
globulin.for.myasthenia.gravis..Cochrane.Database.
Syst.Rev.2006(2):CD002277.
MYASTHENIA GRAVIS
66
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
66
AMYOTROPHIC LATERAL SCLEROSISCLINICaL INfORMatIONAmyotrophic lateral sclerosis. (ALS). is. a. form.of.motor.
system. disease. which. is. a. progressive. degenerative.
disorder.of.motor.neurons.in.the.spinal.cord,.brainstem.
and.motor.cortex...Motor.system.disease.is.subdivided.
into. several. subtypes. on. the. basis. of. the. particular.
grouping. of. symptoms. and. signs.. . ALS. is. the. most.
frequent.form.in.which.there.is.a.combination.of.muscle.
weakness. and. wasting. and. hyperreflexia. from.
involvement.of. lower.motor.neurons.in.the.spinal.cord.
and.brainstem.and.upper.motor.neurons. in. the.motor.
cortex...Other.forms.include.spinal muscular atrophy.in.
which. weakness. and. atrophy. occur. alone. without.
evidence.of.corticospinal.tract.dysfunction,.progressive
bulbar palsy.in.which.weakness.and.wasting.predominate.
in.muscles.innervated.by.the.motor.nuclei.of.the.lower.
brainstem. and. primary lateral sclerosis. in. which. the.
clinical.feature.is.dominated.by.pyramidal.weakness.and.
spasticity.with.the.degenerative.process.being.confined.
to.the.corticospinal.tract.
. ALS. manifests. clinically. by. signs. which. reflect.
disorders.of.both.lower.and.upper.motor.neurons,.i.e.,.
progressive. muscle. weakness,. atrophy,. spasticity. and.
hyperreflexia...In.typical.cases,.the.initial.clinical.features.
are.of.asymmetrical.weakness.and.wasting.of.hand.and.
forearm.muscles,. fasciculations.of. the.muscles.of. the.
forearms,.upper.arms.and.shoulder.girdles,.spasticity.of.
the.legs.and.generalized.hyperreflexia.without.sensory.
loss.. . The. muscles. of. the. upper. arms. and. shoulder.
girdles.are.usually.weak.and.wasted.at.a.later.stage...As.
the.disease.progresses,.the.atrophic.weakness.spreads.
to. the. neck,. pharyngeal. and. laryngeal. muscles,. trunk,.
and.lower.extremities1...One.of.the.most.characteristic.
clinical. pictures. is. spastic. dysarthria. with. wasting. and.
fasciculations.of.the.tongue...At.this.stage,.the.patients.
often.have.difficulty.in.swallowing...Involvement.of.the.
respiratory.muscles.and.diaphragm.results. in.difficulty.
in.breathing.which.are.sinister.signs. late. in.the.course.
of.the.disease.
. The.pathogenesis.is.unknown.and.various.etiologies.
have. been. proposed. for. ALS.. . Excitotoxins. (including.
glutamate)2,. chemicals3,. metals�,�. and. autoimmunity6,7.
have.been.among.the.candidates...It.is.likely.that.ALS.is.
caused. by. various. causes. which. share. the. common.
mechanism. of. cell. death.. . Most. cases. of. ALS. are.
sporadic,.that.is.without.an.obvious.genetic.component...
Approximately.10%.are.inherited.in.a.dominant.manner.
and. referred. to. as. familial. ALS.. . An. important. break-
through.was. the. finding.of.mutations.within. the.gene.
encoding.Cu,.Zn.superoxide.dismutase.(SOD1).in.some.
67
AMYOTROPHIC LATERAL SCLEROSIS
of.the.familial.ALS.patients8.. .SOD1.is.thought.to.help.
reduce. oxidative. stress.. . Sporadic. and. familial..
ALS. produce. similar. pathological. hallmarks. which..
reflect.the.degeneration.and.death.of.upper.and.lower.
motor.neurons.
. The.diagnosis.of.ALS.is.made.on.the.basis.of.clinical.
criteria. and. exclusion. of. conditions. which. can. be.
mistaken. for. ALS.. . The. most. common. disorder. that.
requires. exclusion. is. cervical. spondylitic. myelopathy...
Others. include. pseudobulbar. palsy,. multiple. system.
atrophy,. myasthenia. gravis,. and. lead. intoxication...
Multifocal.motor.neuropathy.(MMN).should.be.excluded.
in. patients. with. predominantly. lower. motor. neuron.
features.. .There. is. no. pathognomonic. laboratory. test...
Nerve.conduction.study.and.EMG.serve.to.demonstrate.
or.confirm.the.presence.of.abnormalities.indicative.of.a.
motor.neuropathy.and.the.absence.of.conduction.block.
which.is.seen.in.MMN9...The.common.findings.include.
small.amplitude.of.compound.muscle.action.potentials.
with. slightly. slow. motor. conduction. velocities. and.
normal. sensory. conduction. compatible. with. either.
motor. axonopathy. or. neuronopathy.. .The. presence. of.
conduction.block.and.predominantly.lower.motor.neuron.
type.of.limb.weakness.(especially.asymmetrical).raises.
the.possibility.of.MMN.or.other.immune-mediated.poly-
neuropathies.which.may.be.treatable...High.titer.of.anti-
GM1. antibodies. are. detected. in. up. to. 8�%. of. MMN.
patients10,11...However,.the.presence.of.these.antibodies.
is.supportive.of,.but.not.essential. for,. the.diagnosis.of.
MMN12,13...ALS.is.a.disease.of.middle.life.and.the.course.
of. this. illness. is. inexorably. progressive. and. invariably.
fatal1.. . Patients. usually. develop. respiratory. failure. that.
may.require.tracheostomy.and.mechanical.ventilation.
. A. number. of. drugs. and. agents. including. riluzole.
have.been.reported.to.give.marginal.benefit.for.patients.
with.ALS.but.none.have.been.shown.to.provide.effects.
that.are.visible.to.the.patients.or.physicians9.
OBJECtIVETo.examine.the.efficacy.of.IVIG.in.ALS.
IVIG as MaINtENaNCE thERapYDalakas.et. al. treated.9.patients.with. classic.ALS.who.
had.a.rapidly.progressive.course.with.IVIG.in.an.open-
label.study...A.patient.with.multifocal.motor.neuropathy.
(MMN). was. concurrently. treated. to. document. the.
efficacy. of. the. IVIG. in. a. potentially. treatable. disease...
IVIG. was. given. once. a. month. for. 3. months. with. the.
dose. of. 2. g/kg. over. 2. days.. . All. patients. with. ALS.
worsened. during. the. study. whereas. the. patient. with.
MMN.responded.to.the.treatment1�.
. Meucci.et.al.treated.7.patients.with.ALS.with.IVIG.
at. the. dose. of. 0.�. g/kg/day. for. �. days. followed. by.
monthly.2-day. infusions.at. the.same.daily.dosage.and.
continued.with.oral.cyclophosphamide.at.1-2.mg/kg/day.
for.�-13.months. (mean.8.1).. .All.patients.continued. to.
deteriorate.during.treatment1�.
sUMMaRYEvidence.from.open-label.studies.showed.that.IVIG.has.
no.apparent.therapeutic.role.in.improving.the.symptoms.
or. arresting. the. pace. of. progression. in. patients..
with.ALS.
EXpERt CONsENsUsIVIG. is. not. indicated. in. the. treatment. of. patients..
with.ALS.
REfERENCEs1.. .Victor.M,.Ropper.AH...Amyotrophic.lateral.sclerosis...
In.Victor.M,.Ropper.AH.(eds):.Principal.of.Neurology,.
7th.ed...New.York,.McGraw-Hill,.2001,.pp.11�3-�.
2.. .Rothstein. JD,. Martin. LJ,. Kuncl. RW.. . Decreased.
glutamate.transport.by.the.brain.and.spinal.cord. in.
amyotrophic. lateral.sclerosis.. .N.Engl.J.Med.1992;.
326:.1�6�-8...
3.. .Gunnarsson.LG...Motor.neuron.disease.and.exposure.
to.chemicals.-.aetiological.suggestions.from.a.case-
control.study...J.Neurol.Sci.199�;.12�.(Suppl.62-3).
�.. .Yasui.M,.Yase.Y,.Ota.K,.Garruto.RM.. .Evaluation.of.
magnesium,. calcium. and. aluminum. metabolism. in.
rats. and. monkeys. maintained. on. calcium-deficient.
diets...Neurotoxicology.1991;.12:.603-1�.
68
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGYBRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
�.. .Garruto.RM,.Shankar.SK,.Yanakihara.R,.Salazar.AM,.
Amyx.HL,.Gajusek.DC...Low-calcium,.high-aluminum.
diet-induced.motor.neuron.pathology.in.cynomolgus.
Monkeys...Acta.Neuropathol.(Berlin).1989;.78:.210-9.
6.. .Appel. SH,. Engelhardt. JI,. Garcia. J,. Stefani. E...
Autoimmunity. and. ALS:. a. comparison. of. . animal.
models. of. immune-mediated. motor. neuron.
destruction.and.human.ALS...Adv.Neurol.1991;.�6:.
�0�-12.
7.. .Sanders.KA,.Rowland.LP,.Murphy.PL,.Younger.DS,.
Latov.N,.Sherman.WH,.Pesce.M,.Lange.DJ....Motor.
neuron. diseases. and. amyotrophic. lateral. sclerosis:.
GM1. antibodies. and. . paraproteinemia.. . Neurology.
1993;.�3:.�18-20.
8.. .Rosen. DR,. Siddique.T,. Patterson. D,. Figlewics. DA,.
Sapp.P,.Hentati.A,.Donaldson.D,.Goto.J,.O'Regan.JP,.
Deng. HX,. et. al.. . Mutations. in. Cu/Zn. superoxide.
dismutase. gene. are. associated. with. familial.
amyotrophic. lateral. sclerosis.. . Nature. 1993;.
362(6�1�):. �9-62.. . Erratum. in. Nature. 1993;. 36�.
(6�3�):.362.
9.. .Rowland. LP.. . Muscular. atrophies,. motor. neuropa-
thies,.amyotrophic.lateral.sclerosis.and.immunology...
In. Kimura. J,. Kaji. R. (eds):. Physiology. of. ALS. and.
related. diseases.. . Amsterdam,. Elsevier,1997,. pp.
3-11.
10...Taylor. BV,.Gross.L,.Windebank.AJ.. .The. sensitivity.
and. specificity. of. anti-GM1. antibody. testing...
Neurology.1996;.�7:.9�1-�.
11.. .Pestronk.A,.Choksi.R...Multifocal.motor.neuropathy:.
Serum.IgM.anti-GM1.ganglioside.antibodies.in.most.
patients.detected.using.covalent.linkage.of.GM1.to.
ELISA.plates...Neurology.1997;.�9:.1289-92.
12...Bouche. P,. Moulonguet. A,. Younes-Chennoufi. AB,.
Adams.D,.Baumann.N,.Meininger.V,.Leger.JM,.Said.
G.. . Multifocal. motor. neuropathy. with. conduction.
block:.a.study.of.2�.patients.. .J.Neurol.Neurosurg.
Psychiatry.199�;.�9:.38-��.
13...Saperstein. DS,. Katz. JS,. Amato. AA,. Barohn. R...
Clinical. spectrum. of. acquired. demyelinating. poly-
neuropathies...Muscle.Nerve.2001;.2�.;.311-2�.
1�...Dalakas.MC,.Stein.DP,.Otero.C,.Sekul.E,.Cupler.EJ,.
McCrosky. S.. . Effect. of. high-dose. intravenous.
immunoglobulin. on. amyotrophic. lateral. sclerosis.
and. multifocal. motor. neuropathy.. . Arch. Neurol.
199�;.�1:861-�.
1�...Muecci.N,.Nobile-Orazio.E,.Scarlato.G...Intravenous.
immunoglobulin. therapy. in. amyotrophic. lateral.
sclerosis...J.Neurol.1996;.2�3:.117-20.
69
LAMBERT-EATON MYASTHENICSYNDROMECLINICaL INfORMatION. Lambert-Eaton. myasthenic. syndrome. (LEMS). is. a.
disorder.of.neuromuscular.transmission.first.recognized.
clinically. in. association.with. lung. cancer1,.2. and. subse-
quently. in.cases. in.which.no.neoplasm.was.detected..
Patients.with.LEMS.have.a.presynaptic.neuromuscular.
junction.defect.. .The.clinical.picture. is.characterized.by.
proximal.muscle.weakness,.autonomic.symptoms.(dry.
mouth,. constipation,. erectile. failure). and. depressed.
deep.tendon.reflexes3.
. The. symptoms. are. caused. by. antibodies. against.
voltage-gated.calcium.channels.(VGCC).at.the.presynaptic.
motor.nerve.terminals.resulting.in.decreased.acetylcho-
line.release�,.�...LEMS.exists.in.2.forms:.paraneoplastic.
(P-LEMS).and.nonparaneoplastic.(NP-LEMS)..Carcinoma.
was. detected. in. �1-�0%. of. the. cases3,. 6.. .The. most.
common.associated.tumor.is.small-cell.lung.cancer3.but.
association.with.lymphoproliferative.disorders.has.been.
reported7..NP-LEMS.can.occur. in.childhood.as.well.as.
adult.life.whereas.P-LEMS.is.unusual.before.30.years.of.
age..Therefore,.NP-LEMS.tends. to.be.younger. than.P-
LEMS..The.clinical.features.of.both.forms.are.otherwise.
indistinguishable8.. The. onset. of. LEMS. may. precede.
radiological. evidence. of. tumor. for. many. years.. The.
longest.interval.was.3.8.years.in.one.series3..Therefore,.
it. is. recommended.that.patients.should.be.kept.under.
surveillance.for.up.to.at.least.�.years..Autoantibodies.to.
P/Q-type.VGCC.are.provoked.by.tumor.VGCC.in.P-LEMS.
but.the.stimulus. in.NP-LEMS.is.not.known9,.10.. . In.both.
groups,. serum. antibodies. to.VGCC. can. be. detected. in.
more.than.90%.of.patients�,.�.
. LEMS. may. occur. in. association. with. other.
autoimmune. diseases. which. were. more. frequently.
found. in. LEMS. patients. without. a. tumor.. . Thyroid.
disorders.and.insulin.dependent.diabetes.mellitus.were.
the.most.common.associated.autoimmune.diseases. in.
one.study6..There.have.been.a.few.reports.of.LEMS.and.
myasthenia.gravis.(MG).coexisting.in.the.same.patient11,.
12.. Dermatomyositis. has. also. been. reported. to. occur.
together.with.LEMS13.
. LEMS.is.an.uncommon.condition.and.patients.with.
LEMS. can. be. misdiagnosed. as. suffering. from. other.
more. common. diseases. with. similar. clinical. features,.
e.g.,.MG...There.has.to.be.a.high.index.of.suspicion.and.
features.favoring.the.diagnosis.of.LEMS.are.the.relative.
absence.of.ophthalmoparesis.and.facial.weakness,.the.
presence. of. dysautonomia. (especially. a. dry. mouth),.
muscle. ache. or. pain. and. decreased. or. absent. deep.
tendon. reflexes.which.may.be. increased.by.sustained.
voluntary.contraction.or.exercise. (posttetanic.potentia-
LAMBERT-EATON MYASTHENIC SYNDROME
70
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
tion)3..There.may.be.mild.or.moderate.ptosis..Diagnosis.
is.confirmed.by.repetitive.nerve.stimulation.test.which.
shows. small. initial. compound. muscle. action. potential.
that. increases. by. 100%. or. more. following. maximum.
voluntary. contraction. or. during. high. rate. nerve.
stimulation. and. a. raised. serum. titer. of..
VGCC.antibodies9.
. Most.P-LEMS.patients.die.within.3.years.after.tumor.
detection..Those.patients.who.had.successful.treatment.
of. the. tumor. lived. longer. and. also. had. complete.
remission.of.LEMS.symptoms.. .Prognosis. is.good. for.
NP-LEMS. and. the. causes. of. death. were. usually.
conditions.other.than.this.disorder3.
. The.mainstay.of.therapy.is.3,�-diaminopyridine.(10-20.
mg. �. times. daily). which. can. partially. or. fully. control.
weakness. and. autonomic. dysfunction1�-17... . When. 3,�-.
diaminopyridine. is. not. available,. pyridostigmine. can. be.
used.but.it.is.less.effective9...Intravenous.immunoglobulin.
(IVIG). or. plasma. exchange. (PE). provides. short-term.
improvement18,.19...In.those.at.risk.from.P-LEMS.(cigarette.
smokers),.an.intensive.search.for.lung.cancer.should.be.
undertaken.and.specific.tumor.therapy.is.likely.to.improve.
the. neurological. deficit20.. . Prednisolone. is. indicated. in.
those. who. fail. to. respond. to. symptomatic. treatment21...
Azathioprine. can. be. added. as. corticosteroid. sparing.
medication19.. . Cyclosporine. should. be. considered. in.
patients.who.fail.to.respond.to.azathioprine8.
OBJECtIVEsTo. examine. the. efficacy. of. IVIG. in. the. treatment..
of.LEMS.
INtRaVENOUs IMMUNOGLOBULIN fOR LEMs. IVIG. was. shown. to. neutralize. the. presynaptic.
inhibitory. activity. of. LEMS. IgG. on. quantal. release. of.
acetylcholine. in. one. study.. . The. effect. of. sera. and.
purified.IgG.from.six.patients.with.LEMS.on.presynaptic.
evoked. quantal. release. was. investigated. after. direct.
application.to.the.motor.nerve.terminal.by.the.perfused.
macro-patch-clamp.electrode.in.mouse.hemidiaphragms...
The.effect.of.LEMS. IgG.was.analyzed.alone.and.after.
coincubation. with. IVIG.. . All. LEMS. sera. and. purified.
LEMS. IgG. inhibited.evoked.quantal. release. in. a.dose-
dependant.manner...When.LEMS.IgG.was.coincubated.
with. a. therapeutic. IVIG. preparation,. the. inhibitory.
activity. of. LEMS. IgG. was. diminished. in. a. dose-
dependant. fashion..These.direct.neutralizing.effects.of.
IVIG.may.explain.its.therapeutic.efficacy22.
. There.has.been.only.one.randomized.controlled.trial.
(RCT).comparing.the.effects.of.IVIG.with.placebo.
IVIGVERSuSPLACEBoBain. et. al. studied. 9. patients. with. NP-LEMS. using..
2.g/kg.of.IVIG.over.2.days.in.a.randomized.double-blind.
placebo-controlled. crossover. trial. (using. 0.3%. albumin.
as.placebo)...The.study.showed.a.significant.improvement.
in. limb. strength. and. in. the. amplitude. of. the. resting.
CMAP. associated.with. a. decline. in. the. serum. titer. of.
VGCC.antibodies..The.maximum.change.was.reached.at.
2-�.weeks.and.declined.by.8.weeks18...This.trial.studied.
NP-LEMS. in.a.small.number.of.patients. for.efficacy. in.
short-term.therapy.
IVIGASMAINtENANCEtHERAPyMuchnik.et.al.reported.a.case.of.NP-LEMS.with.efficacy.
of.monthly. IVIG.courses. at. a.dose.of.0.�.g/kg/day. for..
�.days.up.to.2�.months23.
. Bird. reported. a. case. of. NP-LEMS. who. had. been.
treated.with.repeated.PE.with.excellent.response.but.this.
had. to. be. discontinued. due. to. the. loss. of. adequate.
intravenous.access.for.further.PE...She.was.then.treated.
with.IVIG.at.0.�.g/kg/day.for.�.days.with.good.response...
There. was. a. relapse. after. 10. weeks. and. repeated.
treatment. with. 1. g/kg/day. for. 2. days. resulted. in. similar.
improvement...Five.additional.treatments.were.given.and.
each.resulted.in.a.sustained.response.of.10-12.weeks2�.
. Takano.et.al.reported.a.case.of.small-cell.lung.cancer.
(SCLC).who.was.treated.with.�.courses.of.chemothera-
py.every.�.weeks.together.with.PE.just.before.the.2nd.
and. 3rd. courses.. . He. improved. (could. walk. a. longer.
distance). after. the.2nd.PE.and. the.3rd. chemotherapy...
Then.IVIG.was.given.just.before.the.�th.chemotherapy.
with. marked. improvement.. .The. authors. commented.
that.PE.had.no. immediate.effect.on. their.patient.who.
showed. gradual. improvement. with. chemotherapy. and.
that.IVIG.was.also.effective.for.LEMS.with.SCLC...His.
condition.remained.good.7.months.after. IVIG. (and.the.
�th.course.of.chemotherapy)2�.
71
. Rich.et.al. treated.6.patients.with.LEMS.(3.women.
and.3.men).with.IVIG..All.3.men.had.SCLC...One.woman.
had.breast.carcinoma.which.developed.7.years.after.the.
diagnosis.of.LEMS...No.malignancy.was.found.in.other.
2.women...In.all.patients,.the.total.dose.of.IVIG.at.each.
treatment.was.2.g/kg.given.over.1-�.days...No.patients.
had. any. serious. side.effects. from. the. IVIG. treatment..
Three.of.the.6.patients.had.clinical.improvement.lasting.
�-10. weeks. following. each. IVIG. treatment. (total. 6-20.
treatments).. . One. patient. responded. to. the. initial.
treatment.but.not.to.a.subsequent.treatment.with.IVIG..
Another. patient. had. no. improvement. following. IVIG.
infusion. and. was. not. further. treated.. .The. 6th. patient.
responded. to. the. initial. treatment. but. did. not. require.
any.further.treatments.after.his.second.dose.of.IVIG.as.
he. improved. following. treatment. of. his. SCLC...
Surprisingly,.although.most.of.these.patients.responded.
clinically,.a. reproducible. improvement. in.electrophysio-
logical.study.was.seen.only.in.one.patient..However,.the.
clinical.improvement.in.a.subset.of.the.patients.suggests.
that.IVIG.may.be.effective.in.treating.selected.patients.
with.LEMS26.
sUMMaRYIVIG.treatment.may.be.useful.short-term.therapy.particu-
larly. in. severely. affected. NP-LEMS. patients.. Although.
there.are.some.suggestions.that.IVIG.may.be.effective.in.
selected. patients. with. LEMS26,. there. is. not. sufficient.
evidence. at. present. to. support. its. use. as. long-term.
therapy8.. For. P-LEMS,. the. role. of. IVIG. is. not. obvious.
since.chemotherapy.alone.can.result.in.improvement.of.
the.neurological.deficit..For. long-term.use,.3,�-diamino-
pyridine.remains.the.mainstay.of.treatment..IVIG.may.be.
applied. as. supplementary. or. bridging. therapy. together.
with. other. therapies. such. as. prednisolone. and. other.
immunosuppressants...Pyridostigmine.may.be.considered.
if.3,�-diaminopyridine.is.not.available.although.its.benefit.
is.likely.to.be.less...There.have.been.no.trials.comparing.
IVIG.with.PE.or.other.treatments.
.
DoSAGE:.The.sole.RCT.trial.used.2.g/kg.over.2.days.but.
due. to. the. high. frequency. of. headache,. the. authors.
stated.that.this.might.have.been.reduced.by.administer-
ing.over.�.days.rather.than.2.days.
ADVERSE EffECtS:. (from. the. RCT). headache,..
aseptic.meningitis.
EXpERt CONsENsUs1.. Treat.the.underlying.tumor.in.P-LEMS
2.. .3,�-diaminopyridine. is. effective. but. not. always..
available.
3.. .Pyridostigmine. is. of. some.benefit. although.not. as.
effective.as.3,�-diaminopyridine
�.. .If. 3,�-diaminopyridine. and. pyridostigmine. are. not.
effective,. immunosuppressants. can. be. added..
Prednisolone. and. azathioprine. are. the. most.
frequently.used.immunosuppressants.and.they.are.
given.alone.or.together27.
�.. .IVIG. or. PE. produces. temporary. improvement..
Therefore,.each.has.a.role.as.second.line.therapy.
6.. .There.is.a.theoretical.concern.that.immunosuppres-
sion. may. reduce. the. immunologic. suppression. of.
tumor.growth..Therefore,.aggressive. immunothera-
py.in.LEMS.may.be.more.justified27.
REfERENCEs1.. .Anderson. H,. Churchill-Davidson. H,. Richardson. A..
Bronchial. neoplasm. with. myasthenia:. prolonged.
apnoea. after. administration. of. succinylcholine..
Lancet.19�3;ii:1291-3.
2.. .Henson.R..Discussion.of.unusual.manifestations.of.
bronchial. carcinoma.. Proceedings. of. the. Royal.
Society.of.Medicine.19�3;�6:8�9-61.
3.. .O'Neill. JH,. Murray. NM,. Newsom-Davis. J.. The.
Lambert-Eaton. myasthenic. syndrome..A. review. of.
�0.cases..Brain.1988;111.(.Pt.3):�77-96.
�.. .Motomura. M,. Johnston. I,. Lang. B,. Vincent. A,.
Newsom-Davis.J..An.improved.diagnostic.assay.for.
Lambert-Eaton. myasthenic. syndrome.. J. Neurol.
Neurosurg.Psychiatry.199�;�8(1):8�-7.
LAMBERT-EATON MYASTHENIC SYNDROME
72
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
�.. .Lennon.VA,.Kryzer.TJ,.Griesmann.GE,.O'Suilleabhain.
PE,. Windebank. AJ,Woppmann. A,. et. al.. Calcium-
channel.antibodies.in.the.Lambert-Eaton.syndrome.
and.other.paraneoplastic.syndromes..N.Engl.J.Med.
199�;332(22):1�67-7�.
6.. .Wirtz.PW,.Bradshaw.J,.Wintzen.AR,.Verschuuren.JJ..
Associated.autoimmune.diseases. . in.patients.with.
the.Lambert-Eaton.myasthenic.syndrome.and.their.
families..J.Neurol.200�;2�1(10):12��-9.
7.. .Argov. Z,. Shapira. Y,. Averbuch-Heller. L,. Wirguin. I..
Lambert-Eaton. myasthenic. syndrome. (LEMS). in.
association. with. lymphoproliferative. disorders..
Muscle.Nerve.199�;18(7):71�-9.
8.. .Newsom-Davis.J..Therapy.in.myasthenia.gravis.and.
Lambert-Eaton.myasthenic.syndrome..Semin.Neurol.
2003;23(2):191-8.
9.. .Newsom-Davis. J.. Lambert-Eaton. myasthenic.
syndrome..Rev.Neurol.(Paris).200�;160(2):177-80.
10...Roberts.A,. Perera. S,. Lang. B,.Vincent.A,. Newsom-
Davis. J.. Paraneoplastic. myasthenic. syndrome. IgG.
inhibits.��Ca2+.flux.in.a.human.small.cell.carcinoma.
line..Nature.198�;317(6039):737-9.
11.. .Oh.SJ,.Sher.E..MG.and.LEMS.overlap.syndrome:.case.
report. with. electrophysiological. and. immunological.
evidence..Clin.Neurophysiol.200�;116(�):1167-71.
12...Sha.SJ,.Layzer.RB..Myasthenia.gravis.and.Lambert-
Eaton. myasthenic. syndrome. in. the. same. patient..
Muscle.Nerve.2007.
13...Mossner. R,. Tings. T,. Beckmann. I,. Neumann. C,.
Paulus. W,. Reich. K.. A. close. look. at. autoimmune.
muscle. disorders:. association. of. Lambert-Eaton.
myasthenic.syndrome.with.dermatomyositis..Scand.
J.Rheumatol.200�;33(�):271-�.
1�...Lundh.H,.Nilsson.O,.Rosen.I..Treatment.of.Lambert-
Eaton. syndrome:. 3,�-. diaminopyridine. and. pyr-
idostigmine..Neurology.198�;3�(10):132�-30.
1�...McEvoy. KM,. Windebank. AJ,. Daube. JR,. Low. PA..
3,�-Diaminopyridine. in. the. treatment. of. Lambert-
Eaton. myasthenic. syndrome.. N. Engl. J. Med.
1989;321(23):.1�67-71.
16...Lundh.H,.Nilsson.O,.Rosen.I,.Johansson.S..Practical.
aspects. of. 3,�-diaminopyridine. treatment. of. the.
Lambert-Eaton. myasthenic. syndrome..Acta. Neurol.
Scand.1993;88(2):136-�0.
17.. .Sanders.DB,.Massey.JM,.Sanders.LL,.Edwards.LJ..
A.randomized.trial.of.3,�-.diaminopyridine.in.Lambert-
Eaton.myasthenic.syndrome..Neurology.2000;��(3):.
603-7.
18...Bain. PG,. Motomura. M,. Newsom-Davis. J,. Misbah.
SA,.Chapel.HM,.Lee.ML,.et.al..Effects.of.intravenous.
immunoglobulin.on.muscle.weakness.and.calcium-
channel. autoantibodies. in. the. Lambert-Eaton.
myasthenic. syndrome.. Neurology. 1996;�7(3):678-
83.
19...Newsom-Davis. J,. Murray. NM.. Plasma. exchange.
and. immunosuppressive. drug. treatment. in. the.
Lambert-Eaton. myasthenic. syndrome.. Neurology.
198�;3�(�):�80-�.
20...Chalk.CH,.Murray.NM,.Newsom-Davis.J,.O'Neill.JH,.
Spiro. SG.. Response. of. the. Lambert-Eaton.
myasthenic. syndrome. to. treatment. of. associated.
small-cell. lung. carcinoma.. Neurology.
1990;�0(10):1��2-6.
21.. .Streib.EW,.Rothner.AD..Eaton-Lambert.myasthenic.
syndrome:. long-term. treatment. of. three. patients.
with.prednisone..Ann.Neurol.1981;10(�):��8-�3.
73
22...Buchwald. B,. Ahangari. R,.Weishaupt. A,.Toyka. KV..
Presynaptic. effects. of. immunoglobulin. G. from.
patients.with.Lambert-Eaton.myasthenic.syndrome:.
their. neutralization. by. intravenous. immunoglobu-
lins..Muscle.Nerve.200�;31(�):�87-9�.
23...Muchnik. S,. Losavio.AS,.Vidal.A,. Cura. L,. Mazia. C..
Long-term. follow-up. of. Lambert-. Eaton. syndrome.
treated. with. intravenous. immunoglobulin.. Muscle.
Nerve.1997;20(6):67�-8.
2�...Bird.SJ..Clinical.and.electrophysiologic.improvement.
in.Lambert-Eaton.syndrome.with.intravenous.immu-
noglobulin. therapy.. Neurology. 1992;�2(7):.
1�22-3.
2�...Takano.H,.Tanaka.M,.Koike.R,.Nagai.H,.Arakawa.M,.
Tsuji. S.. Effect. of. intravenous. immunoglobulin. in.
Lambert-Eaton. myasthenic. syndrome. with. small-
cell. lung. cancer:. correlation. with. the. titer. of. anti-
voltage-gated. calcium. channel. antibody.. Muscle.
Nerve.199�;17(9):1073-�.
26...Rich.MM,.Teener.JW,.Bird.SJ..Treatment.of.Lambert-
Eaton.syndrome.with.intravenous.immunoglobulin..
Muscle.Nerve.1997;20(�):61�-�.
27.. .Sanders.DB..Lambert-Eaton.myasthenic.syndrome:.
diagnosis. and. treatment.. Ann. N. Y. Acad. Sci.
2003;998:�00-8.
LAMBERT-EATON MYASTHENIC SYNDROME
7�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
NEUROMYOTONIA(ISAACS’ SYNDROME)BaCKGROUNdNeuromyotonia.or.Isaacs'.syndrome.is.a.rare.condition.
of.spontaneous.and.continuous.muscle.fiber.activity.of.
peripheral.nerve.origin...It.manifests.clinically.by.muscle.
cramps,.pseudomyotonia.(slow.relaxation.of.the.muscle).
and. undulating. myokymia. (continuously. rippling.
muscles),. muscle. stiffness,. weakness. and. excessive.
sweating.. . Less. constant. features. are. distal. muscle.
wasting,. decreased. deep. tendon. reflexes. and. distal.
decrease. in.sensation1-3.. .Neuromyotonia.may.occur. in.
association. with. dysautonomia. and. encephalopathy.
characterized.by.confusion,. insomnia,.hallucination.and.
agitation.known.as.Morvan's.syndrome�,.�.
. Neuromyotonia.represents.a.rather.severe.peripheral.
nerve.hyperexcitability.with.electromyographical.features.
of.spontaneous,.continuous,.irregularly.occurring.doublet,.
triplet.or.multiplet.single.motor.unit.discharges.firing.at.a.
high. intraburst. frequency. (30-300.Hz)3,.6,. 7.. .This. activity.
continued.during.sleep.and.general.anesthesia...Detailed.
electrophysiological. studies. on. this. group. of. patients.
have. revealed. that. most. bursts. arise. from. one. focal.
generator. site,. perhaps. most. commonly. in. the. distal.
portion.of.the.nerve...There.have.been.no.neurophysio-
logical. evidences. of. abnormality. in. the. cortical. motor.
axon.and.central.motor. conduction.as.studied.by. tran-
scranial.magnetic.stimulation...In.addition,.there.has.been.
no.evidence.of.a.direct.defect.in.neuromuscular.transmis-
sion. as. measured. by. single-fiber. electromyography7...
Neuromyotonia. has. been. seen. in. patients. with. chronic.
inflammatory. demyelinating. polyneuropathy. and.
incomplete.recovery.from.Guillain-Barré.syndrome...Other.
cases.had.electrophysiological.or.morphological.evidence.
of.a.mild.neuropathy2...The.exact.cause.of.the.disease.is.
unknown.but.it.has.been.considered.as.an.autoimmune.
neuromuscular. junction. channelopathy.. . Antibodies. to.
voltage-gated.potassium.channels.(VGKCs).are.present.in.
�0%.of.neuromyotonia.patients8...It.can.occur.as.a.para-
neoplastic. disorder. associated. with. small-cell. lung.
cancer9-11.or.thymoma12-1�...In.neuromyotonia.cases.with.
thymoma,. some. had. clinical. features. of. myasthenia.
gravis1�.or.had. raised. titers.of.antibody. to.acetylcholine.
receptor. without. evidence. of. myasthenia. gravis16...
Neuromyotonia.has.also.been.reported.to.be.associated.
with. myasthenia. gravis. without. thymoma17,. 18.. . A.
pulmonary. carcinoma. was. disclosed. at. autopsy. in. a.
patient. with. Morvan's. syndrome�.. . Recent. studies.
suggest.an.autoimmune.mechanism.in.which.presynaptic.
voltage-gated. potassium. channels. may. be. targeted. by.
autoantibodies. in.at. least.a.subset.of.patients. including.
patients.with.Morvan's.syndrome2,.�,.19,.20...
7�
NEUROMYOTONIA (ISAACS’ SYNDROME)
. The. diagnosis. of. neuromyotonia. is. made. on. the.
basis.of.clinical.features...Nerve.conduction.study.may.
show. evidence. of. polyneuropathy.. . Electromyogram.
shows. spontaneous. and. continuous. motor. unit.
potentials. consisting.of.high. frequency.doublet,. triplet.
or. multiplet. single. unit. discharges.. .The. presence. of.
antibodies.to.VGKCs.along.with.the.characteristic.clinical.
features.is.diagnostic.of.this.condition....
. The.natural.history.has.not.been.clearly.documented...
Remission.may.occur.spontaneously.as.is.also.sometimes.
observed.in.other.autoimmune.disorders2,.21.
. Most. patients. symptomatically. improve. with. anti-
convulsant.drugs.that.block.sodium.channels,.e.g.,.car-
bamazepine.and.phenytoin...Immunosuppressants,.e.g.,.
corticosteroids. or. azathioprine. have. been. used. with.
variable. success.. . In. some. cases,. plasma. exchange.
proved. to. be. beneficial13,. 1�,. 22.. . Limited. case. reports.
show.a.variable.response.with.IVIG13,.22,.23.
INtRaVENOUs IMMUNOGLOBULIN fOR NEUROMYOtONIaIVIGASMAINtENANCEtHERAPyAlessi.et.al.reported.a.patient.with.neuromyotonia.who.
had.failed.to.respond.to.anticonvulsants,.benzodiazepine.
and.plasma.exchange.(PE)23...Corticosteroid.and.azathio-
prine.were.not.tolerated...IVIG.was.given.at.a.dose.0.�.
g/kg/day.for.�.days...The.symptoms.improved.after.the.
�th. day. up. to. 3. weeks.. . IVIG. was. administered. at. 6-
weekly. intervals. with. substantial. improvement. after. 6.
months.of.therapy23.
. van.den.Berg.et.al.reported.a.patient.with.two.para-
neoplastic.syndromes,.i.e.,.acquired.neuromyotonia.and.
nephrotic.syndrome.in.association.with.a.thymoma11...A.
few.weeks.after.removal.of.the.thymoma,.the.patient's.
clinical. condition.deteriorated.. .A.�-day. treatment.with.
IVIG.at.0.�.g/kg/day.had.no.effect.on.the.clinical.manifes-
tations...Three.weeks.later,.PE.(�.times.a.week,.2.�.l,.for.
2. weeks). resulted. in. a. dramatic. improvement...
Subsequently,.immunosuppressive.treatment.(predniso-
lone. and. azathioprine). was. associated. with. disappear-
ance.of.all.clinical.symptoms.and.signs13.
. Ishii.et.al.evaluated.the.effects.of.PE.and.IVIG.in.a.
patient.with.neuromyotonia.who.showed.an.insufficient.
response. to.pharmacological. treatment.. .After.PE,. the.
symptoms. almost. disappeared. for. 2-3. weeks. and. the.
recorded. continuous. muscle. action. potentials. were.
considerably. decreased.. . In. contrast,. symptoms.
worsened.after.IVIG.at.a.dose.of.0.2.g/kg/day.for.�.days.
with.an.increase.in.continuous.muscle.activity.in.EMG.
and.these.improved.after.another.course.of.PE22.
sUMMaRYThe. limited. information.available.on. IVIG.use. in.neuro-
myotonia.shows.variable.efficacy...Case.reports.indicate.
that.PE.was.more.beneficial.than.IVIG.in.2.patients.and.
IVIG. was. beneficial. with. sustained. improvement. on.
maintenance.therapy.in.another.patient.
CONsENsUsThere. is. insufficient. evidence. of. benefit. of. IVIG..
in.neuromyotonia.
REfERENCEs1.. .Victor. M,. Ropper. A.. . Continuous. muscle. activity..
(Isaacs.Syndrome)...In:.Victor.M,.Ropper.A,.editors...
Principal.of.Neurology...7th.ed...New.York:.McGraw-
Hill;.2001...p...1�68-9.
2.. .Newsom-Davis.J,.Mills.KR...Immunological.associa-
tions.of.acquired.neuromyotonia.(Isaacs'.syndrome)...
Report. of. five. cases. and. literature. review.. . Brain.
1993;116.(.Pt.2):��3-69.
3.. .Auger. RG.. . AAEM. minimonograph. #��:. diseases.
associated.with.excess.motor.unit.activity...Muscle.
Nerve.199�;17(11):12�0-63.
�.. .Barber. PA,. Anderson. NE,. Vincent. A.. . Morvan's.
syndrome.associated.with.voltage-.gated.K+.channel.
antibodies...Neurology.2000;��(3):771-2.
�.. .Liguori. R,. Vincent. A,. Clover. L,. Avoni. P,. Plazzi. G,.
Cortelli.P,.et.al...Morvan's.syndrome:.peripheral.and.
central. nervous. system. and. cardiac. involvement.
with.antibodies.to.voltage-gated.potassium.channels...
Brain.2001;12�(Pt.12):2�17-26.
76
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
6.. .Maddison. P.. . Neuromyotonia.. . Clin. Neurophysiol.
2006;117(10):2118-27.
7.. .Maddison.P,.Mills.KR,.Newsom-Davis.J...Clinical.elec-
trophysiological.characterization.of.the.acquired.neuro-
myotonia.phenotype.of.autoimmune.peripheral.nerve.
hyperexcitability...Muscle.Nerve.2006;33(6):801-8.
8.. .Newsom-Davis.J...Neuromuscular.junction.channelop-
athies:. a. brief. overview.. . Acta. Neurol. Belg.
200�;10�(�):181-6.
9.. .Partanen. VS,. Soininen. H,. Saksa. M,. Riekkinen. P...
Electromyographic.and.nerve.conduction.findings.in.a.
patient.with.neuromyotonia,.normocalcemic.tetany.and.
small-cell.lung.cancer...Acta.Neurol.Scand.1980;61(�):216-
26.
10.. .Waerness.E...Neuromyotonia.and.bronchial.carcinoma...
Electromyogr.Clin.Neurophysiol.197�;1�(�-6):�27-3�.
11.. .Walsh.JC...Neuromyotonia:.an.unusual.presentation.of.
intrathoracic.malignancy...J.Neurol.Neurosurg.Psychiatry.
1976;39(11):1086-91.
12.. .Heidenreich. F,. Vincent. A.. . Antibodies. to. ion-channel.
proteins.in.thymoma.with.myasthenia,.neuromyotonia,.
and.peripheral.neuropathy...Neurology.1998;�0(�):1�83-
�.
13.. .van.den.Berg.JS,. van.Engelen.BG,.Boerman.RH,.de.
Baets. MH.. . Acquired. neuromyotonia:. superiority. of.
plasma. exchange. over. high-dose. intravenous. human.
immunoglobulin...J.Neurol.1999;2�6(7):623-�.
1�.. .Hayat.GR,.Kulkantrakorn.K,.Campbell.WW,.Giuliani.MJ...
Neuromyotonia:. autoimmune. pathogenesis. and.
response.to.immune.modulating.therapy...J.Neurol.Sci.
2000;181(1-2):38-�3.
1�.. .Garcia-Merino. A,. Cabello. A,. Mora. JS,. Liano. H...
Continuous.muscle.fiber.activity,.peripheral.neuropathy,.
and.thymoma...Ann.Neurol.1991;29(2):21�-8.
16.. .Halbach.M,.Homberg.V,.Freund.HJ.. .Neuromuscular,.
autonomic. and. central. cholinergic. hyperactivity.
associated.with.thymoma.and.acetylcholine.receptor-.
binding.antibody...J.Neurol.1987;23�(6):�33-6.
17.. .Van. Parijs. V,. Van. den. Bergh. PY,. Vincent. A...
Neuromyotonia. and. myasthenia. gravis. without.
thymoma.. . J. Neurol. Neurosurg. Psychiatry.
2002;73(3):3��-�.
18.. .Antelli.A,.Spengos.K,.Zambelis.T,.Pandis.D,.Tsivgoulis.
G,.Zis.V...Neuromyotonia.and.myasthenia.gravis.in.the.
absence.of.thymoma...Eur.J.Neurol.2006;13(7):e�.
19.. .Shillito.P,.Molenaar.PC,.Vincent.A,.Leys.K,.Zheng.W,.
van. den. Berg. RJ,. et. al.. . Acquired. neuromyotonia:.
evidence. for. autoantibodies. directed. against. K+.
channels. of. peripheral. nerves.. . Ann. Neurol.
199�;38(�):71�-22.
20...Hart. IK,.Waters.C,.Vincent.A,.Newland.C,.Beeson.D,.
Pongs.O,.et.al...Autoantibodies.detected.to.expressed.
K+. channels. are. implicated. in. neuromyotonia.. . Ann.
Neurol.1997;�1(2):238-�6.
21.. .Isaacs. H,. Heffron. JJ.. .The. syndrome. of. 'continuous.
muscle-fibre.activity'.cured:.further.studies...J.Neurol.
Neurosurg.Psychiatry.197�;37(11):1231-�.
22...Ishii. A,. Hayashi. A,. Ohkoshi. N,. Oguni. E,. Maeda. M,.
Ueda.Y,.et.al...Clinical.evaluation.of.plasma.exchange.
and.high.dose.intravenous.immunoglobulin.in.a.patient.
with.Isaacs'.syndrome...J.Neurol.Neurosurg.Psychiatry.
199�;�7(7):8�0-2.
23...Alessi.G,.De.Reuck.J,.De.Bleecker.J,.Vancayzeele.S...
Successful.immunoglobulin.treatment.in.a.patient.with.
neuromyotonia...Clin.Neurol.Neurosurg..2000;102(3):.
173-�.
77
INFLAMMATORY MYOPATHIESBaCKGOUNdThe.inflammatory.myopathies.are.a.set.of.three.discrete.
disorders. of. skeletal. muscle. -. dermatomyositis. (DM),.
polymyositis. (PM),. and. inclusion. body. myositis. (IBM)......
These.disorders.are.acquired,.and.have.in.common.the.
occurrence. of. significant. muscle. weakness. and. the.
presence. of. an. inflammatory. response. within..
the.muscle.
.
A. key. set. of. characteristics. distinguishes. the. three.
disorders.(Table.1)...The.clinical.and.pathological.features.
of.DM,.PM.and.IBM.have.been.previously.reviewed1,.2.
INFLAMMATORY MYOPATHIES
78
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
Dermatomyositis Polymyositis Inclusion.body.myositis
Mean.age.at.onset.symptoms <�0.years. <�0.years. <�0.years.
Mode.of.onset.symptomsSubacute..
(weeks.to.months)
Subacute..
(weeks.to.months)Slow.(years).
Sex.differences F>M F>M M>F
Occurrence.in.childhood Yes Yes.(very.rare) No
Distribution.of.weakness Proximal.>.distal Proximal.>.distal Proximal.&.distal
Rash Yes No No
Association.with.malignancy Yes Yes.(weak). No
Creatine.kinase Usually...or Usually...or Usually
Autoimmune.aetiology Yes Yes Unclear
T.cell-mediated.myocytotoxicity No Yes Yes
Prominent.rimmed.vacuoles No No Yes
Complement-mediated.depletion..
of.capillariesYes.(early). No No
Perifascicular.atrophy Yes.(inconstant). No No
Good.response.to.corticosteroids Yes.(usually). Yes.(usually). No
Table.1:.Key.distinguishing.features.of.DM,.PM.and.IBM
The. diagnosis. of. DM,. PM. or. IBM. is. usually. made. by.
neurologists. or. rheumatologists. and. relies. on. the.
combination. of. careful. clinical. evaluation,. an. elevated.
creatine. kinase. level,. electromyography,. and. muscle.
biopsy...Endocrine.or.toxic.myopathies,.some.types.of.
muscular. dystrophy3. and. occasionally. myophosphory-
lase. deficiency. can. mimic. PM.. . IBM. should. not. be.
confused.with.hereditary.inclusion.body.myopathy.due.
to.mutations.in.the.gene.encoding.UDP-N-acetylglucos-
amine-2-epimerase./.N-acetylmannosamine.kinase�.
. The. natural. history. of. DM. and. PM. is. unclear,. as.
patients.are.almost.always.treated.with.corticosteroids...
However,. spontaneous. remission. in. DM. and. PM. is.
uncommon.. .Patients.with. IBM,.for.whom.there. is.no.
particularly.effective.therapy,.gradually.deteriorate.over.
years...They.eventually.lose.ability.to.form.a.fist.and.to.
extend. the. knee. against. gravity,. but. loss. of..
ambulation. is. unusual.. . More. than. half. eventually..
develop.dyspha-gia6,.7.
79
tREatMENt Of dM aNd pMA)DRuGtREAtMENtThe.drug.treatment.of.DM.and.PM.are.usually.considered.
together.. . Corticosteroids. form. the. mainstay. of.
treatment,.although.no.controlled.trials.have.ever.been.
performed...Resistance.to.corticosteroid.therapy.should.
prompt.a. review.of. the.diagnosis8.. .Azathioprine. is.an.
effective.second-line.immunosuppressive.agent,.but.at.
least. 3. months. is. required. for. a. significant. effect9,. 10...
Oral.methotrexate,.another.commonly.used.second-line.
agent,. is. probably. effective. in. DM. and. PM,. although.
evidence. from. randomised. trials. with. suitable. controls..
is. lacking1,. 3.. . Plasma. exchange. is. ineffective. in. DM..
and.PM1�.
B)IVIGtREAtMENtLevel. II. Evidence:. A. single. double-blind,. randomised,.
controlled. trial. (RCT). has. studied. use. of. IVIG. for.
treatment-resistant.DM1�.. .With.cross-overs,. a. total.of.
12. patients. received. three,. monthly. infusions. of. IVIG.
(each. infusion.2g/kg,.given. in.2.doses).. .Nine.of.these.
12. patients. showed. major. improvement,. three. mild.
improvement,.and.one.no.change...Three.of.11.placebo-
treated. patients. showed. mild. improvement.. . The.
improvement. with. IVIG. was. noticeable. about. 1�. days.
after. the. first. infusion. but. was. definite. only. after. the.
third. infusion.. . Patients. subsequently. required.
maintenance. infusions. of. IVIG. approximately. every. 6.
weeks.(dose.not.stated).
. Uncontrolled. open. label. studies. or. retrospective.
reviews. provide. additional. support. for. the. efficacy. of.
IVIG. treatment. in. DM. and. PM.. . Monthly. infusions. of.
IVIG.were.successful.as.add-on.treatment.in.five.of.five.
patients.with.juvenile.DM.who.had.persistent.weakness.
despite.corticosteroid.therapy16;.the.dose.of.corticoste-
roid.was.subsequently.reduced.in.all.�.patients...Twenty.
four. of. 3�. patients. with. DM10. or. PM2�,. resistant. to.
prednisone. and. second-line. agents,. improved. with.
monthly.courses.of.IVIG.given.for.a.mean.of.�.months17...
Improvement. was. usually. noted. within. the. first. two.
infusions.and.reached.a.maximum.at.the.fourth.infusion...
Most. of. the. patients. who. responded. required.
maintenance.IVIG.therapy,.usually.monthly.or.bimonthly...
Similar. results. were. reported. when. this. series. of.
patients.was.extended18,19.. .Nine.of.nine.patients.with.
treatment-resistant.juvenile.DM.and.corticosteroid.side-
effects.showed.improvement.with.IVIG20...Six.of.seven.
patients. with. juvenile. DM,. some. of. whom. were.
treatment-resistant,. improved. with. IVIG. infusions21...
Eight.of.11.patients.with.treatment-resistant.DM,.PM.or.
an.overlap.syndrome.responed.to.monthly.infusions.of.
IVIG22.. .Twelve. of. 18. patients. with. treatment-resistant.
juvenile.DM.showed.clinical.improvement.and.tolerated.
reduction.of.corticosteroid.dose23...Seven.of.19.patients.
with. DM. responded. to. IVIG2�;. non-responders. in. this.
study.had.severe.muscle.and.skin.disease...The.addition.
of. IVIG. to. prednisone. and. cyclosporine. in. 13. patients.
with. DM. or. PM. increased. the. chances. of. complete.
remission. at. �. years. compared. to. patients. given.
prednisone. and. cyclosporine. alone2�.. . Initial..
monotherapy. with. IVIG. produced. significant. clinical.
improvement. in. only. three. of. 11. patients. with. DM. or.
PM26,. suggesting. that. IVIG. is.probably.not. suitable. as.
first-line.therapy.in.these.disorders.
. Case. reports. further. describe. benefit. from. IVIG.
treatment.in.PM27-32.and.DM29,.30,.33-38.
tREatMENt Of IBMA)DRuGtREAtMENtCorticosteroids. and. second-line. immunosuppressive.
drugs.may.produce,. at.most,.modest.benefit. in. some.
patients.with.IBM6,.39,.�0...Monotherapy.with.oral.metho-
trexate.did.not.seem.effective.in.a.RCT�1.
B)IVIGtREAtMENtThree. RCT. have. assessed. the. value. of. IVIG. in. the.
treatment.of.IBM.
1.. .In. a. double-blind. crossover. RCT,. 19. patients. with.
IBM. received. IVIG. (2g/kg). or. placebo. at. monthly.
intervals. for. 3. months,. followed. by. the. alternative.
treatment�2.. .No.significant.differences.were.found.
in. skeletal. muscle. strength. based. on. the. the.
Medical.Research.Council.(MRC).scale,.the.primary.
outcome. measure.Retrospective. limb-by-limb.
analysis.showed.patchy.improvement.of.strength.in.
the. leg. muscles. of. some. patients.. . Significant.
improvements. with. IVIG. were. found. in. objective.
INFLAMMATORY MYOPATHIES
80
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
measures.of.swallowing,.but.the.clinical.significance.
of.this.improvement.was.not.discussed...Overall,.13.
of. the. patients. indicated. some. degree. of.
improvement.on.IVIG,.and.nine.pursued.IVIG.therapy.
after.the.trial.was.completed.
2.. .In. a. double-blind. crossover. RCT,. 19. patients. with.
IBM.received...IVIG..(2G/kg.monthly).or.placebo.for..
6. months,. followed. by. the. alternative. treatment�3...
Mild. significant. improvement. (11%). was. found. in.
the. Neuromuscular. Symptom. Sore,. but. not. in.
several. other. outcome. measures.. . The. authors.
concluded. that. treatment. with. IVIG. may. be. mildly.
effective. in. IBM.by.preventing.disease.progression.
or.inducing.mild.improvement.
3.. .In.a.further.double-blind.RCT,.36.patients.with.IBM.
were.randomised.to.receive.prednisone.+.IVIG.(2G/
kg. monthly. for. 3. months). or. prednisone. +. place.
bo��.. . In. the. 19. who. received. IVIG,. no. significant.
improvements..were..noted.. in.. .muscle..strength.
scores.or.swallowing...The.number.of.necrotic.fibers.
and. the. amount. of. endomysial. inflammation. were.
reduced. in. repeat.muscle.biopsies,.but. the.clinical.
significance.of.this.was.thought.doubtful.
. Uncontrolled.open.label.trials.and.case.reports.have.
provided. weak. and. conflicting. evidence. that. IVIG. can.
improve.some.patients.with.IBM...In.a.pilot.study,.the.
strength. 'improved. or. normalised'. in. three. of. four.
patients.with.IBM.treated.with.two,.monthly. infusions.
of.IVIG��...In.another.study,.none.of.nine.patients.with.
IBM. improved. on. objective. manual. muscle. testing. or.
functional. disability. scores�6.. . An. extended. course. of.
IVIG.increased.knee.strength.in.one.patient�7...None.of.
five.patients.with.IBM.showed.functional.improvement.
with.monthly.IVIG.infusions,.although.myometry.scores.
improved.in.some.muscles.in.one.patient22...IVIG.given.
each.2.weeks.for.2�.weeks.produced.enduring.benefit.
in.one.patient�8...Monthly.courses.of.IVIG.for.6-8.months.
produced. sustained. improvement. of. dysphagia. in..
four.patients�9.
sUMMaRYDMandPMThere. is. evidence. from. open. label. studies. (Level. III-3.
evidence),. case. reports. (Level. IV. evidence),. and. one.
RCT.(Level.II.evidence).that.monthly.infusion.of.IVIG.is.
effective.add-on.therapy.for.patients.with.DM.who.have.
not.responded.adequately.to.corticosteroids.and.second-
line. immunosuppressive. agents.. . There. is. weaker.
evidence.from.open.label.studies.(Level.III-3.evidence).
and. case. reports. (Level. IV. evidence). that. monthly.
infusion.of.IVIG.is.effective.add-on.therapy.for.patients.
with.PM.who.have.not.responded.adequately.to.cortico-
steroids. and. second-line. immunosuppressive. agents...
There.is.general.consensus.in.the.literature.that.patients.
with.DM.or.PM.require.2-3,.monthly.infusions.of.IVIG.in.
order. to. assess. responsiveness;. and. that. most.
responders. subsequently. need. maintenance. infusions.
at.intervals.of.approximately.�-8.weeks.
. The. high. cost. of. the. treatment. and. the. need. for.
intravenous. administration. must. be. considered. when.
deciding.to.use.IVIG.in.patients.with.DM.or.PM...As.the.
majority. of. patients. with. DM. or. PM. will. respond. to.
treatment. with. corticosteroids. and. second-line. immu-
nosuppressive.agents,.IVIG.cannot.be.recommended.as.
the. first-line. or. sole. therapy.. . Recent. reviews. discuss.
the.use.of.IVIG.in.DM�0,.�1.
2.IBMThere. is. evidence. from. three. RCT. (Level. II. evidence).
that. monthly. infusions. of. IVIG. fail. to. produce. overall.
significant.benefit.in.patients.with.IBM...The.weight.of.
evidence. from. open. label. trials. (Level. 111-3. evidence).
and. case. reports. (Level. IV. evidence). supports. this.
conclusion.. .There. is. conflicting. evidence. among. the.
three. RCT. on. the. efficacy. of. IVIG. for. treating. the.
dysphagia. associated. with. IBM;. additional. weaker.
evidence.from.case.reports.(Level.IV.evidence).suggests.
that.IVIG.may.be.effective.for.this.indication.
81
INFLAMMATORY MYOPATHIES
EXpERt CONsENsUsIVIG. can. be. trialled. as. add-on. treatment. for. patients.
with.DM.or.PM.who.have.not.responded.adequately.to.
corticosteroids. or. another. immunosuppressive. agent...
Patients. should. receive. 2-3. courses. (2g/kg). of. IVIG. at.
monthly. intervals. in. order. to. assess. responsiveness...
Responders. will. often. require. maintenance. therapy. at.
intervals.of. approximately.�-8.weeks.. . IVIG.cannot.be.
recommended.at.this.time.to.treat.the. limb.weakness.
of.IBM...Weak.evidence.suggests.that.it.may.transiently.
benefit. patients. with. severe. dysphagia. associated..
with.IBM.
REfERENCEs1.. .Dalakas.MC,.Hohlfeld.R.Polymyositis.and.dermato-
myositis..Lancet.2003;362:971-82.
2.. .Griggs. RC,. Askanas.V,. DiMauro. S,. et. al.. Inclusion.
body. myositis. and. myopathies. Ann. Neurol.
199�:38:70�-13.
3.. .Gallardo.E,.Rojas-Garcia.R.&.de.Luna.N..Inflammation.
in. dysferlin. myopathy:. immunohisto-chemical. char-
acterization. of. 13. patients.. Neurology.
2001:�7:2136-8.
�.. .Horneff.G,.Paetzke.I.&.Neuen-Jacob.E..Glycogenosis.
type. V. (McArdle's. disease). mimicking. atypical.
myositis..Clin.Rheumatol.2001:20:�7-60.
�.. .Eisenberg. I,. Avidan. N,. Potikha.T,. et. al..The. UDP-
Nacetylglucosamine. 2-epimerase/N-acetylman-
nosamine. kinase. gene. is. mutated. in. recessive.
hereditary. inclusion. body. myopathy. Nat. Genet.
2001;29:83-87.
6.. .Dalakas. MC. Controlled. studies. with. high-dose.
intravenous. immunoglobulin. in. the. treatment. of.
dermatomyositis,.inclusion.body.myositis,.and.poly-
myositis..Neurology.1998;�1(Supplement):S37-.��.
7.. .Houser.SM,.Calabrese.LH,.&.Strome.M..Dysphagia.
in. patients. with. inclusion. body. myositis..
Laryngoscope.1998:108:1001-�.
8. ..Wiles. CM,. Brown. P. Chapel. H,. et. al.. Intravenous.
immunoglobulin.in.neurological.disease:.a.specialist.
review..JNNP.2002:72:��0-8.
9.. .Bunch.TW.Prednisone.and.azathioprine.for.polymyo-
sitis:. long-term. followup.. Arthritis. Rheum..
1981:2�:��-8.
10...Mastaglia.FL,.Phillips.BA,.Zilko.P,.et.al..Relapses.in.
idiopathic. inflammatory.myopathies..Muscle.Nerve.
1999:22:1160-61.
11.. .Wilke.WS.Methotrexate.use.in.miscellaneous.inflam-
matory. diseases.. Rheum. Dis. Clin. North. Am..
1997:23:8��-82.
13...Vencovsky. J,. Jarosova. K,. Machacek. S,. et. al..
Cyclosporine.A.versus.methotrexate.in.the.treatment.
of. polymyositis. and. dermatomyositis.. Scand. J.
Rheumatol.2000:29:9�-102.
1�...Miller.FW,.Leitman.SF,.Cronin.ME,.et.al..A.randomised.
double-blind.controlled.trial.of.plasma.exchange.and.
leukapheresis.in.patients.with.polymyositis.and.der-
matomyositis..NEJM.1992:326:1380-8�.
..
1�...Dalakas.MC,.Ilia.I,.Dambrosia.JM,.et.al..A.controlled.
trial. of. high-dose. intravenous. immune. globulin.
infusions.as. treatment. for.dermatomyositis..NEJM.
1993;329:1993-2000.
16...Lang.BA,.Laxer.RM,.Murphy.G,.et.al..Treatment.of.
dermatomyositis. with. intravenous. gammaglobulin..
Am.J.Med.1991:91:169-72.
17.. .Cherin. P. &. Herson. S. Indications. for. intravenous.
gammaglobulin.therapy.in.inflammatory.myopathies..
JNNP.199�:�7(Supplement):�0-�.
18...Cherin.R.Intravenous. immunoglobulins. in.polymyo-
sitis.and.dermatomyositis.Ann.Med.Interne. (Paris)..
2000:1�1.(Supplement.1):1S�8-�0.
82
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
19...Cherin. P. Pelletier. S,.Teixeira. A,. et. al.. Results. and.
long-term. followup. of. intravenous. immunoglobulin.
infusions. in. chronic,. refractory. polymyositis:. an.
open. study. with. thirty-five. adult. patients.. Arthritis.
Rheum.2002:�6:�67-7�.
20...Sansome.A.&.Dubowitz.V.Intravenous.immunoglob-
ulin. in. juvenile.dermatomyositis-four.year.review.of.
nine.cases.Arch.Dis.Child.199�:72:2�-8.
21.. .Tsai.MJ,.Lai.CC,.Lin.SC,.et.al..Intravenousimmunogl
obulin. therapy. in. juvenile. dermatomyositis.. Chung.
Hua. Min. Kuo. Hsiao. Erh. Ko. I. Hsueh. Hui.Tsa. Chih..
1997:38:111-�.
22...Mastaglia.FL,.Phillips.BA,.Zilko.PJ..Immunoglobulin.
therapy. in. inflammatory. myopathies. JNNP.
1998:6�:107-110.
23...AI-Mayouf. SM,. Laxer. RM,. Schneider. R,. et. al..
Intravenous. immunoglobulin. therapy. for. juvenile.
dermatomyositis:. efficacy. and. safety.. J. Rheumatol.
2000:27:2�98-�03.
2�...Gottfried. I,. Seeber. A,. Anegg. B,. et. al.. High. dose.
intravenous. immunoglobulin. (IVIG). in.
dermato¬myositis:. clinical. response. and. effect. on.
slL-2R.lev¬els..EurJ.Dermatol.2000;10:29-3�.
.
2�...Danieli.MG,.Malcangi.G,.Palmieri.C,.et.al..Cyclosporin.
A.and. intravenous. immunoglobulin. treatment.poly-
myositis/dermatomyositis. Ann. Rheum. Dis.
2002:61:37-�1.
26...Cherin. P. Peitte. JC,.Wechsler. B,. et. al.. Intravenous.
gamma.globulin.as.first.line.therapy.in.polymyositis.
and. dermatomyositis:. an. open. study. in. 11. adult.
patients..J.Rheumatol.199�:21:1092-7.
27.. .Jann.S,.Beretta.S,.Moggio.M.High-dose.intravenous.
human.immunoglobulin. in.polymyositis.resistant.to.
treatment..JNNP.1992:��:60-62.
28...Stoll.T,.Michel.BA,.Neidhart.M,.et. al.. Polymyositis:.
disease. course. and. therapy. with. intravenously.
administered. immunoglobulins. Schweiz. Med.
Wochenschr.1992:122:1��8-6�.
29...Moriguchi.M,.Suzuki.T,.Tateishi.M,.et.al..Intravenous.
immunoglobulin. therapy. for. refractory. myositis..
Intern.Med.1996:3�:663-7.
..
30...Marie.I,.Hachulla.E,.Levesque.H,.et.al.. Intravenous.
immunoglobulins. as. treatment. of. life. threatening.
esophageal.involvement.in.polymyositis.and.derma-
tomyositis..J.Rheumatol.1999:26:2706-9.
31.. .Saito. M,. Saito.Y,. Endo. K,. et. al.. A. case. of. steroid.
resistant.polymyositis.who.made.a.good. response.
to. high. dos. intravenous. immunoglobulins. (IVIG)..
Rinsho.Shinkeigaku.2000:�0:181-3.
32...Genevay.S,.Saudan-Kister.A,.Guerne.PA..Intravenous.
gammaglobulins. in. refractory. polymyositis:. lower.
dose. for. maintenance. treatment. is. effective.. Ann.
Rheum.Dis.2001:60:6.
3�...Vedanarayanan. V,. Subramony. SH,. Ray. LI,. et. al..
Treatment. of. childhood. dermatomyositis. with. high.
dose. intravenous. immunoglobulin. Pediatr. Neurol.
199�:13:336-9.
3�...Sabroe. RA,. Wellington. TB,. Kennedy. CT..
Dermatomyositis.treated.with.high-dose.intravenous.
immunoglobulins. and. associated. with. panniculitis..
Clin.Exp.Dermatol..199�;20:16�-7.
36...Galeazzi.M,.Bellucci.AM,.Girardelli.CR,.et.al..Efficacy.
of.intravenous.immunoglobulin.therapy.in.a.case.of.
juvenile. dermatomyositis. Clin. Rheumatol.
1996:1�:21�-6.
37.. .FuruyaY,.TakahashiT,.Hamamoto.H,.et.al..High-dose.
immunoglobulin.therapy.for.a.patient.with.dermato.
myositis.Intern.Med.1998:37:6�2-�.
83
38...Kokori. H,. Fotoulaki. M,. Giannakopoulou. C,. et. al..
Intravenous.immunoglobulin.treatment.in.a.girl.with.
juvenile.dermatomyositis.Pediatr.Int.1999:�1:696-7.
39...Leff. RL,. Miller. FW,. Hicks. J,. et. al..The. treatment.
ofinclusion. body. myositis:. a. retrospective. review.
and.a.randomized,.prospective.trial.of. immunosup-
pressive. therapy.. Medicine. (Baltimore).
1993:72:22�-3�.
�0...Sayers.ME,.Chou.SM,.Calabrese.LH.Inclusion.body.
myositis:. analysis. of. 32. cases.. J. Rheumatol..
1992:19:138�-9.
�1.. .Badrising.UA,.Maat-Schieman.ML,.Ferrari.MD,.et.al..
Comparison. of. weakness. progression. in. inclusion.
body. myositis. during. treatment.with.methotrexate.
or.placebo..Ann.Neurol..2002:�1:369-72.
�2...Dalakas.MC,.Sonies.B,.Dambrosia.J,.et.al..Treatment.
of.inclusion-body.myositis.with.IVIg:.a.double-blind,.
placebo-. controlled. study.. Neurology.
1997;�8:712-716.
�3...Walter. MC,. Lochmuller. H,.Toepfer. M,. et. al.. High-
dose. immunoglobulin. therapy. in. sporadic. inclusion.
body. myositis:. a. double-blind,. placebo-controlled.
study..J.Neurol.2000;2�7:22-8.
��...Dalakas.MC,.Koffman.B,.Fujii.M,.et.al..A.controlled.
study. of. intravenous. immunoglobulin. combined.
with.prednisone.in.the.treatment.of.IBM..Neurology.
2001:�6:323-7.
��...Soueidan. SA,. Dalakas. MC..Treatment. of. inclusion.
body.myositis.with.high-dose.intravenous.immuno-
globulin..Neurology.1993:�3:876-879.
�6...Amato.AA,.Barohn.RJ,.Jackson.CE,.et.al.. Inclusion.
body.myositis:.treatment.with.intravenous.immuno-
globulin..Neurology.199�:��:1�16-1�18.
�7.. .Dasque. F,. Laroche. M,. Marque. P,. et. al.. Isokinetic.
strength. testing. for. evaluating. the. efficacy. of.
intravenous. immune. globulin. therapy. for. inclusion.
body. myositis.. Rev. Rhum. Engl. Ed..
199�:62:�98-601.
�8...Mukunda. BN,. Kumar. DP. Smith. HR. Long-lasting.
effectiveness. of. intravenous. immunoglobulin. in.
patient.with. inclusion-body.myositis..Ann. Int.Med..
2001:13�:11�6.(letter).
�9...Cherin. P. Pelletier. S,.Teixeira. A,. et. al. Intravenous.
immunoglobulin. for. dysphagia. of. inclusion. body.
myositis..Neurology.2002:�8:326-7.
�0...Dalakas.MC..The.role.of.high-dose.immune.globulin.
intravenous.in.the.treatment.of.dermatomyositis..Int.
Immunopharmacol.2006;6:��0-��6.
�1.. .Pul. R,. Stangel. M.. Using. immunoglobulins. in.
muscular.disease. treatment..Expert.Opin.Biol.Ther.
2008;8:11�3-11�0.
INFLAMMATORY MYOPATHIES
8�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
CHRONIC FATIGUE SYNDROMEBaCKGROUNdChronic. fatigue. syndrome. (CFS). is. a. disorder. of.
unexplained.cause.with.no.specific.biomedical.marker...
It. is.characterized.primarily.by.disabling.and.persistent.
fatigue,. usually. associated. with. other. ill. defined.
symptoms.. . Diagnosis. of. CFS. is,. therefore,. based. on.
clinical.case.definition.and.the.exclusion.of.disorders.of.
known.cause.showing.similar. features7,.9,.13,.2�.. .The.US.
Centre.for.Disease.Control,.which.gave.the.name.to.this.
disorder,. developed. a. case. definition. which. is. now.
widely.used,.even.though.it.was.developed.primarily.for.
research7.. . This. case. definition. requires. at. least. 6.
months.of.persistent.fatigue.that.substantially.reduces.
activity,.accompanied.by. four.or.more.of. the.following..
symptoms. -. impaired. memory. or. concentration,. sore.
throat,.tender.glands,.aching.or.stiff.muscles,.multi-joint.
pain,. new. headaches,. non-refreshing. sleep. and..
post-exertional.pain.
. The.onset.of.CFS.is.usually.acute,.often.with.a.flu-
like. illness.. . Fatigue. exacerbated. by. exertion. is. pre-
eminent,.but.besides.the.associated.symptoms.included.
in.the.case.definition,.patients.with.CFS.also.complain.
of. a. variety. of. other. somatic. symptoms,. including.
anorexia,.nausea,.night.sweats,.dizziness.and.drug.and.
alcohol. intolerance.. .As. is.evident. from.this.definition,.
there. will. be. overlap. of. CFS. with. similar. syndromic.
disorders. that. include. fibromyalgia,. epidemic. myalgic.
encephalomyelitis,. chronic. mononucleosis. syndrome,.
post. viral. fatigue. syndrome,. neurasthenia,. multiple.
chemical. sensitivities,. irritable. bowel. syndrome. and.
temporomandibular.joint.disorder1,.6,.17,.21.
. Studies. from.Western. countries. suggest. that. CFS.
may.not.be.uncommon.and.reported.in.more.than.0.�%.
of.the.adult.population11,.although.prevalence.rates.have.
varied.widely,.depending.on.the.definition.used.and.the.
population.studied.. .A.study.from.the.US.suggested.a.
significant.economic.cost.with.an.estimate.of.$20,000.
loss.per.year.per.case22.
EtIOLOGY, pathOphYsIOLOGY aNd LaBORatORY OBsERVatIONsThe. etiology. of. CFS. remains. unknown. and. unclear.
despite. many. years. of. study.. . However,. there. are.
numerous.reports.of.the.association.of.CFS.with.abnor-
malities. or. dysfunction. of. diverse. organ. systems,.
including.neuroendocrine,.psychiatric,.sleep.and.immu-
nological. systems,. and. with. infections.. .The. interrela-
tionships.between.these.associations.are.unclear...This.
has. given. rise. to. the. concept. that. CFS. is. a. complex.
disorder.with.multi-factorial.etiology1,.6,.17.
8�
CHRONIC FATIGUE SYNDROME
ChRONIC fatIGUE sYNdROMENeuropsychiatric. symptoms. of. impaired. memory. or.
concentration,.depression.and.anxiety.often.manifest.in.
CFS...However,.studies.have.suggested.that.neuropsy-
chiatric. disorders,. especially. depression,. are. not. the.
primary.process.because.of.the.absence.of.neuroendo-
crine.changes.usually.associated.with.depression,.such.
as.hypercortisolism.. .There. are. reports. of. subtle.MRI,.
single. photon. emission. CT. and. fMRI. changes. in. the.
brain.in.CFS,.suggesting.structural.or.functional.changes3...
Several. diverse. neuroendocrine. abnormalities. have.
been.reported,.especially.hypofunction.of.the.hypotha-
lamic-pituitary-adrenal. axis. and. disturbances. in. sero-
toninergic. and. noradrenergic. pathways2.. . The. high.
frequency.of.overlap.of.fibromyalgia.and.CFS.symptoms.
of.musculoskeletal.pains.suggested.a.common.etiologic.
factor,. although. the. etiology. of. fibromyalgia. is. equally.
contentious. and. unresolved.. . CFS. patients. have. been.
reported. to. have. disturbed. and. poorer. sleep.. . CFS.
patients. have. also. been. reported. to. have. reduced.
physical. activity,. with. suggestions. that. this. could.
exacerbate.or.prolong.fatigue.
. Of.particular.relevance.to.the.use.of.IVIG.in.CFS.are.
reports.of.immunological.changes.and.infections.being.
associated. with. CFS.. . Specific. infections. reported. to.
cause. or. trigger. CFS. include. Epstein-Barr. virus. and.
infectious.mononucleosis,.Borrelia.burgdorferi.and.Lyme.
disease,. Q. fever,. human. herpes. virus. type. 6,.
mycoplasma,.parvovirus.B19,.group.B.Coxsackie.virus,.
human.T-cell.lymphotrophic.virus.II,.hepatitis.C,.entero-
viruses. and. retroviruses,. and. others1,. 6,. 17,. 27.. . These.
reports.have.mostly.been.isolated,.and.conversely,.only.
small. percentages. of. patients. with. these. infections.
(with. some. exceptions). are. known. to. proceed. to.
symptoms. of. CFS.. . A. recent. prospective. cohort.
community. based. study. of. patients. acutely. infected.
with.Epstein-Barr.virus,.Coxiella.burnetii.and.Ross.River.
virus.reported.that.11%.of.participants.had.a.prolonged.
illness. for. up. to. 6. months. that. met. the. criteria. of..
CFS. 31.. .Besides.suggesting. the.association.of. certain.
infections.with.CFS,.these.reports.also.suggest.that.the.
host. response. to. infection. may. be. relevant. to. patho-
physiology.in.CFS.
. There. are. many. reports. of. immunological. change.
associated.with.CFS...These.include.reports.of.impaired.
cell. mediated. immunity,. increased. CD8+T. cells,.
decreased.NK.cells,.elevated..TGF-beta,.raised.antinuclear.
antibodies,.elevated.immune.complexes.and.decreased.
C3.and.C�.levels...There.are.also.conflicting.reports.of.
elevated,. reduced. or. unchanged. IL-1. alpha,. IL2,. IL6,.
interferon,.alpha,.tumour.necrosis.factor-alpha.and.beta,.
immune.complexes.and.C3.and.C�. levels1,.6,.17,.19,.27.. .A.
study. of. cerebrospinal. fluid. in. CFS. reported. higher.
frequency. of. protein. or. cell. count. elevation,. lower.
granulocyte.macrophage.colony.stimulating.factor,.and.
higher.IL-8.and.IL-10.levels18...Autoantibodies.to.common.
and.neuron.specific.antigens.were.generally.not.found.
to. be. more. frequent. in. CFS,. although. subsets. with.
higher. rates. of. antibodies. to. microtubule. associated.
protein.2.and.ssDNA.were.noted28...A.report.of.a.2001.
symposium. on. immunologic. aspects. of. CFS. co-
sponsored.by.the.CDC.and.NIH.concluded.that.although.
persons. with. CFS. may. manifest. immune. response.
changes,. it. cannot. be. determined. if. these. were. the.
cause. or. result. of. the. illness8.. . Several. more. recent.
studies. of. gene. and. biomarker. associations. in. CFS.
using.gene.expression.microarray.and.proteomics.tech-
nologies.have.also. indicated. immunity.and.defense. to.
be. predominant. themes32, 33.. . Nevertheless,. the.
conclusion.remains,. following.review.of.these.studies,.
that.while. the.evidence.of. immune. reaction. in.CFS. is.
intriguing.and.suggestive,. it. remains.disparate.and.the.
identification. of. a. specific. host. response. associated.
with.CFS.awaits.validation.
. Recently.there.have.been.proposals.to.sub-classify.
CFS. into. subtypes. according. to. system. dysfunction,.
disability,. demography,. and. biomarkers27,. 10.. . It. was.
suggested. that. such. sub-classification. may. provide.
clarification. for. researchers. and. clinicians,. and. prove.
helpful.in.studies.of.therapy.and.pathophysiology...
thERapY IN CfsWhile.symptomatic.therapy.is.frequently.applied.in.CFS,.
a.specific.treatment.directed.at.the.underlying.etiology.
cannot. be. identified. as. the. underlying. etiology. and.
pathophysiology. remain. unclear.. . However,. several.
diverse.therapies.have.been.proposed.and.studied...In.
86
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
addition. to. IVIG,. these. include.other. immunological.or.
anti-infectious.therapies.such.as.steroids,.anti-inflamma-
tory. and. anti-viral. agents,. and. also. antidepressants,.
hormones,. nutritional. supplements,. alternative. and.
complementary. medicine,. behavioural. interventions.
and.exercise.programs...These.therapies.have.generally.
been.evaluated.by.only.a.small.number.of.studies.each...
Among. these,. the. evidence. for. a. beneficial. effect.
appeared. to. be. most. substantial. and. promising. for.
cognitive. behaviour. therapy. and. graded. exercise.
therapy�,. 16,. 23,. 26.. . No. further. comments. will. be. made.
about.this.wide.variety.of.therapies1,.6,.17,.21,.30.
IVIG IN CfsThere.are.four.randomised.clinical.trials.comparing.IVIG.
with. placebo. in. CFS,. reviewed. below. in. chronological.
order1�,.20,.2�,.29...The.use.of.IVIG.in.these.trials.was.based.
on. the. hypothesis. that. a. chronic. viral. infection. or. an.
immunoregulatory.defect.is.involved.in.CFS...Based.on.
these. hypotheses,. IVIG. could. provide. neutralizing.
antibodies.against.persistent.viral.antigen.or.may.correct.
the. immunoregulatory.defect. in.CFS.by. analogy. to. its.
effectiveness. in. a. variety. of. diseases. with. disordered.
immunoregulation.. .As. reviewed. in. the.section.above,.
while. there. are. many. reports. of. associated. virus.
infections.and.changes.in.a.variety.of. immune.indices,.
these.hypotheses.of. immune.or. infectious.etiology.of.
CFS.remain.unproven.
. The.first.trial20. involving.30.CFS.patients.compared.
monthly.IVIG.(1gm/kg).with.placebo.given.for.6.months...
Response. was. measured. by. self. assessment. of.
symptoms,.functional.status.and.health.perceptions...At.
the.end.of.the.study,.no.significant.therapeutic.benefit.
from. IVIG. treatment. was. detected. in. symptoms. or.
functional.status.
. The.second.trial1�.involving.�9.CFS.patients.compared.
monthly. IVIG.(2g/kg).with.placebo.given.for.3.months,.
with.the.subjects.evaluated.at.6.months...Subjects.were.
evaluated.by.physician.interview.and.by.self.assessment,.
using.subjective.symptom.and.disability.measures...At.
the.6.months.time-point,.the.physician.rated.assessment.
determined.that.�3%.of.the.IVIG.treated.subjects.had.
substantial. improvement. in. symptoms. and. disability,.
compared.to.12%.of.placebo.recipients,.indicating.that.
IVIG.is.effective.in.a.significant.number.of.patients.
. The. third. trial2�. differed. from. the. others. in. being.
conducted.on.a.group.of.71.adolescents.aged.11.to.18.
years...It.compared.IVIG.(1.g/kg).given.monthly.for.three.
months.with.placebo...Response.was.measured.by.the.
investigators. using. functional. scores. of. school,. social.
and.physical.activity.. .A.significant.difference.between.
the. IVIG.and.placebo. treated.groups.was. reported. for.
the.mean. functional. outcome,. i.e. the.mean.of. ratings.
for. all. activities.. . However,. both. the. IVIG. and. placebo.
groups.showed.significant.improvements.from.baseline.
measurements. up. till. the. final. 6. months..
time-point.
. The.fourth.trial29.was.conducted.by.the.same.inves-
tigators.who.led.the.Lloyd.et.al.trial1�.and.was.intended.
to. resolve. the.conflicting. results.of. the. first. two. trials.
reviewed. above,. while. recognizing. the. differences.
between.them,.including.differences.in.dosage...Hence,.
in.this.trial,.99.CFS.patients.were.allocated.randomly.to.
receive.one.of.three.different.doses.of.IVIG.(0.�,.1.and.
2. g/kg). or. to. receive. placebo,. all. given. monthly. for. 3.
months.. .The. subjects.were.evaluated.3.months. after.
the.final.infusion,.i.e...at.the.6.months.time-point...As.in.
the.earlier.study.by. these. investigators,. response.was.
assessed. by. the. investigators. using. a. performance.
score,.and.by.the.subject.using.a.self.report.score...At.
the.6.months.time-point,.irrespective.of.the.treatment,.
all.patients.showed.a.similar.improvement.in.the.inves-
tigator.assessed.functional.capacity,.with.no.significant.
difference. between. the. groups.. . Similar. results. were.
derived. from. the. self. reported. scores.. . Hence,. this.
double-blind,. placebo-controlled. trial. failed. to.
demonstrate. any. significant. benefit. from. IVIG. at. all.
three.doses.of.0.�.g/kg,.1.g/kg.and.2.g/kg.
. Thus,.the.four.reports.reviewed.above.showed.con-
tradictory. outcomes,. with. two. reporting. a. beneficial.
outcome,.and.two.reporting.no.difference...One.general.
limitation.of.all.four.studies.is.the.necessary.reliance.on.
functional. and. symptom. scores,. often. subjective,. by.
investigators.and/or. the.subject. to.measure. response...
Some. limitations. of. the. two. trials. reporting. beneficial.
outcome.may.be.mentioned.. . In. the. report.of.Lloyd.et.
al1�,.the.method.of.physician.assessment.was.potentially.
too. subjective.. . In. the. Rowe. report2�,. both. IVIG. and.
87
CHRONIC FATIGUE SYNDROME
placebo. groups. showed. significant. improvement. in.
scores. compared. to. base-line,. suggesting. a. natural.
history. of. improvement. or. an. effect. of. the. treatment.
environment,.both.of.which.may.be.variables.that.could.
also. influence.the.outcomes...The.adolescent.subjects.
ranging.from.11.to.18.years.may.be.too.heterogenous,.
another. variable. that. may. have. an. impact. on. the.
outcome.. . On. the. other. hand,. the. study. of. Vollmer-
Conna.et.al29.attempted.to.re-evaluate.the.earlier.study.
reporting.beneficial.outcome.by.the.same.study.group1�.
and. the. report. of. Petersen. et. al20,. with. a. larger. study.
population,. an. improved. method. of. evaluation. and. a.
comparison. of. different. IVIG. dosages.. . There. is,.
therefore,.more.to.recommend.this.study.than.the.two.
studies.with.reporting.beneficial.outcomes.
. There.is.some.data.to.suggest.that.subsets.of.CFS.
patients.associated.with.specific.infections.may.respond.
to. IVIG.. . Acute. parvovirus. B19. infection. has. been.
reported. to. be. followed. by. rheumatic. symptoms. and.
CFS...Four.patients.with.CFS.following.acute.parvovirus.
B19.infections.were.reported.in.two.studies12,.1�.to.show.
clearance. of. parvovirus. B19. viremia. and. resolution. of.
CFS. symptoms. with. improvement. in. physical. and.
functional. ability,. following. IVIG. therapy.. . IVIG. may.
potentially.act.via.the.presence.of.neutralising.antibodies.
to.the.virus...Additionally,.the.literature.includes.an.older.
report.of.a.randomised.controlled.trial.of.intramuscular.
gamma.globulin.in22."chronic.mononucleosis.syndrome".
patients.with.antibodies.to.EB.virus�,. in.which.�3%.of.
treated. patients. were. improved. compared. to. 32%. of.
patients.given.placebo.injections.
a). .In.summary,.it.is.concluded.that.there.is.contradic-
tory.and. insufficient.evidence.of.a.beneficial.effect.
from.IVIG.use.in.CFS.
b). .The.question.whether.subsets.of.CFS.may.respond.
to. IVIG,. namely. those. that. have. evidence. of.
association. with. specific. infections. or. disordered.
immune.regulation,.remains.unresolved.and.merits.
further.investigation.
EXpERt CONsENsUsa). .IVIG.AS.TREATMENT.IN.CLINICAL.MANAGEMENT.
OF.CFS.
. .IVIG.cannot.be.recommended.as.routine.therapy.for.
CFS.
b). IVIG.AS.AN.INVESTIGATIONALTHERAPY
. .If.IVIG.is.to.be.applied.as.investigational.therapy.in.
CFS,.this.should.be.considered.as.part.of.a.properly.
constructed.clinical.study.in.a.well.defined.subset.of.
CFS. patients. with. confirmed. specific. infections. or.
specific.immunologic.abnormalities.
REfERENCEs1.. .Afari.N.and.Buchwald.D...Chronic.fatigue.syndrome:.
A.review...Am.J.Psychiatry.2003;.60:.221-236.
2.. .Cleare. AJ.. . The. neuroendocrinology. of. chronic.
fatigue. syndrome.. . Endocrine. reviews. 2003;. 2�:.
236-2�2.
3.. .de.Lange.FP,.Kalkman.JS,.Bleijenberg.G,.Hagoort.P.
van.der.Werf.SP.van.der.Meer. JW,.Toni. I.. .Neural.
correlates. of. the. chronic. fatigue. syndrome. –. an.
fMRI.study...Brain.200�;.127:.19�8-19�7.
�.. .DuBois. RE.. . Gamma. globulin. therapy. for. chronic.
mononucleosis.syndrome...AIDS.Res.1986;.2.Suppl.
1:.S191-19�.
�.. .Edmonds.M,.McGuire.H,.Price.J...Exercise.therapy.
for. chronic. fatigue. syndrome.. . Cochrane. Database.
Syst.Rev.200�;.(3):CD003200.
6.. .Evengard.B.and.Klimas.N...Chronic.fatigue.syndrome:.
Probable. pathogenesis. and. possible. treatments...
Drugs.2002;.62:2�33-2��6.
7.. .Fukuda.K,.Straus.SE,.Hickie.I,.Sharpe.MC,.Dobbins.
JG,. Komaroff. A.. .The. chronic. fatigue. syndrome:. a.
comprehensive.approach.to.its.definition.and.study...
Ann.Intern.Med.199�;.121:.9�3-9�9.
88
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
8.. .Gerrity. TR,. Papanicolaou. DA,. Amsterdam. JD,.
Bingham.S,.Grossman.A,.Hedrick.T,.Herberman.RB,.
Kreuger.G,.Levine.S,.Mohagheghpour.N,.Moore.RC,.
Oleske. J,. Snell. CR;. CFIDS. Assoc. of. America...
Immunologic.aspects.of.chronic. fatigue.syndrome...
Report.on.a.Research.Symposium.convened.by.the.
CFIDS.Association.of.America.and.co-sponsored.by.
the.US.Centers.for.Disease.Control.and.Prevention.
and. the. National. Institutes. of. Health...
Neuroimmunomodulation...200�;.11:.3�1-3�7.
9.. .Holmes. GP. Kaplan. JE,. Gantz. NM,. et. al.. . Chronic.
fatigue.syndrome:. .a.working.case.definition.. .Ann.
Intern.Med.1988;.108:387-389.
10...Jason. LA,. Corradi. K,.Torres-Harding. S,.Taylor. RR,.
King. C.. . Chronic. fatigue. syndrome:. the. need. for.
subtypes...Neuropsychol.Rev...200�;.1�:29-�8.
11.. .Jason.LA,.Richman.JA,.Rademaker.AW,.Jordan.KM,.
et.al.. .A.community-based.study.of.chronic.fatigue.
syndrome...Arch.Intern.Med.1999;.1�9:2129-2137.
12...Kerr. JR,. Cunniffe. VS,. . Kelleher. P. Bernstein. RM,.
Bruce.IN....Successful.intravenous.immunoglobulin.
therapy. in. 3. cases. of. parvovirus. B19-associated.
chronic.fatigue.syndrome...Clin.Infect.Dis.2003;36:.
61000-106.
13...Lloyd.AR,.Hickie.I,.Boughton.CR,.et.al....Prevalence.
of. chronic. fatigue. syndrome. in. an. Australian.
population...Med.J.Aust.1990;.�3:.�22-�28.
1�...Lloyd.A,.Hickie.I,.Wakefield.D,.Boughton.C,.Dwyer.J...
A.double-blind,.placebo-controlled.trial.of.intravenous.
immunoglobulin. therapy. in. patients. with. chronic.
fatigue.syndrome...Am.J.Med.1990;89:.�61-�68
1�...McGhee. SA,. Kaska. B,. Liebhaber. M,. Stichm. ER...
Persistent. parvovirus-associated. chronic. fatigue.
treated.with.high.dose.intravenous.immunoglobulin...
Pediatr.Infect.Dis.J...200�;.2�:.272-27�.
16...Moss-Morris. R,. Sharon. C,.Tobin. R,. Baldi. JC.. . A.
randomized. controlled. graded. exercise. trial. for.
chronic. fatigue. syndrome:. outcomes. and.
mechanisms.of. change.. . J.Health.Psychol.. . 200�;.
10:2��-2�9.
17.. .Natelson. BH. and. Lange. G.. . A. status. report. on.
chronic.fatigue.syndrome...Environ.Health.Perspect.
2002;110:673-677.
18...Natelson. BH,. Weaver. SA,.Tseng. CL,. Ottenweller.
JE.. . Spinal. fluid. abnormalities. in. patients. with.
chronic.fatigue.syndrome...Clin.Diagn.Lab.Immunol..
200�;.12:�2-��.
19...Patarca.R...Cytokines.and.chronic.fatigue.syndrome...
Ann.NY.Acad.Sci.2001;.933:18�-200.
20...Peterson. PK,. Shepard. J,. Macres. M,. Schenck. C,.
Crosson.J,.Rechtman.D,.Lurie.N...A.controlled.trial.
of.intravenous.immunoglobulin.G.in.chronic.fatigue.
syndrome...Am.J.Med.1990;89:���-�60.
21.. .Reid.S,.ChalderT,.Cleare.A,.Hotopf.M.and.Wessely.
S.. . Chronic. fatigue. syndrome.. . Clin.. . Evid. 2002;.
8:107�-1088.
22...Reynolds. KJ,.Vernon. SD,. Bouchery. E. and. Reeves.
WC.. . The. economic. impact. of. chronic. fatigue.
syndrome...Cost.Eff.Resour.Alloc.200�;.2:.�
23...Rimes.KA,.Chalder.T...Treatments.for.chronic.fatigue.
syndrome...Occp.Med.(Lond)...200�;.��:32-39.
2�...Rowe.KS...Double-blind.randomized.controlled.trial.
to.assess.the.efficacy.of.intravenous.gammaglobu-
lin.for.the.management.of.chronic.fatigue.syndrome.
in.adolescents...J.Psychiatr.Res.1997;31:.133-1�7.
2�...Sharpe. MC,. Archard. LC,. Banatvala. JE,. et. al.. . A.
report. -. chronic. fatigue. syndrome:. guidelines. for.
research...JR.Soc.Med.1991;8�:.118-121.
89
CHRONIC FATIGUE SYNDROME
26...Stulemeijer.,.de.Jong.LW,.Fiselier.TJ,.Hoogveld.SW,.
Bleijenberg. G.. . Cognitive. behaviour. therapy. for.
adolescents. with. chronic. fatigue. syndrome:.
randomized.controlled.trial...BMJ.200�;.330:1�.
27.. .Tan.EM,.Sugiura.K.and.Gupta.S...The.case.definition.
of. chronic. fatigue. syndrome.. . J. Clin. Immun.
2002;22:8-12.
28...Vernon.SD,.Reeves.WC...Evaluation.of.autoantibodies.
to. common. and. neuronal. cell. antigens. in. chronic.
fatigue.syndrome...J.Autoimmune.Dis...200�;.2�:2-�.
29...Vollmer-Conna.U,.Hickie.I,.Hadzi-Pavlovic.D,.Tymms.
K,. Wakefield. D,. Dwyer. J,. Lloyd. A.. . Intravenous.
immunoglobulin. is. ineffective. in. the. treatment. of.
patients.with.chronic.fatigue.syndrome...Am.J.Med.
1997;.3:38-�3.
30...Whiting. P. Bagnall. A-M,. Sowden. AJ,. Cornell. JE,.
Mulrow. CD,. Ramirez. G.. . Interventions. for. the.
treatment. and. management. of. chronic. fatigue.
syndrome...JAMA.2001;286:.1360-1368.
31.. .Hickie.I,.Davenport.T,.Wakefield.D,.Vollmer-Conna.U,.
Cameron.B,.Vernon.SD,.Reeves.WC,.Lloyd.A...Post-
infective.and.chronic.fatigue.syndromes.precipitated.
by.viral.and.non-viral.pathogens:.prospective.cohort.
study...BMJ.2006;333:�7�.
32...Kerr.JR,.Christian.P,.Hodgetts.A,.Langford.PR,.Devanur.
LD,. Petty. R,. Burke. B,. Sinclair. LI,. Richards. SD,.
Montgomery.J,.MdDermott.C,.Harrison.TM,.Kellam.P,.
Nutt. DJ,. Holgate. ST.. . Current. research. priorities. in.
chronic. fatigue. syndrome/myalgic. encephalomyelitis.
(CSF.ME):.disease.mechanisms,.a.diagnostic.test.and.
specific.treatments...J.Clin.Pathol...2007;.60:113-116...
33...Vernon.SD,.Whistler.T,.Aslakson.E,.Rajeevan.M,.Reeves.
WC.. . Challenges. for. molecular. profiling. of. chronic.
fatigue.syndrome.Pharmacogenomics.2006;.7:211-8.
90
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
PARANEOPLASTIC NEUROLOGICAL DISORDERSINtROdUCtIONParaneoplastic. neurological. disorders. (PND). are. a. rare.
group. of. neurological. disorders. believed. to. be. due. to.
immune-mediated. damage. of. the. central. and/or.
peripheral.nervous.system.(CMS.and/or.PNS).as.a.result.
of.immune.response.triggered.by.a.remote.neoplasm1,.2.
The. identification.of.paraneoplastic.autoantibodies.and.
subsequent.characterization.of.the.autoantigens.bound.
by. these. antibodies. have. provided. insight. into. under-
standing.of.basic.neuroscience.and.neuropathogenesis.
of. PNDs.3.These. antigens. are. ascribed. as. onconeural.
proteins. as. they. are. expressed. by. both. the. neoplasm.
and.neural.tissues...Immune.response.triggered.by.the.
neoplasm.aim.to.eliminate.the.tumour.cells,.with.neural.
elements. damaged. simultaneously. by. the. immune.
response.targeting.at.the.onconeural.proteins.
PND.are.diagnostically.difficult.and.a.high. index.of.
suspicion.is.required...A.variety.of.neurological.manifes-
tations.can.be.the.presenting.features...Table.1.lists.the.
paraneoplastic. anti-neuronal. autoantibodies. with.
associated. oncological. and. neurological. features...
Detection. of. these. autoantibodies. facilitates. the. early.
diagnosis.of.PND...PND.are.important.to.diagnose.as.in.
more.than.half.of.the.patients,.neurological.manifesta-
tions.precede.the.detection.of.the.tumour...Hence.early.
diagnosis.of.PND.help.to.initiate.prompt.and.aggressive.
search. for. underlying. malignancy,. which. is. usually.
occult.". Early. tumour. therapy. helps. to. optimize. the.
patient's. survival. and. neurological. prognosis,. with..
or. without. specific. immunomodulatory. therapy. for..
the.PND.
CLINICaL fEatUREsPND.can.affect.any.site.of.the.neuroaxis.and.can.have.
multifocal.involvement.in.a.single.patient,.increasing.its.
diagnostic. difficulty.3,. 6,. 1�. For. instance,. a. patient. with.
paraneoplastic.encephalomyelitis.associated.with.small.
cell. lung.carcinoma. (SCLC).with.anti-Hu.antibody. (also.
called. anti-neuronal. nuclear. antibody. type. 1,. ANNA-1).
can. also. have. Lambert-Eaton. myasthenic. syndrome.
(LEMS). with. voltage-gated. calcium. channel. antibodies.
(VGCC.antibodies).
ENCEPHALItISCortical.encephalitis,. limbic.encephalitis.and.brainstem.
encephalitis.have.been.described.in.PND.7,.9.Confusion,.
impairment.of.higher.mental.functions.such.as.aphasia,.
apraxia,. agnosia,. labile. mood. and. other. psychiatric.
symptoms.are.common.features.for.cortical.encephali-
tis.. . Paraneoplastic. limbic. encephalitis. is. characterized.
91
PARANEOPLASTIC NEUROLOGICAL DISORDERS
by.subacute.progressive.course.presenting.with.short-.
term. memory. impairment,. seizures,. confusion,.
depression,. hallucinations,. personality. change,. bulbar.
dysfunction,.hypothalamic.dysfunction.such.as.abnormal.
appetite,. cognitive. dysfunction.. Tumours. associated.
with. limbic. encephalitis. include. SCLC,. testicular.
tumours,.breast. tumours.and.Hodgkin's. lymphoma.9,.10.
Magnetic.resonance. imaging,.cerebrospinal.fluid. (CSF).
and.electroencephalogram.(EEG).may.show.abnormali-
ties.. .Paraneoplastic.autoantibodies.associated. include.
anti-Hu",. anti-Ta/Ma",. ANNA-36,. and. autoantibodies.
against. collapsin. response. mediated. protein. �..
(CRMP-�.antibody).�
. Gaze.palsy,.diplopia.and.central.sleep.apnoea.causing.
respiratory. failure. have. been. reported. in. patients.
presenting.as.a.brainstem.encephalitis.with.SCLC.with.
anti-Hu,12. anti-Ma2. and. anti-Ri. (also. called. ANNA-2).
antibodies.16
MyELItISThis.is.usually.associated.with.or.followed.by.progression.
to.encephalitis.and.neuropathy..The.pyramidal.tract.and.
anterior. horn. cells. can. be. involved. together. as. grey.
matter. is. mostly. affected. pathologically.1. The. patient.
presents.classically.with.spastic.weakness.and.sensory.
level,. but. combined. spastic. and. flaccid. paralysis. can.
occur.13.CSF.analysis.reveals.an.inflammatory.response...
This.presentation. is.mostly.commonly.associated.with.
SCLC.with.anti-Hu.antibody,.but.has.also.been.reported.
in. associated. with. PCA-2",. anti-CRMP��. and.
ANNA-36.antibodies.
oPSoCLoNuS-MyoCLoNuS-AtAxIAOpsoclonus. is.characterized.by.chaotic. involuntary.eye.
movements.(dancing.eyes)...The.syndrome.was.initially.
recognized. in. children. with. neuroblastoma1�...
Subsequently,. adults. with. this. "dancing. eye,. dancing.
feet".syndrome.were.described...Among.2�.patients.in.
whom. 1�. were. paraneoplastic,. the. most. commonly.
found.cancer.was.lung.(10.patients).followed.by.breast.
(2. patients).. . Testicular. tumour. was. also. reported...
Paraneoplastic. autoantibodies. associated. include. anti-
Hu,.anti-Ri.and.anti-Ta/Ma.16
CEREBELLARAtAxIAPatients. present. with. a. subacute. cerebellar. ataxia...
Those.with.anti-Hu.antibody.(associated.with.SCLC.and.
neuroblastoma).tend.to.progress.rapidly.having.a.median.
survival.of.9-12.months..In.patients.with.anti-Yo.antibody,.
stabilization.is.common.and.the.median.survival.is.100.
months. with. breast. cancer,. and. 22. months. for. those.
with. other. gynecological. cancers.17,. 18. Other. paraneo-
plastic.autoantibodies.associated. include.anti-Ri,16.anti-
Tr. (associated.with.Hodgkin's. lymphoma),.anti-Ma/Ta,11.
PCA2,1�.anti-CRMP��.and.ANNA-36.
SENSoRyANDSENSoRIMotoRNEuRoPAtHyProminent.sensory.ataxia.due.to.sensory.neuronopathy.
is. the. classic. presentation. of. PND. associated. with.
SCLC. and. anti-Hu. antibody".. . Pseudoathetosis. due. to.
severe. loss. of. proprioception. are. the. hallmark...
Neuropathies. with. an. indolent. course. and. resembling.
acute. inflammatory. demyelinating. polyneuropathy.
(AIDP).have.been. reported. in.anti-Hu.associated.PND...
Other. autoantibodies. associated. with. sensory.
neuropathy. are. anti-amphiphysin. antibody,19. anti-
CRMP��.and.ANNA-3.6
. Sensorimotor.polyneuropathy.is.a.common.presen-
tation. of. PND.. . Associated. tumours. include. haema-
tological.malignancy.such.as.myeloma.and.Waldenstrom.
macroglobulinemia. with. monoclonal. gammopathy,.
SCLC,. thymoma. and. breast. cancer.. . Associated. para-
neoplastic.autoantibodies.are.anti-Hu,".anti-amphiphysin19.
and.CRMP-�.antibodies.�
AutoNoMICNEuRoPAtHyIt. is. important. to. consider. PND. in. patients. with. auto-
nomic. dysfunction.. . Presenting. symptoms. include.
postural.dizziness,.abdominal.pain,.diarrhoea,.impotence,.
urinary. retention. and. intestinal. motility. disorders. such.
as.pseudo-obstruction,.dysphagia.and.gastroparesis.�,20.
Paraneoplastic. autoantibodies. associated. include. anti-
Hu.and.CRMP-�.antibodies.
REtINoPAtHyPatients. present. with. visual. symptoms. including.
impaired.visual.acuity,.photosensitivity,.abnormal.color.
vision,. ring. scotomas. and. prolonged. dark. adaptation.
92
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGYBRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
The. retinopathy. usually. runs. a. progressive. course. for.
several.months...Underlying.cancers.are.mostly.SCLC,.
others. include. melanoma37,. breast,. gynecological. and.
endocrine. cancers.21. The. most. common. associated.
autoantibody. is. recoverin,. a. 23. kDa. photoreceptor.
protein.22.Autoantibodies.against.other.antigens.such.as.
enolase.alpha.have.been.reported.23
MyAStHENIA GRAVIS (MG) AND LAMBERt-EAtoN MyAS-tHENICSyNDRoME(LEMS)The. well. known. association. of. autoimmune. MG. with.
thymoma.and.LEMS.with.SCLC.have.been.discussed.in.
other.parts.of.the.consensus.statements.
INfLAMMAtoRyMyoPAtHyDermatomyositis.is.associated.with.a.variety.of.cancers...
Polymyositis. is. less. frequently. associated. with. an.
underlying. malignancy.. . These. disorders. have. been.
discussed.in.detail.in.another.consensus.statement.
pathOGENEsIsThe. discovery. of. anti-neuronal. antibodies. in. PND. that.
also.bind.to.the.associated.tumours.suggest.an.underlying.
autoimmune.pathogenesis...The.paraneoplastic.autoanti-
bodies.probably.do.not.cause.the.inflammatory.response.
and. neuronal. damage. directly,2�. although. anti-recoverin.
antibody.may.be.the.exception.2�.Both.Hu-specific.CD�T.
helper. 1. cells. and. CDS. cytotoxic. T. cells. have. been.
detected.in.patients.serum.26,.27.Importantly,.CDS.cytotoxic.
T.cells.are.abundant. in.the. interstitial. infiltrate.histologi-
cally.while.CD�.T.helper. cells. are. found. in.perivascular.
infiltrate. of. neural. tissues.28. Current. evidence. supports.
the. view. that. cytotoxic.T. cells. specific. for. onconeural.
proteins.cause.direct.damage.to.the.neurons.and.neural.
elements,.when.MHC.class.1.is.upregulated.in.the.proin-
flammatory. environment. produced. by. activated. CD�.T.
helper. cells. specific. for. onconeural. proteins.. . These.
specific.T. helper. cells. cross. the. blood-brain. barrier. and.
mediate. the. production. of. paraneoplastic. anti-neuronal.
autoantibodies.by.B.cells...As.the.PND's.only.occur.in.a.
minority.of.patients.with.tumours,.mechanisms.underlying.
presentation. of. antigen. (onconeural. proteins). such. as.
MHC. moleculers29. to. activate. T. cells. are. probably.
important.in.the.initiation.of.PND.
tREatMENt fOR paRaNEOpLastIC NEUROLOGICaL dIsORdERsGENERAL MEASuRES -. A. strong. index. of. suspicion. is.
essential. for. early. diagnosis. by. serological. testing. for.
paraneoplastic. autoantibodies,. and. prompt. aggressive.
search. for. underlying. malignancy,. especially. if. occult...
Symptomatic. therapies. aim. to. reduce. disability. and.
discomfort. from. the. neurological. deficits. of. PND.. . A.
multi-disciplinary.approach.is.useful.
tuMoRtHERAPy - the.mainstay.of. treatment. for.PND...
As. most. PND's. affect. the. central. nervous. system,.
therapy. is. often. difficult.. . Early. anti-tumor. therapy. is.
recommended.. . Neurological. presentations. such. as.
sensory. neuronopathy. and. limbic. encephalitis. tend. to.
respond.better.than.others.such.as.cerebellar.degenera-
tion.18. There. is. evidence. suggesting. that. complete.
response.to.anti-tumor.therapy.is.a.favorable.prognostic.
factor.for.PND.30
IMMuNoMoDuLAtoRy tHERAPy - therapies. that. have.
been. used. include. plasma. exchange. (PE),. IVIg,. corti-
costeroids,.immunoadsorption,.and.cyclophosphamide...
It. is. generally. accepted. that. earlier. immunotherapy. is.
associated.with.a.better.neurological.prognosis.
Graus.et.al...studied.11.patients.with.PND.with.anti-
Hu.or.anti-Yo.antibodies.and.concluded.that.the.efficacy.
of.PE.with.other. immunosuppressants. in.the.stabiliza-
tion.of.neurological.deficits.of.PND.was.uncertain.31
Stark.et. al.. . reported. improvement.of. neurological.
deficits. in. 2. patients. with. paraneoplastic. cerebellar.
degeneration. treated. with. cyclophosphamide32. Keime-
Guibert.et.al...studied.17.patients.with.PND.with.anti-Hu.
or.anti-Yo.antibodies.given.a.regime.consisting.of.IVIg,.
cyclophosphamide.and.methylprednisolone...Of.the.16.
patients.evaluated,.none.improved.and.3.patients.who.
were.ambulatory.before.treatment.were.stabilized...The.
authors. conclude. that. vigorous. immunomodulatory.
therapy.in.severely.disabled.PND.was.not.useful,.and.in.
a.minority.of.patients.(mainly.with.sensory.neuropathy).
without.severe.disability.at.onset.of.therapy,.a.transient.
stabilization.was.possible.33
93
. Blaes.et.al.. . reported.efficacy.of. IVIg. in.2.patients.
with.PND.when.therapy.was.started.within.3.weeks.of.
onset.of.neurological.deficits,.while.2.other.patients.had.
no.improvement.with.IVIg.given.3-6.months.after.onset.
of.neurological.deficits.3�.All.�.patients.harboured.either.
anti-Hu.or.anti-Yo.antibodies..Uchuya.et.al.. . treated.22.
patients. with. PND. with. anti-Hu. or. anti-Yo. antibodies.
with.IVIG...Of.the.21.patients.evaluated,.1.improved.for.
at.least.1�.months,.10.remained.stable.and.10.deterio-
rated...It.was.suggested.that.improvement.and.stabiliza-
tion. were. more. frequent. in. patients. with. isolated.
involvement. of. the. PNS. (62%). than. those. with. CNS.
damage.(37%).3�
. In. children. with. neuroblastoma. and. paraneoplastic.
opsoclonus-myoclonus-ataxia,. IVIg. improves. motor.
coordination.and.speech.function.rapidly...
sUMMaRYCNSINVoLVEMENt:.no. immunomodulatory.agents.have.
been. shown. to. be. effective.. . Reports. of. marked.
improvement. have. only. been. seen. in. single. patients..
or. small. case. series,. particularly. when. therapy. is..
started.early.�0
PNS INVoLVEMENt:. response. to. immunomodulatory.
therapy.is.probably.better.in.patients.with.isolated.PNS.
involvement,.especially.if.therapy.started.early.
. Voltz.suggests. to.start.with.one.course.of.methyl-
prednisolone. (five. �00mg. pulses). and. observe. for.
effects. for.1. to.2.weeks.. . If. there. is.no. improvement,.
one.course.of.IVIg.(2gm/kg.over.�.days),.and.if.there.is.
still. no. response,. to. try. cyclophosphamide. or..
plasma. exchange. tailored. to. the. individual. patient's.
clinical.characteristics.36,.39
PARANEOPLASTIC NEUROLOGICAL DISORDERS
Table1.Paraneoplasticanti-neuronalautoantibodiesandtheirassociatedoncologicaland
neurologicalfeaturesinPND.
Paraneoplasticanti-neuronal
AutoantibodiesNeurologicalfeatures Commontumoursassociated
ANNA-1.(anti-Hu)CA/PEM/LE/SN/SMN/OMA.
.OMA.(children)
SCLC.(adult).neuroblastoma.
(children)
ANNA-2.(anti-Ri) CA/OMA breast.cancer
ANNA-3.PCA-1.(anti-Yo) CA/PEM/LE/SN/SMN SCLC,.lung.adenocarcinoma
(anti-Yo) CA breast,.ovarian.cancers,.Cancers
.PCA-2.Anti-CRMP� CA/PEM/LE/AD lung.cancer
CA/PEM/LE/SN/CN/EPS SCLC,.thymoma
Anti-Tr CA Hodgkin's.lymphoma
Anti-Ma/Ta CA/BE/LE Testicular.cancers.Others
Anti-amphiphys SMS/SN/SMN/OMA SCLC,.ovarian.cancer
CA=cerebellar. ataxia,. PEM=paraneoplastic. encephalomyelitis,. SN=sensory. neuronopathy,. SMN=sensorimotor.
neuropathy,.AD=.autonomic.dysfunction,.CN=cranial.neuropathy,.BE-brainstem.encephalitis,.LE=limbic.encephalitis,.
EPS=extrapyramidal.symptoms,.SMS=stiff.man.syndrome,.SCLC=small.cell.lung.carcinoma.
9�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
. Patients. with. PND. who. fulfill. clinical. and. electro-
physiological. criteria. of. Guillain-Barré. syndrome. (GBS).
or.chronic.inflammatory.demyelinating.polyradiculoneu-
ropathy.(CIDP).should.be.treated.according.to.standard.
regimens...Patients.with.LEMS.tend.to.response.well.to.
IVIg. and. PE,. but. immunosuppressants. such. as. aza-
thioprine.should.only.be.used.in.the.non-paraneoplastic.
form...For.MG.with.thymoma,.IVIg.and.PE.are.efficacious.
for. rapid.short-term. improvements,.while. thymectomy.
and. immunosuppressants. (steroids. and. azathioprine).
bring. long-term. benefits. in. most. cases.. . IVIg. and. PE.
may. be. beneficial. in. neuromyotonia. associated. with.
thymoma. or. lung. cancer,. and. IVIg. was. proven. to. be.
efficacious.in.stiff-man.syndrome.in.a.controlled.cross-
over.study.
Paraneoplastic. necrotizing. myopathy. presents. with.
subacutely. evolving,. symmetric. proximal. weakness.
associated.with.gastrointestinal.adenocarcinoma,.transi-
tional. cell. carcinoma,. prostatic. carcinoma,. and. non-
small. cell. lung. carcinoma.. . Muscle. pathology. showed.
numerous. necrotic. fibers. (8. to. 100%). and. intense.
alkaline.phosphatase.staining.of.the.muscle.connective.
tissue,.but.little.inflammation...There.are.case.reports.of.
benefit.to.IVIG38.
EXpERt CONsENsUsIVIg. is. useful. in. children. with. opsoclonus-myoclonus-
ataxia. associated. with. neuroblastoma.. . For. patients.
with.involvement.of.the.CMS.(encephalitis,.myelitis).and.
severe.neurological.disability,.IVIg.has.not.shown.to.be.
effective.. . IVIg.with.or.without.other. immunosuppres-
sants.and.corticosteroids.given.before.development.of.
severe. disability. may. lead. to. transient. stabilization,.
especially.for.patients.with.involvement.restricted.to.the.
PNS. (sensory. neuronopathy. and. sensorimotor.
neuropathy).
. IVIg.with.or.without.other.immunosuppressants.and.
corticosteroids. given. before. development. of. severe.
disability. may. lead. to. transient. stabilization,. especially.
for. patients. with. involvement. restricted. to. the. PNS.
(sensory.neuronopathy.and.sensorimotor.neuropathy)...
In. patients. with. involvement. of. CNS. (encephalitis,.
myelitis). and. severe. neurological. disability,. IVIg. is.
generally. not. effective,. except. in. some. patients. with.
paraneoplastic. cerebellar. degeneration. and. anti-Yo.
antibodies.where.early.high.dose. IVIg.with.or.without.
other.therapies.may.be.of.benefit.
REfERENCEs1.. .Posner. JB.. Paraneoplastic. syndromes.. In:. Posner.
JB.. Neurologic. complications. of. cancer..
Contemporary. Neurological. Series,. FA. Davis.
199�;3�3:-38�.
2.. .Lennon. VA.. The. case. for. a. descriptive. generic.
nomenclature:. clarification. of. immunostaining.
criteria. for. PCA-1,. ANNA-1,. and. ANNA-2. autoanti-
bodies..Neurology.199�;��:2�12-2�1�.
3.. .Darnell. RB.. Onconeural. antigens. and. the. paraneo-
plastic. neurologic. disorders:. at. the. intersection. of.
cancer,.immunity,.and.the.brain..Proc.Natl.Acad.Sci.
USA.1996:93:��29-��36.
�.. .Lucchinetti. CF,. Kimmel. DW,. Lennon. VA..
Paraneoplastic. and. oncologic. profiles. of. patients.
seropositive.for.type.1.antineuronal.nuclear.autoan-
tibodies..Neurology.1998;�0:6�2-6�7.
�.. .Yu. Z,. KryzerTJ,. Griesmann. GE,. et. al.. CRMP-�.
neuronal. autoantibody:. marker. of. lung. cancer. and.
thymoma-related. autoimmunity.. Ann. Neurol.
2001;�9:1�6-1��.
6.. .Chan.KH,.Vernino.S,.Lennon.VA..ANNA-3.anti-neu-
ronal.nuclear.antibody:.marker.of. lung.cancer-relat-
ed.autoimmunity..Ann.Neurol.2001;�0:301-311.
7.. .Bierley. JB,. Corsellis. JAN,. Hierons. R,. Nevin. S..
Subacute. encephalitis. of. later. adult. life. mainly.
affecting.the.limbicarea..Brain.1960;83:3�8-368.
8.. .Corsellis. JAN,. Goldberg. GJ,. Norton. RA.. "Limbic.
encephalitis". and. its. association. with. carcinoma..
Brain.1968;91:�81-�96.
9�
9.. .Carr. I.. The. Ophelia. syndrome:. memory. loss. in.
Hodgkin's.disease..Lancet.1982;.1:8��-8��.
10...Gultekin. SH,. Rosenfeld. MR,. Voltz. R,. et. al..
Paraneoplastic. limbic. encephalitis:. neurological.
symptoms,. immunological. findings. and. tumour.
association. in. �0. patients.. Brain. 2000;. 123:.
1�81-1�9�.
11.. .Voltz. R,. Gultekin. SH,. Rosenfeld. MR,. et. al.. A.
serologic. marker. of. paraneoplastic. limbic. and.
brainstem. encephalitis. in. patients. with. testicular.
cancer..N.Eng.J.Med.1999;3�0:.1788-179�.
12...Ball. JA.,. Warner. T,. Reid. P,. et. al.. Central. alveolar.
hypoventilation. associated. with. paraneoplastic.
brainstem. encephalitis. and. anti-Hu. antibodies.. J.
Neurol.199�;2�1:�61-�66.
13...Forsyth.PA,.Dalmau.J,.Graus.F,.et.al..Motor.neuron.
syndromes. in. cancer. patients.. Ann. Neurol.
1997;�1:722-730.
1�...Vernino. S,. Lennon.VA.. New. Purkinje. cell. antibody.
(PCA-2):.marker.of. lung.cancer-related.neurological.
autoimmunity..Ann.Neurol.2000:�7:297-30�.
1�...Rudnick.E,.Khakoo.Y,.Antunes.NL,.et.al..Opsoclonus-
myoclonus-ataxia. syndrome. in. neurob-. lastoma:.
clinical. outcome. and. anti-neuronal. anti-. bodies. -. a.
report.from.the.Children's.Cancer.Group.Study..Med.
Pediatr.Oncol.2001;36:612-622.
16...Budde-Steffen.C,.Anderson.NE,.Rosenblum.MK,.et.
al..An. anti-neuronal. autoantibody. in. paraneoplastic.
opsoclonus..Ann.Neurol.1988;23:�28-�31.
17.. .Rojas. I,.Graus.F,.Keime-Guibert. F,. et. al.. Long-term.
clinical. outcome. of. paraneoplastic. cerebellar..
degeneration. and. anti-Yo. antibodies.. Neurology.
2000:��:713-71�.
18...Graus.F,.Keime-Guibert.F,.Rene.Rad,.et.al..Anti-Hu-
associated. paraneoplastic. encephalomyelitis:.
analysis.of.200.patients..Brain.2001;12�:1138-11�8.
19...Lennon.VA,.Manley.HA,.Kim.K-K,.et.al..Amphiphysin.
autoantibodies:.a.paraneoplastic.serological.marker.
of. breast. and. lung. cancer-related. encephalomyelo-.
radiculoneuritides. but. not. classical. stiffman. syn-.
drome..Neurology.1997;�8:A�3�.
20...Lennon.VA,.Sas.DF,.Busk.MF,.et.al..Enteric.neuronal.
autoantibodies.in.pseudo-obstruction.with.small-.cell.
lung.carcinoma..Gastroenterology.1991;100:137-1�2.
21.. .Thirkill. CE,. FitzGerald,. Sergott. RC,. et. al.. Cancer-
associated. retinopathy. (CAR. syndrome). with.
antibodies. reacting. with. retinal,. optic-nerve,. and.
cancer.cells..N.Eng.J.Med.1989;321:1�89-1�9�.
22...Eichen.JG,.Dalmau.J,.Demopoulos.A,.et.al..The.pho-
toreceptor. cell-specific. nuclear. receptor. is. an.
autoantigen. of. paraneoplastic. retinopathy.. J.
Neuroopthalmol.2001;21:168-172.
23...Adamus.G,.Amundson.D,.Siegel.GM,.Machnicki.M..
Anti-enolase-alpha. autoantibodies. in. cancer-associ-
ated.retinopathy:.epitope.mapping.and.cytotoxicity-
on.retinal.cells..J.Autoimmun.1998;11:671-677..
2�...Verschuuren. JJ,. Dalmau. J,. Hoard. R,. Posner. JB..
Paraneoplastic.anti-Hu.serum:.studies.on.human.cell.
lines..J.Neuroimmunol.1997;79:202-210.
2�...Maeda.T,.Maeda.A,.Maruyama.I,.et.al..Mechanisms.
of. photoreceptor. cell. death. in. cancer-associated.
retinopathy.. Invest. Ophthalmol. Vis. Sci..
2001;�2:70�-710.
26...Benyahia. B,. Liblau. R,. Merle-Beral. H,. et. al.. Cell-
mediated.autoimmunity.in.paraneoplastic.neurologi-
cal.syndromes.with.anti-Hu.antibodies..Ann.Neurol.
1999;��:162-167.
PARANEOPLASTIC NEUROLOGICAL DISORDERS
96
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
27.. .Tanaka. K.Tanaka. M,. InuzukaT,. et. al.. Cytotoxic. T.
lymphocyte-mediated. cell. death. in. paraneoplastic.
sensory. neuronopathy. with. anti-Hu. antibody.. J.
Neurol.Sci.1999;163:1�9-162.
28...Rosenblum.MK..Paraneoplasia.and.autoimmunolog-
ic. injury. of. the. nervous. system:. the. anti-Hu. syn-
drome..Brain.Pathol.1993:3:199-212.
29...Dalmau.J,.Graus.F,.Cheung.NK,.et. al..Major.histo-
compatibility.proteins,.anti-Hu.antibodies,.and.para-
neoplastic.encephalomyelitis. in.neuroblastoma.and.
small.cell.lung.cancer..Cancer.199�:7�:99-109.
30...Keime-Guibert.F,.Graus.F,.Broet.P,.et.al..Clinical.out-
come.of.patients.with.anti-Hu.associated.encepha-
lomyelitis.after.treatment.of.the.tumour..Neurology.
1999:�3:1719-1723.
31.. .Graus. F,.Vega. F,. Delattre. JY,. et. al.. Plasmapheresis.
and.antineoplastic.treatment.in.CNS.paraneoplastic.
syndromes. with. antineuronal. autoantibodies..
Neurology.1992:�2:�36-��0.
32...Starke.E,.Wurster.U,.Patzold.U,.et.al..Immunological.
and. clinical. response. to. immunosuppressive.
treatment.in.paraneoplastic.cerebellar.degeneration..
Arch.Neurol.199�:�2:81�-818.
33...Keime-Guibert.F,.Graus.F,.Fleury.A,.et.al..Treatment.
of.paraneoplastic.neurological.syndromes.with.anti-
neuronal. antibodies. (anti-Hu,. anti-Yo). with. a.
combination. of. immunoglobulins,. cyclophospha-
mide,.and.methylprednisolone..J.Neurol.Neurosurg.
Psychiatry.2000:68:�79-�82.
3�...Blaes. F,. Strittmatter. M,. Merkelbach. S,. et. al..
Intravenous.. immunoglobulins. . in. . the. . therapy. .of.
paraneoplastic. neurological. disorders.. J. Neurol.
1999;2�6:299-303.
3�...Uchuya...M,..Graus..F,.Vega..F,..et.al....Intravenous.
immunoglobulin.treatment. in.paraneoplastic.neuro-
logical. syndromes. with. antineuronal. autoantibod-
ies..J.Neurol.Neurosurg.Psychiatry.1996:60:388-392.
36...Voltz.R..Paraneoplastic.neurological.syndromes:.an.
update. on. diagnosis,. pathogenesis,. and. therapy..
Lancet.Neurology.2002:1:29�-30�.
37.. .Subhadra. C,. Dudek. AZ,. Rath. PP,. Lee. MS..
Improvement. in. visual. fields. in. a. patient. with.
melanoma-associated. retinopathy. treated. with.
intravenous. immunoglobulin.. J. Neuroophthalmol.
2008;28:23-26.
38...Sampson. JB,. Smith. SM,. Smith. AG,. Singleton. JR,.
Chin. S,. Pestronk. A,. Flanigan. KM.. Paraneoplastic.
myopathy:. response. to. intravenous. immunoglobu-
lin..Neuromuscul.Disord.2007;17:�0�-�08.
39...Voltz. R.. Intravenous. immunoglobulin. therapy. in.
paraneoplastic. neurological. syndromes.. J. Neurol.
2006;2�3.Suppl.�:V33-V38..
�0...Phuphanich. S,. Brock. C.. Neurologic. improvement.
after.high-dose.intravenous.immunoglobulin.therapy.
in.patients.with.paraneoplastic.cerebellar.degenera-
tion. associated. with. anti-Purkinje. cell. antibody.. J.
Neurooncol.2007;81:67-69.
97
STIFF-PERSON SYNDROMEBaCKGROUNdStiff.person.syndrome.(SPS).is.a.disorder.first.described.in.
19�6.by.Moersh.and.Woltman1...It.occurs.mainly.in.adult.
life.and.can.be.paraneoplastic.in.20-30%2...It.presents.with.
symptoms.related.to.muscular.rigidity.and.superimposed.
episodic.spasms3...The.rigidity.insidiously.spreads.involving.
axial. muscles. primarily. abdominal. and. thoracolumbar. as.
well. as. proximal. limb. muscles.. . Occasionally. it. is.
asymmetric.and.involves.one.leg.preferentially.(so.-.called.
stiff. -. limb.syndrome).. .Typically,.co-contraction.of.truncal.
agonist. and. antagonistic. muscles. leads. to. a. board-like.
appearance.with.hyperlordosis...Less.frequently,.respiratory.
muscle.involvement.leads.to.breathing.difficulty.and.facial.
muscle.involvement.to.a.mask-like.face3.
. Initially.the.rigidity.fluctuates.but.later.becomes.fixed.
and.results.in.difficult.ambulation.with.significant.disability...
Frequent.falls.are.brought.on.by.episodic.spasms.induced.
by.tactile,.auditory.and.other.stimuli.as.well.as.by.emotional.
stress. leading. to. a. fear. of. ambulating. independently...
About. 2/3. develop. significant. difficulty. in. carrying. out.
activities. of. daily. living. and. many. eventually. become.
bedridden�.
. Examination.reveals.rigid.axial.muscles,.hyperlordosis,.
difficulty. in. bending. forward. and. a. surprisingly. normal.
neurologic.examination.
. About.�-10%.of.patients.will.have.nocturnal.seizures...
Rare. patients. have. been. described. with. myasthenia.
gravis. and. some. of. these. have. invasive. thymoma.
suggesting.that.SPS.can.be.associated.with.other.auto-
immune.disorders.
. The. differential. diagnosis. includes. chronic. tetanus,.
extrapyramidal. syndromes. with. dystonia. and. rigidity,.
neuromyotonia.and.psychogenic.disorders3.
NEUROphYsIOLOGYThe. EMG. hallmark. of. SPS. is. continuous. motor. unit.
activity. occurring. at. rest. in. both. agonist. and..
antagonist.muscles3.
. Electrophysiology.has.established.this.as.a.disorder.
due. to. a. disturbance. of. GABAergic. inhibitory. circuits...
This. results. in. hyperexcitability. of. the. motor. cortex.
caused.by.a.loss.of.intra-cortical.inhibition.by.GABAergic.
neurons3...Although.spinal.GABAergic.circuits.may.also.
be.involved.there.is.no.clear.evidence.supporting.this.at.
present.. . Neurophysiology. studies. have. demonstrated.
abnormal. propagation. of. brainstem. reflexes. in. SPS.
which.bias.towards.an.increase.in.reflex.excitation.and.
attenuation.of.inhibition.
STIFF-PERSON SYNDROME
98
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
aUtO-aNtIBOdIEs aNd IMMUNOpathOGENEsIsIn. 1988. it.was. found. that. about. 6�%.of.SPS.patients.
have. auto-antibodies. to. GAD-6�. or. GAD-67. the. rate-
limiting.enzyme.for.GABA.synthesis�...The.titers.in.SPS.
are. characteristically. very. high. as. compared. to. the.
relatively.lower.titres.in.type.1.diabetes.mellitus...About.
30%. of. SPS. also. have. diabetes. mellitus.. . Other.
conditions. with. low. liters. of. GAD. antibodies. include.
myasthenia.gravis,.hyperthyroidism,.and.polymyositis3.
. It. was. initially. postulated. that. these. antibodies.
reduce. GABA. synthesis. and. cause. a. functional. rather.
than. a. structural. disturbance. by. reducing. GABAergic.
induced. inhibition.. . This. was. supported. by. low. CSF.
GABA. concentrations. and. reduced. GABA. peaks. on.
MRS3...The.serum.and.CSF.of.SPS.patients.inhibit.GAD.
activity. affecting. GABA. synthesis. in. vitro3.. . However.
presently. this. hypothesis. seems. unlikely. as. GAD. is. a.
cytosolic.antigen.and.it.would.be.unlikely.for.circulating.
antibodies. to. target.. . Recently,. a. new. surface.
autoantigen,. GABA. receptor. associated. protein.
(GABARAP).has.been.implicated.in.SPS...Antibodies.to.
GABARAP.are. found. in. 70%.of.SPS.patients. and. this.
inhibits. the. surface. expression. of. the. GABA. receptor...
This. could. then. potentially. be. a. mechanism. by. which.
circulating.antibodies.could.impair.GABAergic.pathways.
leading.to.the.clinical.symptomatology.of.SPS.
. MRI. is. usually. normal. confirming. the. absence. of.
histopathological.changes.in.the.few.autopsies.available...
Recent. reports. have. detailed. non-specific. changes. in.
the.limbic.regions.
. The.paraneoplastic. form.of.SPS. is.associated.with.
antibodies. towards. a. 128. kd. neuronal. protein,.
amphiphysin2.. . These. patients. usually. have. breast.
carcinoma.. . Other. antibodies. described. are. the. anti-
gephryn.and.anti-Ri.antibodies.
. Some. patients. with. SPS. have. no. associated.
malignancy.or.anti-GAD.antibodies.
thERapIEsConsidering.the.pathogenesis.of.SPS.two.main.therapies.
have.been.in.use.
1). .Drugs. enhancing. GABA. activity.. . High. doses. of.
diazepam.up.to.100.mg/day.are.most.widely.used...
Although.no.controlled.trials.are.available,.this.drug.
is.most.often.used.initially...A.dramatic.response.to.
diazepam. is. considered. a. criterion. for. diagnosis.
Adverse.effects. limit.the.use.of.this.drug.however...
Other.drugs.used.with.variable.effects.include.other.
GABAergic.drugs.like.valproate,.vigabatrin,.baclofen.
(oral.and. intrathecal),.gabapentin.and.tiagabine.-.all.
with. variable. effects3.. . Recently,. levetiracetam,. a.
novel. anti-epileptic. agent. with. some. GABAergic.
properties. seems. to. have. a. specific. effect. on. the.
disabling. startle. response. in. SPS. in. a. single..
case.report.
2). .Immunomodulatory. treatments.. . The. initial. focus.
was. on. prednisone. with. anecdotal. evidence.
supporting.its.use...Plasmapharesis.and.IVIG.are.the.
other. modalities. in. use3.. . A. recent. case. report.
highlights. the. use. of. Rituximab,. a. monoclonal.
antibody.targeting.mature.B.lymphocytes.expressing.
the. surface. antigen. CD. 20. and. thereby. depleting.
them...A.dramatic.response.both.in.clinical.and.EMG.
features. was. demonstrated. along. with. complete.
resolution. of. the. CSF. anti-GAD. antibodies. with. 2.
doses.over.2.months...This.report.also.suggests.that.
transient. benefit. could. be. seen. with.
mycophenolate.
.
IVIG IN spsEarly.trials.of.IVIG.in.a.rare.syndrome.like.SPS.suffered.
drawbacks. of. small. sample. size. and. publication. bias...
Other.problems.included.difficulties.in.evaluating.disease.
activity.where.subjective.feelings.of.improvement.may.
easily.overshadow.objective.gains.
. Initial. reports. in. the. early. 1990s. focused. on. open.
label.trials.in.either.single.patients.or.on.a.small.series.
of. patients6-8.. . Most. focused. on. patients. refractory. to.
standard. medications. and. showed. a. fairly. consistent.
response.to.IVIG.sometimes.within.a.couple.of.weeks6,7.
and.sometimes.delayed. till. after.3.months8.. .This.was.
often. transient. lasting.a. few.weeks. to.several.months.
and.the.response.to.a.subsequent.course.of.IVIG.was.
maintained...A.well.designed.study.of.3.patients6.using.
objective.scales.of.gait.(time.to.walk.30.feet).as.well.as.
blinded.video.analysis,.showed.dramatic.subjective.and.
99
objective.improvement.within.a.few.weeks.of.infusion...
The. lordotic. angle.also. reduced.on. radiographs. in.one.
patient...At.about.the.same.time.Karlson7.reported.three.
bedridden.patients.who.became.ambulatory.after.IVIG...
Prednisone.was.slowly.tapered.in.one.of.them.without.
any. ill. effects.. . Similar. benefits. were. shown. in. the.
childhood-onset.form.as.well9.
. This.set. the.stage. for. the. first. randomized.double-
blind,. placebo. controlled. crossover. study. using. either.
high. dose. IVIG. once. monthly. for. 3. months. or. half.
normal. saline. and. then. after. a. washout. period. a.
crossover. to. the. alternate. therapy�.. . Sixteen. patients.
were. recruited.and.1�.were. finally. analyzed.. .Monthly.
evaluation.used.specially.designed.objective.scales.-dis-
tribution-of-stiffness. index. (DSI). and. heightened-
sensitivity. scale. (HSS). along. with. patients'. subjective.
assessments.. . There. was. a. statistically. significant.
decrease. in. the. DSI. during. the. IVIG. period. lasting. a.
month. after. the. last. infusion.. .The. HSS. scores. were.
similar. but. not. significantly. different. during. IVIG. or.
placebo...The.time.taken.to.walk.9.1.m.reduced.signifi-
cantly.after.the.IVIG.and.lasted.even.after.the.washout.
period...12/1�.patients.identified.the.IVIG.period.correctly.
and. many. continued. the. IVIG. after. the. trial. was. over...
The.anti-GAD.antibody.liters.decreased.signifcantly.after.
IVIG. and. rebounded. significantly. after. it.was. stopped...
The. authors. concluded. that. IVIG. was. a. safe. and.
effective. therapy. for. persons. with. SPS. and. improved.
quality.of. life. (QOL).as.well.. .The.effect.appears. to.be.
short-lived.in.some.patients.though.it.lasts.up.to.a.year.
in.others...In.a.subsequent.open.label.study.of.QOL.in.
6.patients.this.benefit.was.confirmed10.
sUMMaRYThere.is.level.2.evidence.supporting.the.use.of.IVIG.in.
SPS.. . Periodic. infusions. may. need. to. be. given. for.
optimal.benefit...No.clear-cut.data.are.available.for.para-
neoplastic. forms. of. SPS;. however. the. probable.
autoimmune. nature. of. this. syndrome. suggests. that.
IVIG.should.be.used.here.as.well.
EXpERt CONsENsUsConsidering.the.disabling.progressive.course.of.the.stiff.
person. syndrome,. IVIG. should. be. offered. as. the. first.
line. treatment.. . Though. periodic. infusions. would. be.
required.in.the.majority,.further.studies.are.needed.to.
determine.optimal.dosage.and.duration.
REfERENCEs1.. .Moersh. FP. Woltman. HW.. Progressive. fluctuating.
muscular. rigidity. and.spasm. (stiff-man.syndrome);.
report.of.a.case.and.some.observations.in.13.other.
cases..Mayo.Clin.Proc.19�6;.31:�21-7.
2.. .Bataller. L,. Dalmau. J.. Paraneoplastic. Neurologic.
Syndromes:.Approaches.to.diagnosis.and.treatment..
Seminars.Neurol..2003;.23.(2):21�-2�.
3.. .Levy.LM,.Dalakas.MC,.Floeter.MK...The.stiff-person.
syndrome:. an.autoimmune.disorder. affecting.neu-
rotransmission. of. gamma-aminobutyric. acid.. .Ann.
Internal.Med.1999;.131.(7);.�22-�30.
�.. .Dalakas. MC,. Fuji. M,. Li. M,. et. al.. High-dose.
intravenous. immune. globulin. for. stiff-person.
syndrome..N.Engl.J.Med.2001;.3��.(26):.1870-76.
�.. .Solimena. M,. Folli. F,. Denis-Donini. S,. et. al..
Autoantibodies.to.glutamic.acid.decarboxylase.in.a.
patient.with.stiffman.syndrome,.epilepsy.and.type.
1. diabetes. mellitus.. N. Engl.. J. Med. 1988;.
318:101220.
6.. .Amato. AA,. Cornman. EW,. Kissel. JT..Treatment. of.
stiff-man.syndrome.with.intravenous.immunoglobu-
lin..Neurology.199�;.��(9):.16�2-��.
7.. .Karlson. EW,. Sudarsky. L,. Ruderman. E,. et. al..
Treatment.of.stiff-man.syndrome.with.IVIG..Arthritis.
Rheum.199�;.37(6):.91�-18.
STIFF-PERSON SYNDROME
100
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
8.. .Barker. RA,. Marsden. CD.. Successful. treatment. of.
stiff-man.syndrome.with. IVIG.. J.Neurol.Neurosurg.
Psychiatry.1997;.62:�26-7.
9.. .Mikaeloff.Y,.Jambaque.I,.Mayer.M,.et.al..Benefit.of.
intravenous. immunoglobulin. autoimmune. stiff-
person.syndrome.in.a.child..J.Pediatr.2001;.139(2).:3�0.
10. .Gerschlager.W,. Brown. P.. Effect. of. treatment. with.
IVIG. on. quality. of. life. in. patients. with. stiff-person.
syndrome.. Movement. Disorders. 2002;17. (3):. �90.
93..6/11/200�.
.
11. .Bataller. L,. Dalmau. J.. Paraneoplastic. Neurologic.
Syndromes:.Approaches.to.diagnosis.and.treatment..
Seminars.Neurol..2003;.23.(2):21�-2�.
12. .Levy.LM,.Dalakas.MC,.Fleeter.MK..The.stiff-person-
syndrome:.an.autoimmune.disorder.affecting.neuro-
transmission. of. gamma-aminobutyric. acid.. Ann.
Internal.Med.1999;.131.(7);.�22-�30.
13. .Dalakas.MC,.Fuji.M,.Li.M,.et.al..High-dose.intravenous.
immune.globulin.for.stiff-person.syndrome..N.Engl.J.
Med.2001;.3��.(26):.1870-76.
101
EPILEPSYBaCKGROUNdThe.epilepsies.are.a.heterogeneous.group.of.diseases.
characterized.by.two.or.more.unprovoked.seizures.more.
than. 2�. hours. apart.. . The. etiology,. natural. history,.
response. to. interventions,. co-existence. of. disabilities.
and. the. final. outcome. is. vastly. different. amongst. this.
group.. .The. classification. into. more. specific. epilepsy.
syndromes.is.an.attempt.to.put.together.disorders.with.
similar.characteristics...These.are.essentially.divided.into.
the. idiopathic. epilepsies. (presumably. genetic),. the.
symptomatic. epilepsies. (due. to. underlying. diseases. /.
lesions).and.the.cryptogenic.epilepsies.(where.a.lesion.
or.an.underlying.disorder. is.presumed.but.not.demon-
strated).epilepsies.
INtRaCtaBLE EpILEpsIEsAbout. 10-20%. of. the. epilepsies. are. refractory. to. the.
AEDs. and. this. is. more. commonly. encountered. in. the.
symptomatic. and. the. cryptogenic. epilepsies. and. in.
certain. syndromes. like. the. West. syndrome. (WS),.
Lennox-Gastaut.syndrome.(LGS).etc...This.state.disrupts.
normal.activities.of.living.and.has.a.significant.deleterious.
effect.on.cognition,.memory.and.learning...Newer.AEDs.
have. made. some. inroads. in. management. but. there.
remains.a.substantial.number.who.remain.uncontrolled...
It. is. in. this. group. that. alternative. treatments. like.
resective. surgery,. the. ketogenic. diet,. vagal. nerve.
stimulation,.etc.are.often.used.and.are.now.accepted.as.
valid.treatment.options.
WEStSyNDRoME(WS)This.epileptic.syndrome.is.usually.limited.to.infancy.but.
can.occasionally.start. later.and.sometimes.persist. into.
the. teenage. years. -. the. so-called. juvenile. spasms1...
Most.patients.are.symptomatic.and.the.rest.cryptogenic...
Symptomatic.WS.has.a.poorer.prognosis.both.in.devel-
opmental. and. seizure. outcome2.. . ACTH3-�,. vigabatrin�,.
nitrazepam6. and. valproate7. have. been. shown. to. be.
effective. in. randomized.comparative. trials.. .Topiramate.
has.recently.been.shown.to.be.useful.as.an.add-on. in.
open.label.studies8-9...The.ketogenic.diet10.and.resective.
surgery11. in. selected. patients. are. other. treatment.
options.in.refractory.spasms.
LENNox-GAStAutSyNDRoME(LGS)This. is. one. of. the. most. refractory. of. all. childhood.
epilepsies...About.2/3.are.symptomatic.and.about.�0%.
evolve.from.the.WS...Mental.retardation.is.the.ultimate.
outcome. in. virtually. all. uncontrolled. LGS. patients. and.
symptomatic.cases.have.a.worse.prognosis.for.develop-
EPILEPSY
102
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
mental.outcomes...About.6%.of.symptomatic.and.2�%.
of. cryptogenic. LGS. cases. finally. recover. from..
their.seizures2...
. Since. the.early.1990's.a. few.new.AEDs. like. felba-
mate12.,.lamotrigine13.and.topiramate1�.have.been.shown.
to.be.partially.effective.in.controlling.the.major.seizures.
of.LGS.and. improving.the.quality.of. life. in. randomized.
controlled. trials.. .The. effect. appears. to. be. maintained.
over.the.long.term.in.felbamate1�.and.topiramate16...The.
ketogenic. diet,. corpus. callosotomy. and. vagal. nerve.
stimulation. are. other. alternative. procedures. used. in..
this.disorder17.
RASMuSSEN'SENCEPHALItIS(RE)Rasmussen's. encephalitis. (RE). is. a. rare. condition.
occurring.usually.in.children.and.adolescence,.character-
ized.by.progressive.unilateral.hemispheric.dysfunction,.
intractable. focal. epilepsy. including. epilepsia. partialis.
continua,.cognitive.and.behavioural.changes,.and.inflam-
matory.histopathology...There.is.an.adult.form.of.RE.as.
well.though.this.appears.to.have.a.more.variable.course.
with. slower. progression18.. . The. etiology. appears. to.
favour.a.dysimmune.process.since.the.role.of.autoanti-
bodies. against. the. GluR3. receptor. was. highlighted19...
This. however. may. not. be. specific. for. RE. as. these.
antibodies.are.seen. in.other. focal.epilepsies.with.high.
seizure.frequency20.
. The. natural. history. seems. to. be. divided. into.
prodromal,.acute.and.residual.stages21.. .The.prodromal.
stage.has.an.intermediate.frequency.of.seizures.and.no.
or.little.hemiparesis;.the.acute.stage.lasts.for.a.median.
of.8.months.and.has.a.high.frequency.of.focal.seizures,.
progressive. hemiparesis. and. hemispheric. atrophy. on.
MRI.. .This.stage. is. finally. followed.by.a. residual.stage.
with. a. marked. decrease. in. seizure. frequency.. . Hence.
the.maximum.intensity.of.the.disease.is.in.the.first.year.
of.onset.and.this.would.have.a.bearing.on.the.disease's.
management...The.rarer.adult.onset.variant.seems.to.be.
a. milder. variant. with. a. prolonged. course. and. only.
modest.disability...
. Hemispherectomy. seems. to. be. the. only. definitive.
treatment. halting. further. progress. of. the. disease2;.
however. it. is. difficult. to. recommend. early. before. the.
development. of. a. permanent. hemiparesis.. . Other.
immunomodulatory. treatments. include. steroids,. IVIg,.
cyclopophosphamide,.therapeutic.plasma.exchange.and.
protein. A. immunoglobulin. G. immunoadsorption22-23...
These.are.usually.used.in.the.initial.stages.when.there.
is.no.hemiparesis.and.hemispherectomy.is.therefore.a.
difficult. option.. .Antivirals. have. been. used. in. the. past.
with.variable.effect.
LANDAukLEffNERSyNDRoME(LkS)The. Landau. Kleffner. syndrome. (LKS). and. electrical.
status.in.slow.wave.sleep.(ESES).are.now.classified.as.
epileptic.encephalopathies...The.severe.paroxysmal.EEG.
disturbances.disrupt.already.acquired.language.function.
and.other. cognitive. /.behavioural.processes2�.. .Clinical.
seizures.may.or.may.not.be.a.part.of.the.syndrome.and.
usually. have. a. benign. prognosis2�.. . Language. deficits.
are.usually.long.lasting2�.especially.in.those.with.young.
age. at. onset. and. a. prolonged. period. of. severe. EEG.
abnormality2�-26...However.recovery.of.normal.language.
may.occur.in.a.small.minority26.
. Treatment. with. AEDs. results. in. control. of. the.
epilepsy.but.not.necessarily.improves.language.function...
There. is. some. evidence. that. LKS. may. have. an.
autoimmune.basis...A.positive.autoimmune.reaction.to.
peripheral. and. central.myelin. has.been.demonstrated...
Recently,. LKS. patients. were. shown. to. have. IgG.
antibodies. to. brain. endothelial. cells27.. . Steroids,. both.
oral. and. high. dose. parenteral. seem. to. be. the. most.
effective.so.far28...There.has.been.recent.interest.in.IVIG.
in. this. condition.. . In. resistant. cases. multiple. sub-pial.
transactions.(MSTs).may.be.useful29.
BasIs fOR UsING IMMUNOMOdULatIONThere. are. several. lines. of. evidence. suggesting. immune.
dysfunction.in.at.least.some.of.the.epilepsies30...Viral.infections.
and.vaccinations.often.have.a.negative.or.sometimes.a.positive.
effect.on.seizure.frequency...Certain.immunodeficiencies.like.
lgG2.and.IgA.are.fairly.commonly.encountered.in.epilepsies31...
Studies.on. animal.models.have. shown. that. seizure. activity.
could.be.induced.by.specific.antisera.to.brain.proteins.which.
persisted.after.withdrawal.of.the.antisera...
. Rasmussen's. encephalitis. is. possibly. due. to. autoanti-
bodies.and.immunomodulatory.treatments.have.been.at.least.
partially.effective30.
103
. Recent.case.reports.have.focused.on.several.auto-
antibodies. in.some.epilepsy.syndromes. including.anti-
GAD. antibodies. in. myoclonic. seizures. and. refractory.
partial.seizures.with.or.without.cerebellar.ataxia.as.well.
as. anti-voltage. gated. potassium. channels. in. non-para-
neoplastic. limbic.encephalitis,.where.seizures.are.part.
of. a. subacute. neuropsychiatric. syndrome. of. amnesia,.
confusion.and.sometimes.psychosis...
IVIG IN EpILEpsYThere. has. been. an. interest. in. IVIG. in. epilepsy. since.
Prichard.demonstrated.a.benefit.of.intramuscular.immu-
noglobulins.in.eight.of.ten.patients.in.197732...Most.of.
the. literature. focuses. on. the. intractable. epilepsies.
including. WS,. LGS,. and. Rasmussen's. encephalitis...
Other.syndromes.where. IVIG.has.been.used. includes.
LKS.and.the.intractable.partial.epilepsies.
. The.evaluation.of.efficacy.has.been.difficult.due.to.
the. heterogeneity. of. the. available. studies. with. high.
variability. in. the. study. designs,. patient. selection,.
treatment. modalities,. IVIG. dosage. and. regimens. and.
outcome.parameters...Most.studies.are.not.double.blind.
and.placebo.controlled.probably.because.of.the.limitation.
related.to.the.route.of.IVIG.administrations...A.publication.
bias. must. be. also. considered. because. the. results. of.
small.series.of.non-responders.may.not.be.published.
. Since. the. initial. reports. in. the. seventies,. several.
case.reports.and.small.series.were.published.highlight-
ing.the.use.of. IVIG. in. IE.. .Most.of. these.were.uncon-
trolled,. unblinded. and. often. retrospective.. . Up. until.
1996,.a.total.of.29.studies.had.used.IVIG.in.373.patients.
with.a.benefit.in.17�.patients30...In.a.critical.review31.Van.
Engelen. reported. an. improvement. in. seizures. in. �2%.
with.complete. remission. in.23%.. .EEG. improvements.
were.noted. in.��%.with.behavioural. improvements. in.
63%.of.patients...The.dosage.used.varied.from.0.3.gm/
kg.upto.6.8gm./kg.over.periods.of.�.days.to.12.months...
Adverse.effects.were.minimal...The.authors.concluded,.
"IVIG. is. likely. to.be.effective. in. some.patients.with. IE.
and. may. be. considered. as. a. safe. add-on. medication..
in.it.”
. In. the. only. large. multi-center. double. blind.
randomized. placebo. controlled. study. using. three.
different. dosage. regimens.of. IVIG. in. 61.patients,.Van.
Rijekevossel33.showed.a.reduction.in.seizure.frequency.
in. �2.�%. patients. as. compared. to. 27.78%. in. those.
given.placebo...Though.these.results.suggested.a.trend.
they.were.not.significant...In.a.subgroup.analysis.of.�6.
patients. with. partial. epilepsy. there. was. a. significant.
difference.between.patients.and.controls.. .Also. there.
was. a. highly. significant. global. improvement. noted. in.
these.patients.by.the.family.or.caregivers...An.important.
point. to.note.was.that. it. took.more.than.�.months.to.
elicit. a. favourable. response.. . Also. there. was. no.
difference. in. low,. medium. or. high. dosage. regimens...
The. only. caveat. was. the. short. follow. up. of. only..
6.months.
. A.recent.open-label.study.of.IVIG.in.13.patients.with.
refractory. childhood-onset. epilepsy. demonstrated. a.
modest.response.in.�.patients.with.a.>.�0%.reduction.
in. their. seizure. frequency.. .Though. CSF. IL-6. and. IL-8.
were.elevated.in.all.patients,.these.did.not.change.sig-
nificantly.after.treatment�2.
IVIGINWSIVIG.was.used. first.by.Arizumi11. in.a.systematic.open.
label.study.in.11.infants.with.WS...Remarkably.all.6.with.
cryptogenic.WS.responded,.�.within.1.month...The.EEG.
and. development. also. improved. concurrently.. .There.
were.poor.results.in.the.symptomatic.group.with.only.
1/�. responding.. . Low. dose. recurrent. infusions. were.
used...Echenne.in.19913�.conducted.the.first.prospective.
study. in. 23. patients. using. standard. doses. of. 2g/kg.
given. periodically. every. few. weeks.. . Only. �. children.
responded.dramatically.with.seizure.freedom.and.2.of.
these. had. normal. or. near. normal. development. on.
follow. up.. . Cryptogenic. WS. were. under-represented.�-23. which. may. have. had. a. bearing. on. the. results...
Rescue. ACTH. was. used. after. a. short. observation.
period. of. only. a. week,. which. may. have. resulted. in.
underestimating.the.responder.rates...The.IVIG.used.in.
this. study. was. enzymatically. treated. which. may. have.
reduced.its.efficacy.
EPILEPSY
10�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
. Van. Engelen. conducted. a. well-designed. add-on.
study.in.1�.patients.where.3.had.WS.and.demonstrated.
efficacy.in.only.one.of.these3�...A.more.recent.retrospec-
tive. study. in. the. very. refractory. "juvenile". spasms�1.
demonstrated.clinical.improvement.in.�/�.patients.with.
1.becoming.seizure.free...However.2.of.these.patients.
also. had. other. interventions. carried. out. at. the. same.
time.. .An. important.weakness. in. these.studies. is. that.
video.EEG.was.not.used. to.confirm.spasm.disappear-
ance.and.only.clinical.reports.were.relied.upon.
IVIGINLGSInitial.reports.in.the.1980s.suggesting.benefit.led.to.two.
well.designed.open.label.studies3�-36.with.add.on.IVIG.in.
LGS.patients.and.one.single.blind.placebo.randomized.
controlled.study37...Though.different.dosage.and.regimens.
were.used.both.found.significant.benefit...Van.Engelen.3�. reported.>.7�%.improvements. in.seizure.frequency.
in.9/12.patients.over.the.short.term.while.Gross-Tsur17.
reported. improvements. in. 7/9. (8. had. LGS). with. long.
term.remission.in.3.over.22.months...The.response.took.
up. to. 6. weeks.. . Ilium37. compared. IVIG. infusions. to.
placebo. in. 10. patients. with. a. crossover. design. at. 2.
week.intervals.and.demonstrated.substantial.benefit.in.
�.with.complete.seizure.freedom.in.2...Significant.EEG.
improvements.and.improved.neurobehavioural.outcomes.
were.reported.in.responders.in.all.3.studies.
. The.only.caveat. is. that.when. IVIG.was.used.other.
effective.treatments.for.LGS.like.the.newer.AEDs.were.
not.in.use...A.comparative.randomized.controlled.multi-
center. study. with. use. both. in. recently. diagnosed. and.
refractory.cases.would.be.useful.
IVIGINREHart. initially. reported. a. multi-center. prospective. open.
label.study.of.steroids.or.IVIG.or.both.in.mostly.biopsy.
proven.RE23.. .The. treatment.protocol.was.variable.and.
hence.statistical.analysis.was.not.possible...There.was.a.
benefit.in.7/9.patients.treated.with.IVIG.(2.were.also.on.
steroids).. . However. this. was. transient. in. 3.. .The. two.
adult.RE's.did.not.improve.contrary.to.later.reports.(vide.
below)...Steroids.were.also.beneficial.in.8/19.patients.
Granata22.in.a.more.recent.paper.reports.their.experience.
of.different.immunomodulatory.therapies.in.1�.patients.
of. RE.. . Steroids. were. temporarily. beneficial. in. 6/11.
patients.but.were.associated.with.worsening.of.seizures.
if. they. were. withdrawn.. . Eight. patients. were. treated.
with. periodic. infusions. of. IVIG.. . The. response. in. 7.
children.was.disappointing.with.'slight.improvement'.in.
only. 2.. .The. single. adult. patient. had. a. fairly. dramatic.
response.with.>7�%.improvement.in.seizure.frequency.
and. a. reduction. in. neurologic. deficits.. . This. robust.
response.in.adult.RE.was.re-emphasized.by.Villani18.and.
Leach38...Periodic.full.dose.IVIG.in.3.adults.several.years.
into.disease.with.disabling.deficits.resulted.in.a.dramatic.
improvement.over.a.few.months.with.clear.reductions.
not. only. in. seizure. frequency. but. also. in. deficits..
and.disability.
. Double.blind.placebo.controlled.studies.in.RE.will.be.
difficult. as. it. is. a. rare. disease. necessitating. patient.
recruitment.from.multiple.centers;.placebo.control.in.a.
progressive.disease.with.a.variable.fluctuating.course.is.
poses.problems.
IVIGINLkSInitially.three.case.reports27,.39,.�0.suggested.a.role.of.IVIG.
in.LKS...In.all.patients.a.dramatic.response.in.language.
functions. as. well. as. near. normalization. of. the. EEG.
occurred.within.3-7.days.of.starting.the.infusions...One.
of. the. patients. was. steroid. unresponsive39,. the. other.
was.steroid.dependent�0.and.in.the.third.IVIG.was.used.
as. initial. montherapy27.. . The. dosage. used. was. the.
standard.2g/kg.over.a.few.days...Importantly.2/3.children.
relapsed.and.needed.repeated.doses.every.few.weeks.
/. months. for. optimal. response.. . An. open. label. well.
designed.prospective.study.of.five.patients.from.Beirut.
(�1).confirmed.a.significant.difference. in. language.and.
EEG. scores. after. a. 2g/kg. infusion. of. IVIG. within. 1.
month.. .Two. of. these. five. patients. had. already. been.
reported27,. �0. and. did. extraordinarily. well. with. normal.
language. scores. 18m. -�. years. after. their. last. dose. of.
IVIG.. .These. appeared. to. be. the. 'pure'. LKS. while. the.
other.three.were.symptomatic.of.prior.brain.insults...The.
CSF. IgG. index. was. elevated. in. the. two. patients. who.
responded.dramatically.suggesting.an.immune.basis.for.
their. symptoms.. . The. other. three. patients. improved..
only.mildly...
10�
sUMMaRYIntractable. epilepsy. is. heterogeneous. and. the. bulk. of.
the.evidence.supporting.IVIG.use.is.level.2.or.3.
. There. is. a. single. RCT. supporting. its. use. in. partial.
epilepsy.. . In.WS,. there. is. level. 3. evidence. supporting.
IVIG.use.and.a.small.subset.of.refractory.patients.may.
have.a.dramatic.response.to.it...The.dosage,.duration.of.
treatment.and.long.term.results.have.been.variable.and.
need. further. study.. . Similarly. there. is. level. 2. or. 3.
evidence. for. its. use. in. LGS.. . However. these. studies.
were.done.before.the.newer.AEDs.and.VNS.and.before.
the. ketogenic. diet. became. popular.. . It. could. be. used.
prior. to. considering. corpus. callosotomy.. . In. RE. there.
appears.to.be.good.level.3.evidence.of.IVIG.efficacy.in.
the. rare. adult. onset. RE. and. periodic. infusions. are.
probably. needed. even. several. years. after. onset.. .The.
data.in.children.appears.less.promising.and.it.cannot.be.
recommended.. . In. LKS. there. seems. to. be. level. 3.
evidence.of.a.promising.role.of.IVIG.in.at.least.a.subset.
of.patients.with.this.syndrome.and.a.large.multi-center.
randomized. controlled. trial. is. needed. before. it. is.
recommended. over. steroids.. . It. should. be. used. in.
steroid. failures. and. before. the. surgical. option.. . In. the.
rare. cases. of. non-paraneoplastic. limbic. encephalitis.
evidence.of.clear.benefit.is.unclear.at.present.
EXpERt CONsENsUs1).. .The. evidence. for. the. use. of. IVIG. as. a. standard.
treatment.in.the.majority.of.the.intractable.epilepsy.
syndromes. is. not. adequate. at. this. stage.. Other.
treatment.options.are.comparatively.more.effective..
IVIG. could. be. considered. after. other. options. have.
failed. especially. if. the. cause. of. the. epilepsy. is.
suspected.to.be.immune.–.mediated.
2).. .In.adult.Rasmussen's.syndrome.there.seems.to.be.
a. role. for. periodic. IVIG. therapy. before. surgical.
treatment. is. considered,. especially. in. the. patient.
without.deficits.
3).. .In. the. Landau-Kleffner. syndrome,. IVIG. might. be.
considered.especially.in.steroid.failures.
REfERENCEs1.. .Bingel. U,. Pinter. JD,. Sotero. de. Menezes. M,. et. al..
Intravenous. immunoglobulin. as. adjunctive. therapy.
for. juvenile. spasms.. J. Child. Neurol.. 2003;. 18.
(6):379-82.
2.. .Rantala. H,. Putkonen. I. Occurrence,. outcome,. and-
prognostic. factors.of. infantile. spasms.and.Lennox-
Gastaut. syndrome.. Epilepsia.. 1999.
Mar;�0(3):286-9.
3.. .Yanagaki.S,.Oguni.H,.Hayashi.K,.et.al..A.comparative.
study.of.high-dose.and. low-dose.ACTH.therapy. for.
West.syndrome..Brain.Dev..1999;.21(7):.�61-7.
�.. .Baram.TZ,.Mitchell.WG,.Tournay.A,.et.al..High-dose-
corticotropin. (ACTH). versus. prednisone. for. infantil.
spasms:. a. prospective,. randomized,. blinded. study..
Pediatrics..1996;.97(3):.37�-9.
�.. .Vigevano. F,. Cilio. MR.. Vigabatrin. versus. ACTH. as.
first-line.treatment.for.infantile.spasms:.a.randomized,.
prospective. study.. Epilepsia.. 1997;.
38(12):1270-127�.
6. .Driefuss. F,. Farwell. J,. . Holmes. G,. et. al....
Infantile. spasms.. Comparative. trial. of. nitrazepam.
and. corticotropin.. Arch. Neurol.. 1986;. �3(11):.
1107-1110.
7.. .Dyken.PR,.DuRant.RH,.Minden.DB,.et.al..Short.term.
effects. of. valproate. on. infantile. spasms.. Pediatr.
Neurol..198�;.1(1):.3�-37.
8.. .Glauser.TA,.Clark.PO,.Strawsburg.R..A.pilot.study.of.
topiramate. in. the. treatment. of. infantile. spasms.
Epilepsia..1998;.39(12).:132�-1328.
9.. .Glauser..TA,.Clark.PO,.McGee.K..Long-term.response.
to. topiramate. in. patients. with. West. syndrome..
Epilepsia..2000;.�1.Suppl.1:.S91-9�.
EPILEPSY
106
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
10...Kossoff.EH,.Pyzik.PL,.McGrogan.JR,.et.al..Efficacy.
of.the.ketogenic.diet.for.infantile.spasms..Pediatrics..
2002;.109(�):.780-3.
11.. .Ariizumi. M,. Baba. K,. Hibio. S,. et. al..
Immunoglobulintherapy. in. the. West. syndrome..
Brain.Dev.1987;9(�):.�22-�2�.
12...The. Felbamate. Study. Group. in. Lennox-Gastaut.
Syndrome.. Efficacy. of. Felbamate. in. childhood.
epileptic. encephalopathy. (Lennox-Gastaut. syn.
drome)..N.Engl.J.Med..1993.7;.328:29-33.
13...Eriksson.AS,.Nergardh.A,.Hoppu.K..The.efficacy.of.
lamotrigine. in.children.and.adolescents.with. refrac.
tory. generalized. epilepsy:. a. randomized,. double-
blind,. crossover. study.. Epilepsia.. 1998;. 39(�):.
�9�-�01.
..
1�...Sachdeo. RC,. Glauser.TA,. Ritter. F,. et. al.. A. double.
blind,. randomized. trial. of. topiramate. in. Lennox-
Gastaut. syndrome.. Topiramate. YL. Study. Group.
Neurology..1999.10;.�2(9):.1882-87.
1�...Dodson.WE..Felbamate.in.the.treatment.of.Lennox-
Gastaut.syndrome:.results.of.a.12-month.open-label.
study.following.a.randomized.clinical. trial.Epilepsia..
1993;.3�.(Suppl.7):S18-2�.
16...Glauser.TA,.Levisohn.PM,.Ritter.F,.et.al..Topiramate.
in. Lennox-Gastaut. syndrome:. open-label. treatment.
of.patients.completing.a.randomized.controlled.trial..
Topiramate.YL.Study.Group..Epilepsia..2000;�1(Suppl.
1):S86-90.
17.. .Schmidt.D,.Bourgeois.B..A.risk-benefit.assessment.
of.therapies.for.Lennox-Gastaut.syndrome..DrugSaf..
2000;.22(6):�67-77.
18...Villani. F,. Spreafico. R,. Farina. L,. et. al.. Positive.
response.to.immunomodulatory.therapy.in.an.adult-
patient. with. Rasmussen's. encephalitis..
Neurology.2001.23;�6(2):2�8-�0.
19...Rogers. SW,. Andrews. PI,. Gahring. LC. et. al..
Autoantibodies. to. glutamate. receptor. GluR3. in.
Rasmussen's. encephalitis.. Science.. 199�. 29;.
26�:6�8-�1.
20...Wiendl. H,. Bien. CG,. Bernasconi. P,. et. al.. GluR3.
antibodies:. prevalence. in. focal. epilepsy. but. no.
specificity.for.Rasmussen's.encephalitis..Neurology..
2001.23;�7(8):1�11-�.
21.. .Bien. CG,.Widman. G,. Urbach. H,. et. al..The. natural.
history. of. Rasmussen's. encephalitis.. Brain..
2002;12�(Pt8):17�1-9.
22...Granata.T,.Fusco.L,.Gobby.G,.et.al..Experience.with.
immunomodulatory. treatments. in.
Rasmussen'sencephalitis.. Neurology.. 2003. 23;.
61(12):1807-10.
23...Hart.YM,. Cortez. M,. Andermann. F,. et. al.. Medical.
treatment. of. Rasmussen's. syndrome. (chronic.
encephalitis. and. epilepsy):. effect. of. high-dose.
steroids. or. immunoglobulins. in. 19. patients..
Neurology..199�;.��(6):1030-6.
2�...Smith. MC,. Hoeppner.TJ.. Epileptic. encephalopathy.
of.late.childhood:.Landau-Kleffner.syndrome.and.the.
syndrome. of. continuous. spikes. and. waves. during.
slow-wave. sleep.. J. Clin. Neurophysiol..
2003;20(6):�62-72.
2�...Praline.J,.Hommet.C,.Barthez.MA,.et.al..Outcome.at.
adulthood. of. the. continuous. spike-waves. during.
slow. sleep. and. Landau-Kleffner. syndromes.
Epilepsia..2003.Nov;��(11):1�3�-�0.
26...Robinson. RO,. Baird. G,. Robinson. G,. et. al.. Landau-
Kleffner.syndrome:.course.and.correlates.with.outcome..
Dev.Med.Child.Neurol..2001;.�3(�):.2�3-7.
27.. .Mikati. MA,. Saab. R.. Successful. use. of. intravenous.
immunoglobulin.as.initial.monotherapy.in.LandauKleffner.
syndrome..Epilepsia..2000.Jul;�1(7):880-6.
.
107
28...Tsuru.T,.Mori.M,.Mizuguchi.M,.et.al..Effects.of.high-
dose. intravenous. corticosteroid. therapy. in. Landau-
Kleffner.syndrome..Pediatr.Neurol..2000;.22(2):1��-7.
29...Irwin.K,.Birch.V,.Lees.J,.et.al..Multiple.subpial.tran-
section.in.Landau-Kleffner.syndrome..Dev.MedChild.
Neurol..2001;.�3(�):2�8-�2.
30...Duse.M,.Notarangelo.LD.Tiberti.S,.et.al..IVIG.in.the.
treatment. of. intractable. childhood. epilepsy.. Clin.
ExpImmunol.1996;.10�.(Suppl.1):.71-76.
31.. .Van.Engelen.BG,.Renier.WO,.Weemaes.CM,.et.al..
Immunoglobulin. treatment. in. human. and. experi-
mental.epilepsy..J.Neurol.Neurosurg.Psychiatry.199�;.
�7.(Suppl):.72-7�..
.
32...Pechadre. JC,. Sauvezie. B,. Osier. C,. et. al.. The.
treatment.of.epileptic.encephalopathies.with.gamma.
globulin. in. children. (authors. translation). Rev.
Electroencephalogr. Neurophysiol. Clin.. 1977;. 7.
(�):��3-��7..
33...van. Rijckevorsel-Harmant. K,. Delire. M,. Schmitz-
morrman.W,.et.al..Treatment.of. refractory.epilepsy.
with. intravenous. immunoglobulins.. Results. of. the.
first.double-.blind./.dose.finding.clinical.study..Int.J.
ClinLab.Res.199�.2�:.162-166.
3�...Echenne. B,. Dulac. 0,. Parayre-Chanez. MJ,. et. al..
Treatment.of. infantile.spasms.with.IVIG..Brain.Dev.
1991;.13:313-319.
3�...van. Engelen. BG,. Renier.WO,.Weemaes. CM,. et. al..
High-dose. intravenous. immunoglobulin. treatment. in.
cryptogenic.West.and.Lennox-Gastaut.syndrome;.an.
add-on.study..Eur.J.Pediatr..199�;.1�3(10):762-9.
36...Gross-Tsur..V,.Shalev.RS,.Kazir.E,.et.al..Intravenous.
high-dose.gammaglobulins.for.intractable.childhood.
epilepsy..Acta.Neurol.Scand..1993;.88(3):20�-9.
37.. .Ilium. N,.Taudorf. K,. Heilmann. C,. et. al.. Intravenous.
immunoglobulin:.a.single-blind. trial. in.children.with.
Lennox-Gastaut. syndrome.. Neuropediatrics..
1990;21(2):87-90.
38...Leach.JP.Chadwick.DW,.Miles.JB,.et.al..Improvement.
in. adult-onset. Rasmussen'sencephalitis. with. long-
term. immunomodulatory. therapy.. Neurology.. 1999.
10;.�2(�):738-�2.
39...Fayad. MN,. Choueiri. R,. Mikati. M.. Landau-Kleffner.
syndrome:. consistent. response. to. repeated.
intravenous. gamma-globulin. doses:. a. case. report.
Epilepsia..1997;.38(�):�89-9�.
�0...Lagae. LG,. Silberstein. J,. Gillis. PI,. et. al.. Successful.
use. of. intravenous. immunoglobulins. in. Landau-
Kleffner. syndrome.. Pediatr. Neurol.. 1998;.
18(2):16�-68.
�1.. .Mikati. MA,. Saab. R,. Fayad. MN,. et. al.. Efficacy. of.
intravenous. immunoglobulin. in. Landau-Kleffner.
syndrome..Pediatr.Neurol..2002;.26(�):298-300.
�2...Billiau. AD,. Witters. P,. Ceulemans. B,. Kasran. A,.
Wouters.C,.Lagae.L.. Intravenous. immunoglobulins.
in. refractory. childhood-onset. epilepsy:. effects. on.
seizure. frequency,. EEG. activity,. and. cerebrospinal.
fluid.cytokine.profile..Epilepsia.2007;�8:1739-17�9.
.
EPILEPSY
108
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
OPSOCLONUS-MYOCLONUS-ATAXIABaCKGROUNdOpsoclonus-myoclonus-ataxia. (OMA). is. an. immune.
mediated.monophasic.or.multiphasic.disorder.affecting.
both.children.and.adults....It.is.a.rare.and.is.either.para-
neoplastic.or.idiopathic,.presumably.parainfectious....In.
children. it. complicates. 2-3%. of. all. neuroblastomas.
while. in.adult. life. it. is.seen. in.association.with.several.
cancers. most. commonly. small. cell. lung. and. breast.
carcinomas.. . Characteristically. it. has. an. acute. to.
subacute. onset. of. opsoclonus. (conjugate. chaotic. eye.
movements),. action. arrhythmic. myoclonus. affecting.
limbs,.trunk.and.head.and.ataxia....About.two-thirds.of.
patients.have.the.complete.syndrome....Initial. imaging.
is.usually.normal....In.later.chronic.and.ongoing.disease,.
cerebellar,.especially.vermian.atrophy. is.often.seen.on.
imaging1....The.pathogenesis.of.OMA.was.thought.to.be.
antibody.mediated....Anti-Ri,.anti-.Hu.and.other.antineu-
ronal. antibodies. are. sometimes. found. in. adult. onset.
paraneoplastic. OMA2.. . . In. childhood. anti-Purkinje. cell.
and.anti-neurofilament.antibodies.have.been.reported1-3....
However. these. are. not. consistent. and. a. recent. study.
suggests. that. most. do. not. have. any. persistent.
antibodies�....Recent.work.on.CSF.lymphocyte.subsets.
have.shown.higher.percentage.of.B.cells.and.other.T.cell.
abnormalities. with. correlation. to. disease. severity,.
suggesting.that.this.may.be.a.primary.B.cell.mediated.
disorder�....In.childhood.paraneoplastic.OMA.the.onset.
is.typically.after.the.first.year.with.a.mean.age.of.around.
22. months6.. . . Neuroblastoma. is. the. most. common.
tumor. associated. with. this. syndrome. in. childhood....
There. is.a. lack.of. tumour.myc-.oncogene.amplification.
suggesting.a.better. tumour.prognosis.. . .There. is.often.
no.increased.excretion.of.VMA6....The.tumor.is.often.not.
abdominal. and. is. most. often. does. not. metastasize6....
The.OMA.often.precedes.the.diagnosis.of.tumor.
. The. course. of. the. disease. is. often. punctuated. by.
relapses. precipitated. by. intercurrent. illness.. . . The.
idiopathic. form,. especially. in. adults. is. often..
monophasic2....It.must.be.highlighted.that.neuroblasto-
mas.in.infancy.may.spontaneously.regress.and.this.may.
occur. before. the. OMA. becomes. apparent. raising..
the. possibility. that. many. 'idiopathic'. OMAs. are..
actually.paraneoplastic.
. Long. term. follow. up. in. childhhod. paraneoplastic.
OMA.suggest.that.the.prognosis.of.the.neuroblastoma.
is.generally.good.with.>.90%.surviving.3.yrs6....However.
the.neurologic.and.developmental.outcome.is.far.from.
satisfactory.. . . Earlier. short-term. follow. up. identified.
significant. delays,. cognitive,. behavioural. and. motor.
deficits.in.the.majority.of.such.children6-8....
109
OPSOCLONUS-MYOCLONUS-ATAXIA
Longer. follow-ups. have. suggested. continued.
improvement. with. about. half. the. children. achieving.
average.intelligence1.
CONVENtIONaL MaNaGEMENtThe. first. line. treatment. of. the. immune. syndrome. has.
been.ACTH./.oral.steroids6.with.or.without.pulse.meth-
ylprednisolone. therapy9.. . . Other. immunomodulatory.
treatments.like.plasma.exchange10.and.immunoadsorp-
tion11.may.also.be.successful.though.the.evidence.is.in.
single.case.reports.or. in.small.series.. . .Chemotherapy.
given. for. the.associated.cancer.seems. to.be.effective.
for.the.OMA.symptoms.as.well6.presumably.due.to.its.
immunosuppressive.effects....It.forms.the.backbone.of.
therapy.in.adult-onset.paraneoplastic.OMA2....
. Initial. promising. results. with. Rituximab2�. led. to. a.
large.open-label.prospective.trial.in.16.patients21....81%.
of. the. children. improved. in. the. motor. severity. score.
while. ��%. improved. by. one. severity. category.. . . All.
children.had.lowering.of.CD19/CD20.B-cells.in.the.CSF.
with. these. becoming. undetectable. in. 6.. . . Other. case.
reports. document. the. benefit. of. Rituximab22-2�. or. in.
combination.with.IVIG19....Another.promising.treatment.
is. high-dose,. pulse. dexamethasone. with. or. without.
pulse.cyclophosphamide20....
IVIG IN OMaIt. is.difficult. to.conduct. randomized.controlled. trials. in.
such.a. rare.disorder.. . .The.evidence.of. the.efficacy.of.
IVIG. is. limited.to.case.reports.since. it's.first.use. in.an.
infant.by.Sugie.in.199213... .Pless.used.IVIG.in.an.adult.
with. parainfectious. OMA. who. had. failed. ACTH. and..
thiamine1�.. . .A. rapid. improvement.was.noted.within.a.
week.after.the.IVIG.infusion....A.similar.adult.patient.of.
parainfectious. OMA. and. an. abnormal. CSF. responded.
within.2.days.after.having.failed.treatment.with.methyl-
prednisolone.and.valproate1�....The.problem.with.these.
two.studies.was.the.short.follow.up.and.the.possibility.
that.the.steroids.and.other.medications.may.have.had.a.
delayed.effect....Prantazelli.reported.the.most.convincing.
case.study16....This.�1.year.follow.up.was.on.a.patient.
who.presented.first.in.infancy.with.post-vaccinial.OMA.
with. a. good. initial. response. to. ACTH.. . . The. first.
remission. lasted. 10. years.. . . At. 22. years. he. had. a.
disabling.pan-cerebellar.syndrome.responsive.to.ACTH....
He.however.kept.relapsing.over.the.next.few.years....At.
36. years. intermittent. IVIG. resulted. in. a. sustained.
response.for.�.years.and.the.patient.has.gone.back.to.
his. activities. of. daily. living.. . .This. case. illustrates. that.
OMAs.can.relapse.over.several.decades.but.still.retain.
their. responsiveness. to. immunotherapy.. . . The. study.
clearly.shows.the.long-term.benefits.with.IVIG.therapy.
. In.paraneoplastic.adult.OMAs,.what.appears.clear.is.
that.unless.the.primary.tumour.is.in.remission.all.immu-
notherapies.are.unhelpful....In.childhood.paraneoplastic.
OMAs. associated. with. neuroblastoma,. two. long-term.
case. studies. suggest. clear. benefit. to. immunotherapy....
Petruzzi.reported.its.use.in.an.18.month.old.girl.with.a.
non-resectable. ganglioneuroblastoma. who. responded.
significantly.to.IVIG.�8.hours.before.chemotherapy.was.
begun3.. . . She.has.been.symptom. free. for. 2. years.on.
long. term. IVIG.maintenance.given. for. 1�.months.. . . It.
was. noted. that. symptoms. would. relapse. a. few. days.
before. the. next. IVIG. infusion. was. due. suggesting. a.
clear. cause-effect. relationship.. . . Eiris. noted. similar.
results. in. a. 1�. month. girl17. with. paraneoplastic. OMA.
who. had. only. transient. response. to.ACTH.. . . She. has.
been.symptom.free.after.only.a.single.low.dose.of.IVIG.
(1�0. mg/kg. over. 3. days). though. this. response. was.
gradual.and.may.suggest.a.natural.remission....Borgna-
Pignatti.however. report. less. favourable. results. in.a.22.
month.old.infant.girl.with.paraneoplastic.OMA18.where.
periodic. IVIG. infusions.were.continued. for.10.months....
The. tumour. was. diagnosed. fairly. late. and. the. dosage.
used.was.very.low.(�00.mg/kg),.which.may.have.been.
some.of.the.factors.responsible.for.this.therapeutic.failure.
sUMMaRY1).. .There. is. Level. IIIb. evidence. supporting. the. use. of.
IVIG.in.OMA..It.seems.to.be.useful.in.both.idiopathic.
OMA. and. in. childhood. paraneoplastic. OMA.
associated. neuroblastoma.. The. response. is. often.
only. transient. in.some.and. long-term.maintenance.
therapy. may. be. needed. for. continued. response....
Some.children.however.do.fail.to.respond.and.there.
may. be. a. paucity. of. reports. of. such. therapeutic.
failures.in.the.literature.due.to.a.publication.bias.
110
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
2).. .It. is. possibly. less. useful. in. adult. paraneoplastic.
OMA.where.tumor.control.seems.more.crucial.
3).. .Most. successes. were. continuing. other. therapies.
like. ACTH. /. chemotherapy. and. this. may. have.
influenced.the.results.
�).. .The. dosage. of. IVIG. used. has. been. variable. from.
very. low.doses.given.once.to.high.doses.given.for.
several.years....The.dosage./.duration.would.need.to.
be. addressed. in. any. long. term. RCT. in..
the.future.
�).. .Side.effects.were.transient.and.did.not.limit.the.use.
of.this.treatment.option.
6).. .Long. –. term. ACTH. /. oral. steroids,. rituximab. and.
high-dose. dexamethasone. are. other. effective.
therapies.with.sustained.remissions....
EXpERt CONsENsUsIVIG. might. be. considered. as. one. of. the. therapies. for.
this.difficult.and.devastating.syndrome..Further.studies.
are. needed. to. validate. efficacy. and. decide. on. optimal.
dosage.and.duration.of.therapy.
REfERENCEs1.. .Hayward. K,. Jeremy. RJ,. Jenkins. S,. Barkovich. AJ,.
Gultekin.SH,.Kramer.J,.Crittenden.M,.Matthay.KK.
Long-term. neurobehavioral. outcomes. in. children.
with. neuroblastoma. and. opsoclonus-myoclonus-
ataxia. syndrome:. relationship. to. MRI. findings. and.
anti-neuronal. antibodies.. . J. Pediatr.. . 2001;.
139(�):��2-�9.
2.. .Bataller. L,. Graus. F,. Saiz. A,. Vilchez. JJ;. Spanish.
Opsoclonus-Myoclonus. Study. Group.. Clinical.
outcome. in.adult.onset. idiopathic.or.paraneoplasti-
copsoclonus-myoclonus.Brain..2001;.12�(Pt.2):.�37-�3.
3.. .Petruzzi.MJ,.de.Alarcon.PA...Neuroblastoma-associ-
ated. opsoclonus-myoclonus. treated. with. intrave-
nously. administered. immune.globulin.G.. . JPediatr...
199�;.127(2):.328-9.
�.. .Pranzatelli.MR,.Tate.ED,.Wheeler.A,.Bass.N,.Gold.
AP.Griebel.ML,.Gumbinas.M,.Heydemann.PT,.Holt.
PJ,. Jacob. P. Kotagal. S,. Minarcik. CJ,. Schub. HS.
Screening.for.autoantibodies.in.children.with.opso-
clonus-myoclonus-ataxia.. . Pediatr. Neurol...
2002;27(�):.38�-87.
.
�.. .Pranzatelli.MR,.Travelstead.AL,.Tate.ED,.Allison.TJ,.
Moticka.EJ,.Franz.DN,.Nigro.MA,.Parke.JT,.Stumpf.
DA,.Verhulst.SJ...B-.and.T-cell.markers.in.opsoclonus-
myoclonus.syndrome:.immunophenotyping.of.CSF.
lymphocytes...Neurology...200�;.62(9):.1�26-32.
6.. .Rudnick. E,. Khakoo. Y,. Antunes. NL,. Seeger. RC,.
Brodeur. GM,. Shimada. H,. Gerbing. RB,. Stram. DO,.
Matthay. KK.. . Opsoclonus-myoclonus-ataxia.
syndrome. in. neuroblastoma:. clinical. outcome. and.
anti-neuronal. antibodies. -. a. report. from. the.
Children's.Cancer.Group.Study...Med.Pediatr.Oncol...
2001;36(6):612-22.
7.. .Hammer. MS,. Larsen. MB,. Stack. CV.. Outcome. of.
children. with. opsoclonus-myoclonus. regardless. of.
etiology...Pediatr.Neurol.199�.I;.13(1):21-�.
8.. .Russo. C,. Cohn. SL,. Petruzzi. MJ,. de. Alarcon. PA...
Long-term. neurologic. outcome. in. children. with.
opsoclonus-myoclonus. associated. with. neuroblas-
toma:.a.report.from.the.Pediatric.Oncology.Group.
Med.Pediatr.Oncol...1997;28(�):28�-88.
9.. .Emir.S,.Akyuz.C,.Buyukpamukcu.M...Treatment.of.
the. neuroblastoma-associated. opsoclonus-
myoclonus-ataxia.syndrome.with.high.dose.methyl-
prednisolone...Med...Pediatr...Oncol...2003;.�0:139..
10...Yiu. VW,. Kovithavongs. T,. McGonigle. LF,. Ferreira..
P.. Plasmapheresis. as. an. effective. treatment. for.
opsoclonus-myoclonus. syndrome.. .Pediatr.Neurol...
2001;2�(1):.72-7�.
111
OPSOCLONUS-MYOCLONUS-ATAXIA
11.. .Batchelor. TT,. Platten. M,. Hochberg. FH...
Immunoadsorption. therapy. for. paraneoplastic.
syndromes...J.Neurooncol...1998;.�0(2):131-36.
.
12...Michael. R.. . Pranzatelli,. Elizabeth. D.. . Tate,. Anna.
L.Travelstead,. Steven. J.. .Verhul.. . CSF. B-Cell. Over.
Expansion.in.Paraneoplastic.Opsoclonus.Myoclonus:.
Effect. of. Rituximab,. an. Anti-B-Cell. Monoclonal.
Antibody.. . Research. abstracts.. . Opsoclonus. -.
myoclonus.USA...www.omausa.org.
13...Sugie.H,.Sugie.Y,.Akimoto.H,.Endo.K,.Shirai.M,.Ito.
M...High-dose.IV.human.immunoglobulin.in.a.case.
with. infantile. opsoclonus-polymyoclonia. syndrome...
Acta.Paediatr...1992;.81(�):.371-2.
1�...Pless. M,. Ronthal. M.. . Treatment. of. opsoclonus-
myoclonus. with. high-dose. intravenous. immuno-
globulin...Neurology.1996;.�6(2):.�83-�.
1�...Glatz. K,. Meinck. HM,. Wildemann. B...
Parainfectiousopsoclonus-myoclonus. syndrome:.
high. dose. intravenous. immunoglobulins. are..
effective.. . J. Neurol. Neurosurg. Psychiatry....
2003;.7�(2):.279-80.
16...Pranzatelli.MR,Tate.ED,.Kinsbourne.M,.Caviness,.VS.
Jr,.Mishra.B...Forty-one.year.follow-up.of.childhood.
onset. opsoclonus-myoclonus-ataxia:. cerebellar.
atrophy,.multiphasic.relapses,.and.response.to.IVIG...
Mov.Disord...2002;.17(6):.1387-90.
17.. .Eiris.J,.del.Rio.M,.Castro-Gago.M...Immune.globulin.
G. for. treatment. of. opsoclonus-polymyoclonus.
syndrome...J.Pediatr.1996;.129(1):.17�.
18...Borgna-Pignatti.C,.Baiter.R,.Marradi.P.Colamaria.V..
Treatment. with. intravenously. administered..
immunoglobulins. of. the. neuroblastoma-associated.
opsoclonus-myoclonus.. . J. Pediatr.1996;. 129(1):.
179-80.
19...Leen.WG,.Weemaes.CM,.Verbeek.MM,.Willemsen.
MA,.Rotteveel.JJ...Rituximab.and.intravenous.immu-
noglobulins.for.relapsing.postinfectious.opsoclonus-
myoclonus. syndrome.. . Pediatr. Neurol.
2008;39:213-217.
20...Ertle.F,.Behnisch.W,.Al.Mulla.NA,.Bessisso.M,.Rating.
D,.Mechtersheimer.G,.Hero.B,.Kulozik.AE...Treatment.
of. neuroblastoma-related. opsoclonus-myoclonus-
ataxia. syndrome. with. high-dose. dexamethasone.
pulses...Pediatr.Blood.Cancer.2008;�0:683-687.
21.. .Pranzatelli.MR,.Tate.ED,.Travelstead.AL,.Barbosa.J,.
Bergamini. RA,. Civitello. L,. Franz. DN,. Greffe. BS,.
Hanson. RD,. Hurwitz. CA,. Kalinyak. KA,. Kelfer. H,.
Khakoo.Y,.Mantovani.JF,.Nicholson.SH,.Sanders.JM,.
Wegner.S...Rituximab.(anti-CD20).adjunctive.therapy.
for. opsoclonus-myoclonus. syndrome.. . J. Pediatr.
Hematol.Oncol.2006;28:�8�-�93.
22...Burke. MJ,. Cohn. SL.. . Rituximab. for. treatment. of.
opsoclonus-myoclonus.syndrome.in.neuroblastoma...
Pediatr.Blood.Cancer.2008;�0:679-680.
23...Bell.J,.Moran.C,.Blatt.J...Response.to.rituximab.in.a.
child.with.neuroblastoma.and.opsoclonus-myoclonus...
Pediatr.Blood.Cancer.2008;�0:370-371.
2�...Pranzatelli.MR,.Tate.ED,.Travelstead.AL,.Longee.D...
Immunologic.and.clinical.responses.to.rituximab.in.a.
child. with. opsoclonus-myoclonus. syndrome...
Pediatrics.200�;11�:e11�-e119.83.
112
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
ACUTE DISSEMINATED ENCEPHALOMYELITISCLINICaL fEatUREsAcute. disseminated. encephalomyelitis. (ADEM). is. an.
idiopathic. inflammatory. demyelinating. disorder.. . It. is.
more. common. in. children,. classically. occurs. after. an.
infectious.illness.or.post-vaccination...Typical.ADEM.is.a.
monophasic.disorder.with.neurological.symptoms.that.
usually. appear.1. to.20.days.after. a. febrile. illness.with.
non-specific. respiratory. symptoms.. . Patients. present.
with.an.altered.conscious.state.with.multifocal.neuro-
logical.signs...Optic.neuritis,.which.is.often.bilateral,.and.
paraparesis.or.tetraparesis.with.a.sensory. level.due.to.
transverse.myelitis.can.also.occur.
EtIOLOGY Post-infectious. ADEM. in. infants. and. children. mostly.
commonly. followed. viral. infections. by. measles. (Litvak.
et.al...19�3)...Other.associations.include.herpes.simplex.
virus.(Kaji.et.al.,.1996),.HIV.(Silver.et.al.,.1997),.mumps.
(Hart.and.Earle,.197�),.influenza.virus.(Hoult.and.Flewett,.
1960). and. Ebstein-Barr. virus. (Ambler. et. al.,. 1971),.
Mycoplasma. pneumoniae. (Pellegrini. et. al.,. 1996). and.
Legionella. cincinnatiensis. (Spieker. et. al.,. 1998).. . Post-
immunization.ADEM.is.most.commonly.associated.with.
measles,.mumps.and.rubella.vaccinations.(Nalin.1989),.
and. has. reported. with. vaccination. against. Semple.
antirabies. (Murthy. 1998). and. Japanese. encephalitis.
(Plesner.et.al.,.1998)...In.this.era.of.organ.transplantation.
with.use.of.immunosuppressants,.post-organ.transplan-
tation.ADEM.is.recognized...Kim.et.al.reported.ADEM.in.
heart-lung. transplant. recipients. (Kim. et. al.,. 1998),. and.
Horowitz. et. al.. . described. a. patient. who. developed.
ADEM.after.renal.transplant.and.had.Ebstein-Barr.virus.
antibody.(Horowitz.et.al.,.199�)...Subsequent.reports.of.
ADEM.following.other.organs.transplantation.and.bone.
marrow. transplantation. appeared.. . It. is. believed. that.
long-term. immunosuppression. in. these. patients.
increases.their.risk.of.acute.microbial.infection.or.reacti-
vation.of. latent.viral. infection,. triggering.ADEM.. .Also,.
certain. immunosuppressants. such. as. cyclosporine,.
methotrexate. and. cyclophosphamide. can. cause. white.
matter. disease. mimicking. ADEM. (Laxmi. et. al.,. 1996;.
Apsner.et.al.,.1997).
pathOGENEsIsHistological. examinations. of. affected. brain. or. cord.
lesions. showed. areas. of. demyelination. and. inflamma-
tion.with.perivenous.mononuclear.cells,.and.occasional.
neutrophils. and. lipid-laden. macrophages;. which. is.
replaced.by.astrocytic.hyperplasia.and.glosis.in.the.late.
stage.(Allen.197�)...The.exact.pathogenesis.is.uncertain...
113
ACUTE DISSEMINATED ENCEPHALOMYELITIS
ADEM. is. considered. to. be. the. clinical. counterpart. of.
experimental.allergic.encephalomyelitis.(EAE).(Tolley.et.
al.,. 1999).. . Studies. of. animal. models. of. ADEM. using.
intracerebral.injection.of.Theiler’s.murine.encephalomy-
elitis. virus. suggest. that. an. initial. injury. caused. by. the.
infectious. agent. may. be. followed. by. secondary.
autoimmune.response.that.lead.to.demyelination.(Lipton.
197�).. . Molecular. mimicry. may. be. the. pathogenic.
mechanism. with. a. common. antigen. shared. by. the.
infectious. agent. and. myelin.. . Myelin. basic. protein,.
proteolipid.protein.and.myelin.oligodendrocyte.glycopro-
tein. can. induce. ADEM. after. immunization. in. Freund’s.
adjuvant,. probably. via. T-cell. mediated. autoimmune.
response.. . Both. CD�+. and. CD8+.T. cells. reactive. to.
these.myelin.autoantigens.are.involved.in.this.secondary.
autoimmune. response. (Murray. et. al.,. 1998),. further.
supported.by. the. finding. that.CD�+.and.CD8+.T. cells.
reactive. to. myelin. autoantigens. were. observed. after.
viral.infection.(Miller.et.al.,.1997)...B.cells.and.antibodies.
to. gangliosides. such. as. GM1. and. GD1a. may. a. play. a.
role. in. the. pathogenesis. of. ADEM. (Laouini. et. al.,.
1998)...
dIaGNOsIsIn. the.appropriate.clinical.context,.one.should.suspect.
ADEM.. . MRI. scans. are. useful. for. demonstrating. dis-
seminated.lesions.of.inflammatory.demyelination,.but.a.
temporal.delay.of.�.to.1�.days.between.onset.of.neuro-
logical.signs.and.appearance.of.lesion.on.MRI.can.occur.
(Kimura.et.al.,.1996;.Kesselring.et.al.,.1990)...Typical.MRI.
appearance.in.ADEM.consist.of.multiple.patchy.areas.of.
hyperintense.signals.on.T2W,.proton.density.and.fluid-
attenuated. inversion. recovery. sequence. in. subcortical.
white.matter,.cerebellum,.brainstem,.and.thalamic.grey.
matter.which.are.atypical.for.MS.(Kesselring.et.al.,1990)...
Large. tumor-like. demyelinating. lesions. may. be. seen.
(Kepes.1993)...
. CSF. analysis. often. reveals. protein. elevation. and. a.
mild.lymphocytic.pleocytosis.usually.without.oligoclonal.
bands...There.is.no.diagnostic.test...Electroencephalogram.
may. be. normal. or. consistent. with. an. encephalopathy.
(Apak.et.al.,.1999).
tREatMENtThe. aim. of. treatment. in. ADEM. is. to. suppress. the.
autoimmune.inflammatory.demyelinating.response.that.
damage. the. CNS. and. optic. neuritis.. . Hence. immuno-
modulatory.treatments.are.employed...Intravenous.cor-
ticosteroids.are.commonly.used.despite.the.absence.of.
controlled.trials.to.prove.its.efficacy...There.are.anecdotal.
reports. of. good. recovery. with. the. use. of. high. dose.
intravenous. methylprednisolone. (IVMP). in. acute.
fulminant.ADEM.(Straub.et.al.,.1997),.but.not.all.patients.
respond.(Kanter.et.al.,.199�)...In.patients.with.fulminant.
ADEM.with.no.or.unsatisfactory.response.to.high.dose.
corticosteroid,. plasmapheresis. has. been. reported.
effective. in. case. reports,. and. a. cross-over. study. of.
patients.with. idiopathic. inflammatory.demyelination.of.
the. CNS. (Weinshenker. et. al.,. 1999).. . Khurana. et. al...
studied.13.children.with.ADEM.retrospectively,.eleven.
were. treated. initially.with. intravenous.methylpredniso-
lone. (20-30mg/kg). for. �. days. followed. by. 2-week.
tapering. course. and. one. initially. treated. with. IVIG. for.
presumed. Miller-Fisher. syndrome.. . One. recovered.
spontaneously.without.specific.treatments...Six.patients.
developed.rapidly.progressive.course.and. IVIG.0.�g/kg.
daily. for. �. days. were. given. in. addition. to. steroid...
Without.significant.improvement,.all.6.then.underwent.
plasmapheresis.and.five.of.the.6.had.significant.neuro-
logical.recovery...With.their.treatment.sequence.of.initial.
corticosteroids.for.�.days.followed.by.observation.for.3-
�.days,.then.IVIG.for.�.days.followed.by.observation.for.
3-�.days,. and. then.plasmapheresis.alternate.day. for.�.
courses. if. there. was. no. significant. improvement. or.
deterioration;. these. authors. suggested. that. plasma-
pheresis. should. be. considered. for. ADEM. when. the.
disease. course. is. aggressive. or. severe. without..
satisfactory. improvement. to. corticosteroids. and. IVIG.
(Khurana.et.al.,.200�).
ROLE Of IVIG IN adEMIVIG.has.been.reported.to.be.efficacious.in.case.reports.
or. series. (Kleiman. et. al.,. 199�;. Hahn. et. al.,. 1996;.
Nishikawa. et. al.,. 1999;. Assa. et. al.,. 1999).. . Pittock.
reported.a.17-year-old.patient.with.ADEM.who.improved.
with.pulse.corticosteroid,.she.had.relapses.and.refused.
further. steroid. therapy.. . IVIG. was. substituted. and.
11�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
induced.a. rapid.clinical. remission. (Pittock.et.al.,.2001)...
Pradhan.et.al...described.their.experience.of.use.of.IVIG.
in. �. patients. with. severe. ADEM. who. did. not. show.
immediate. response. to.high.dose. intravenous.methyl-
prednisolone.. .All. �. patients. had. a. dramatic. recovery...
Straussberg. et. al.. . reported. the. rapid. neurological.
recovery. of. a. 3-year-old. girl. with. severe. ADEM. to.
concomitant.IVIG.(1g/kg.daily.for.3.days).and.high.dose.
intravenous. methylprednisolone. (10mg/kg. daily. for. 3.
days,. then. 2mg/kg. for. 10. days,. then. tapered. over. �.
weeks)...It.was.suggested.that.high.dose.IVIG.and.cor-
ticosteroids.act.by.similar.mechanisms.and.had.additive.
therapeutic. effects. in. combination. (Straussberg. et. al.,.
2001).. . Marchioni. et. al.. . reported. that. among. �. adult.
patients.with.ADEM.(3.classical.and.2.restricted.form),.
only.1.had.good.response.to.high.dose.corticosteroid,.
while. all. �. had. marked. functional. improvement. onset.
within. the. first. �. days. of. IVIG. administration. with.
maximum. improvement. within. 3. weeks. (Marchioni. et.
al.,.2002)...
EXpERt CONsENsUs1.. .There.are.no.controlled.trials.to.confirm.the.benefits.
of. IVIG. in. ADEM,. but. anecdotal. reports. and. case.
series. suggest. that. IVIG. may. be. efficacious. in.
ADEM.
2.. .IVIG. can. be. used. in. ADEM. patients. who. do. not.
respond.to.high.dose.corticosteroids.or. in.patients.
where.steroids.are.contraindicated.(e.g..suspicion.of.
CNS.infection).
REfERENCEs1.. .Allen. IV.. Demyelinating. diseases.. In:. Greenfield’s.
neuropathology,. �th. ed. Adams. JH,. Corsellis. JAN,.
Duchen.LW.(editors)..London:.Edward.Arnold;.198�.
pp..338-38�.
2.. .Assa. A,. Watemberg. N,. Bujanover. Y,. et. al..
Demyelinative.brainstem.encephalitis.responsive.to.
intravenous. immunoglobulin. therapy.. Pediatrics.
1998;10�:301-30�.
3.. .Ambler.M,.Stoll.J,.Tzamaloukas.A,.Abala.MM..Focal.
encephalomyelitis.in.infectious.mononucleosis..Ann.
Intern.Med.1971;7�:�7�-�83.
�.. .Aspner. R,. Schulenburg. A,. Steinhoff. N,. et. al..
Cyclosporin. A-induced. ocular. flutter. after. marrow.
transplantation.. Bone. Marrow. Transplant.
1997;20:2��-2�6.
�.. .Khurana.DS,.Melvin.JJ,.Kothare.V,.et.al..Acute.dis-
seminated.encephalomyelitis.in.children:.Discordant.
neurologic. and. neuroimaging. abnormalities. and.
response. to. plasmapheresis.. Pediatrics.
200�;116:�31-�36.
6.. .Hahn. JS,. Seigler. DJ,. Enzmann. D.. Intravenous.
immunoglobulin.therapy.in.recurrent.acute.dissemi-
nated. encephalomyelitis.. Neurology.
1996;�6:1173-117�.
7.. .Hart. MN,. Earle. KM.. Hemorrhagic. and. perivenous.
encephalitis:. a. clinical-pathological. review. of. 38.
cases.. J. Neurol. Neurosurg. Psychiatry.
197�;38:�8�-�91.
8.. .Hoult. JG,. Flewett. TH.. Influenzal. encephalopathy.
and. post-influenzal. encephalitis.. Histological. and.
other.observations..B.Med.J.1960;1:18�7-18�0.
9.. .Kaji.M,.Kusuhara.T,.Ayabe.M,.et.al..Survey.of.herpes.
simplex. virus. infection. of. the. central. nervous.
system,. including. acute. disseminated. encephalo-
myelitis,. in. the. Kyushu. and. Okinawa. regions. of.
Japan..Mult.Scler.1996;2:83-87.
10...Kleiman. M,. Brunquell. P.. Acute. disseminated.
encephalomyelitis:. response. to. intravenous. immu-
noglobulin?.J.Child.Neurol.199�;10:�81-�83.
11.. .Laxmi. SN,. Takahashi. S,. Matsumoto. K,. et. al..
Treatment-related. disseminated. necrotizing. leuko-
encephalopathy. with. characteristic. contrast.
enhancement. of. the. white. matter.. Radiat. Med.
1996;1�:303-307.
11�
ACUTE DISSEMINATED ENCEPHALOMYELITIS
12...Lipton. HL.. Theiler’s. virus. infection. in. mice:. an.
unusual.biphasic.disease.process.leading.to.demye-
lination..Infect.Immun.197�;11:11�7-11��.
13...Litvak.AM,. Sands. IJ,. Gibel. H.. Encephalitis. compli-
cating. measles:. report. of. �6. cases. with. follow-up.
studies.in.32..Am.J.Dis.Child.19�3;6�:26�-29�.
1�...Marchioni. E,. Marinou. Aktipi. K,. Uggetti. C,. et. al..
Effectiveness. of. intravenous. immunoglobulin.
treatment. in. adult. patients. with. steroid-resistant.
monophasic. or. recurrent. acute. disseminated.
encephalomyelitis.
1�...Murray.PD,.Pavelko.KD,.Leibowitz.J,.et.al..CD�+.and.
CD8+.T.cells.make.discrete.contributions.to.demye-
lination. and. neurologic. disease. in. a. viral. model. of.
multiple.sclerosis..J.Virol.1998;72:7320-7329.
16...Nishikawa.M,.Ichiyama.T,.Hayashi.T,.et.al..Intravenous.
immunoglobulin. therapy. in. acute. disseminated.
encephalomyelolitis.. Pediatr. Neurol.
1999;21:�83-�86.
17.. .Pellegrini.M,.O’Brien.TJ,.Hoy.J,.Sedal.L..Mycoplasma.
pneumoniae. infection. associated. with. an. acute.
brainstem. syndrome.. Acta. Neurol. Scand.
1996;93:203-206.
18...Silver.B,.McAvoy.K,.Mikesell.S,.Smith.TW..Fulminating.
encephalopathy. with. periventricular. demyelination.
and.vacuolar.myelopathy.as. the. initial.presentation.
of. human. immunodeficiency. virus. infection.. Arch.
Neurol.1997;��:6�7-6�0.
19...Spieker.S,.Petersen.D,.Rolfs.A,.et.al..Acute.dissemi-
nated.encephalomyelitis.following.Pontiac.fever..Eur.
Neurol.1998;�0:169-172.
20...Straussberg. R,. Schonfeld. T,. Weitz. R,. et. al..
Improvement. of. atypical. disseminated. encephalo-
myelitis.with.steroids.and.intravenous.immunoglob-
ulins..Pediatr.Neurol.2001;2�:139-1�3.
21.. .Tolley.ND,.Tsunoda.I,.Fujinami.RS..DNA.vaccination.
against. Theiler’s. murine. encephalomyelitis. virus.
leads.to.alteratons.in.demyelinating.disease..J.Virol.
1999;73:993-1000.
22...Weinshenker. BG,. O’Brien. PC,. Patterson. TM,.
Noseworthy. JH,. Lucchinetti. CF,. Dodick. D,. et. al.. A.
randomized.trial.of.plasma.exchange.in.acute.central.
nervous.system. inflammatory.disease..Ann.Neurol.
1999;�6(6):878-86.
116
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
MULTIPLE SCLEROSIS
CLINICaL fEatUREsMultiple. sclerosis. (MS). is. characterized. by. recurrent.
attacks.of.inflammatory.demyelination.affecting.different.
areas.of. the.central.nervous.system.(CNS).. .The.most.
common.form.of.MS.is.relapsing.remitting.MS.(RRMS),.
which.make.up.80%.of.patients.. . It. is.the.prototypical.
idiopathic. inflammatory. demyelinating. disorder. (IIDD).
though. the. exact. etiology. is. still. uncertain. (Compston.
2002)...Primary.progressive.MS.occurs.in.about.20%.of.
patients.with.an.even.more.uncertain.pathogenesis.and.
treatment. (Noseworthy. et. al.,. 2000).. . Classical. MS. is.
more. frequent. in.Caucasians.and. is. associated.with. a.
high. frequency. of. having. oligoclonal. bands. (OCB). in.
cerebrospinal.fluid.(CSF)... In.Asian.populations,.optico-
spinal.MS.(OSMS).is.more.common.and.has.restricted.
involvement.of.optic.nerves.and.spinal.cord,.sparing.the.
cerebral. hemispheres.. . It. is. . associated. with. a. low.
frequency.of.CSF.OCB. (Yu.et.al.,.1989).. .Most. recent.
data.suggest.that.OSMS.is.probably.the.same.as.neuro-
myelitis.optica.(NMO),.which.has.a.different.pathogen-
esis. and. pathologies. from. classical. MS..
(Lennon.et.al.,.200�).
. In. RRMS,. relapses. typically. present. as. visual.
impairments.due.to.unilateral.optic.neuritis.(ON),.diplopia.
due.to.internuclear.ophthalmoplegia,.sensory.symptoms.
such. as. paresthesia,. Lhermitte’s. sign,. limb. weakness,.
clumsiness,.ataxic.gait.due. to.cerebral,.brainstem.and.
spinal. cord. inflammatory.demyelination.which.develop.
over.several.days,.stabilize.and.then.commonly.resolve.
within.weeks.spontaneously.or. in.response.to.cortico-
steroid...Fatigue.is.common.in.many.patients...Worsening.
of. symptoms. with. increase. of. body. temperature.
(Uhthoff’s. phenomenon). and. fever,. and. onset. during.
post-partum.period.suggest. that.diagnosis.. .Recurrent.
paroxysmal. phenomenon. such. as. painful. spasm,.
paresthesia,. episodic. clumsiness. and. trigeminal.
neuralgia.may.occur.and.may.be.overlooked.or.misdiag-
nosed.as.manifestations.of.psychiatric.illness.
. Studies. on. the. natural. history. of. MS. showed. that.
about.10%.of.patients.have.benign.disease.and.remain.
well.for.more.than.20.years...About.70%.of.RRMS.will.
develop. secondary. progressive. MS. when. there. is.
progressive. deterioration. of. neurological. deficits.
(Weinshenker. et. al.,. 1989).. . Axonal. degeneration. is.
believed. to. be. the. underlying. pathology,. but. recent.
evidences.show.that.axonal.injury.can.occur.early.in.MS.
and.can.be.severe.(Lassmann.2003)...The.clinical.course.
of.an.individual.is.largely.unpredictable.
117
MULTIPLE SCLEROSIS
EtIOLOGICaL faCtORs aNd pathOGENEsIsClassical. MS. is. an. immune-mediated. neurological.
disorder. but. the. exact. pathogenetic. mechanisms. are.
uncertain.. . Genetic. factors. clearly. play. a. role. in. the.
etiology.of.MS.as.evidenced.by.the.concordance.rate.of.
31%. among. monozygotic. twins. compared. to. �%. for.
dizygotic.twins...The.presence.of.HLA-DR2.increase.sus-
ceptibility.to.develop.MS.(Jersild.et.al.,.1973)...Candidate-
genes.studies.and.scanning.of.the.entire.genome.have.
been. performed,. and. the. conclusion. is. that. multiple.
genes.influence.the.susceptibility.to.develop.the.disease,.
but.no.single.gene.with. the.possible.exception.of.HLA.
has. a. strong. influence. (Noseworthy. et. al.,. 2000)...
Environmental. factors. also. contribute. as. evidenced. by.
the.change.in.frequency.of.MS.among.people.and.their.
offspring. that. migrate. into. and. out. of. high-prevalence.
areas. (Dean. 1967).. . Infection. by. micro-organisms. have.
been.suggested.to.be.causative.factor. including.herpes.
simplex.virus.type.6.(Challoner.et.al.,.199�).and.chlamydia.
pneumonia. (Sriram. et. al.,. 1999). but. consensus. is. not.
available.from.other.studies...
. Lucchinetti. et. al.. . proposed. that. MS. is. probably. a.
heterogeneous. group. of. disorders. with. different. histo-
logical.features.on.brain.biopsy.(Lucchinetti.et.al.,.2000)...
They. found. that. brain. histological. abnormalities. in. MS.
patients.can.be.divided.into.four.groups.–.1.macrophage.
induced. demyelination,2. antibody-mediated. demyelin-
ation.likely.with.complement.activation,3.distal.oligoden-
drogliopathy. and. apoptosis. possibly. related. to. toxins,.
ischemia.and.viruses.and�.primary.oligodendrogliopathy...
Interestingly.individual.patients.were.different.in.the.his-
tological.findings.but.lesions.were.uniform.within.a.single.
patient,.suggesting.that.the.focus.of.injury.was.different.
between. different. patients.. . MS. is. likely. a. group. of.
disorders. with. different. causes. and. pathogenetic.
mechanisms. including. cellular-mediated. immunological.
injury,.antibody.and.complement-mediated.injury.or.oligo-
dendrocyte. dystrophy.. .This. hypothesis. can. explain. the.
variable.clinical.severity.and.response.to.immunomodula-
tory. treatments. among. different. MS. patients,. and..
was. supported. by. report. that. patients. with. antibody-
mediated. demyelination. on. histology. might. respond..
to. plasmapheresis. better. than. other. groups.. . (Keegan.
.et.al.,.200�).
. Chronic.demyelinated.plaques.consist.of.hypocellu-
lar.regions.with.loss.of.myelin,.relative.preservation.of.
axons.and.astrocytic.scars,.which.commonly.surround.
medium.sized.vessels...Perivascular.inflammatory.cells.
consisting. of. macrophages. and. lymphocytes. are.
common. though. diffuse. inflammatory. infiltrate. of.
parenchyma. may. be. seen.. . In. acute. attacks,. early.
symptoms. are. probably. due. to. axonal. demyelination.
with. recovery. following. resolution. of. inflammatory.
oedema. and. partial. remyelination.. . Inflammatory.
cytokines.may.cause.axonal.dysfunction...As.mentioned,.
axonal. injury. may. occur. early. and. be. severe. with.
uncertain.etiology.. .The.initial.event. in.acute. inflamma-
tory.demyelinating.episode.is.unclear,.it.is.believed.that.
CD�+.T. cells. specific. for. autoantigens. migrate. to. the.
central. nervous. system. after. adhering. to. endothelial.
cells. when. the. blood-brain-barrier. (BBB). is. broken.. .T.
cells.reactive.to.myelin.basic.protein,.myelin-associated-
glycoprotein,. myelin. oligodendrocyte. glycoprotein. and.
other. autoantigens. have. been. proposed. (Steinman.
1996)...In.the.CNS,.antigen-presenting.cells.present.the.
autoantigen. to. the. specific. CD�+.T. cells,. starting. to.
amplify.the.immunological.response.with.production.of.
cytokines,. recruitment. of. macrophages. and. autoanti-
bodies.. .Autoantibodies.against.myelin.antigens.might.
activate.complement.and.cause.demyelination.directly.
(Piddlesden. et. al.,. 1993).. . Hence. antoantibodies. also.
plays.an.important.role.in.pathogenesis.of.MS.besides.
T-cells...In.addition,.activated.macrophages.are.important.
effector. of. inflammatory. demyelination. . by. producing.
pro-inflammatory. cytokines. such. as. tumor. necrosis.
factor,. generating. excitatory. amino. acids. and. reactive.
oxygen.and.nitrogen.species.
dIaGNOsIs MS. remains. to. be. a. clinical. diagnosis. supported. by.
investigation. findings.with.exclusion.of.other.diseases.
that. can. mimic. MS.. . Poser’s. criteria. require. recurrent.
clinical. episodes. of. inflammatory. demyelination. to.
enable.diagnosis.of.clinically.definite.MS.(Poser.1983)...
In.view.of.possible.benefits.from.early.use.of.disease-
modifying.agents.such.as.β-interferon,.MRI.criteria.were.
employed.to.facilitate.earlier.diagnosis.of.MS.especially.
for. patients. who. presented. after. a. single. attack. of.
118
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
inflammatory.demyelination,.clinically.isolated.syndrome.
(CIS).. .The.McDonald.criteria.employ.MRI.evidence. to.
show.spatial.and.temporal.dissemination.of.lesions.and.
have.been.proven.useful.for.earlier.diagnosis...No.single.
blood. test. can. confirm. the. diagnosis. of. MS,. but. CSF.
OCB. testing. is. useful. for. MS. diagnosis.. . MRI. of. the.
spinal. cord. in. addition. to.MRI.brain.might. help. in.MS.
diagnosis.
tREatMENtGeneralprinciplesMS.is.a.chronic.disease.which.may.create.tremendous.
adverse.effects.and.stress.to.patients’.work,.quality.of.
life.and.family.members.. .Multidisciplinary.approach. is.
usually. employed. in. patients’. management.. . The.
treatments.of.MS.aim.at.the.following.issues:
•..reduce.relapse.rate
•..prevent.fixed.disability.directly.attributable.to.relapse
•..symptomatic.treatment.of.fixed.neurological.deficits
•..prevent.disability.acquired.through.progression
•..treat.established.progression..
GeneralmeasuresMedications.to.reduce.spasticity,.central.pain.syndrome,.
paresthesia,. fatigue. and. relieve. urinary. symptoms. are.
important.. . Depression. especially. in. the. progressive.
phase. of. disease. needs. careful. attention.. . Sexual.
dysfunction.should.not.be.overlooked.
IMMUNOMOdULatORY tREatMENts1.AcutephaseDuring. attack. of. inflammatory. demyelination,. pulse.
methylprednisolone.(MP).helps.to.hasten.recovery...MP.
at. 0.�. to. 1gm. daily. for. 3-�. days. intravenously. (IV). is.
commonly.employed.. . In. the.Optic.Neuritis.Treatment.
Trial. (ONTT),. pulse. MP. hastened. recovery. of. ON. and.
was. suggested. to. delay. the. development. of. clinically.
definite. MS. in. the. long. term.. . Among. �27. patients.
studied.randomized.placebo.or.corticosteroid.(IV.or.oral),.
at.1.year,. there.was.no.difference. in.visual. function.of.
affected.eye.between.2.groups...At.2.years,.there.was.
significant.increase.in.recurrent.ON.in.oral.corticosteroid.
group.while.there.was.significant.reduction.in.proportion.
of.patients.with.a.second.demyelinating.episode.in.the.
IV. corticosteroid. group.. . At. �. years. there. was. no.
difference...
2.Longtermdisease-modifyingagentsAgents.that.reduce.relapse.rate
BEta-INtERfERONsBeta-interferon. has. been. proven. partially. effective. to.
reduce.relapse.rate.of.RRMS.by.about.30%...Possible.
dose-dependent. effect. exist. as. evidenced. by. PRISMS.
trial,. a. phase. III,. double-blind,. place. controlled. study.
comparing.effects.of.22ug.or.��ug.beta-IFN1a. tiw.SC.
with.placebo.in.RRMS...A.total.�60.RRMS.patients.with.
EDSS. score. 0-�. were. randomized. to. 3. arms.. . The.
primary. outcome. was. relapse. count. over. the. study.
course...At.2.yrs,.the.relapse.count.of.the.placebo.group.
was.2.�6.compared.to.1.82.and.1.73.(32%.reduction.in.
RR).for.the.22ug.and.��ug.groups.respectively.. .There.
was. also. significant. difference. in. the. sustained.
progression.of.disability.and.MRI.outcome...The.time.to.
first. progression. of. disability. (confirmed. after. 3m). for.
the.2�th.percentile.of.patients.11.9.months.for.placebo,.
and.18.�.and.21.3.months.for.the.22ug.and.��ug.groups.
respectively.
. Two.studies.on.the.effects.of.beta-IFN.initiated.after.
first. demyelinating. episode. in. those. with. MRI. brain.
lesions.compatible.with.MS.(Jacobs.et.al...2000,.Comi.
et. al,. 2000).. . Both. studies. showed. that. the. effect. of.
beta-IFN. on. relapse. rates. were. reproduced. and.
treatment. reduced. chance. of. developing. a. second.
attack.over.2-3.yrs.by.2�-��%.There.was..difference.in.
disability. between. the. groups. with. such. a. short.
observation. period;. these. studies. cannot. detect. any.
effect.on.rate.of.transition.to.SPMS.
. Other. agents. that. reduce. relapse. rate. include.1. .
Glatiramer. acetate. is. a. mixture. of. synthetic. peptides.
composed.of.�.amino.acids.. . It.might.act.by. reducing.
antigen.binding.to.T.cell.receptor.and.alter.phenotype.of.
myelin. reactive. autoreactive.T. cells.. . In. a. trial. of. 2�1.
patients,.relapse.rate.was.reduced.by.2�%.2..Azathioprine..
inhibits. lymphocyte. proliferation. by. inhibiting. purine.
synthesis. and. has. marginal. benefit. in. reduction. of.
relapse. rate.. . Mitoxantrone. inhibits. DNA. repair. and.
synthesis.in.dividing.and.non-dividing.cells.by.inhibiting.
DNA.topoisomerase.II...It.was.licensed.in.the.US.for.use.
119
MULTIPLE SCLEROSIS
in. aggressive. relapsing. patients,. including. those. with.
high.relapse.frequency.in.the.progressive.phase.(Goodin.
et. al.,. 2003).. . Agents. that. reduce. disability. after..
acute.attacks.
CORtICOstEROIdsZivadinov. et. al. studied. 90. RRMS. patients. who. were.
randomized. to. corticosteroid. only. during. relapses. OR.
regular.pulsed.CS. (�g.MP.over.�.days.Q�m.for.3.yrs,.
then.Q6m.for.2.yrs)...The.annual.relapse.rate.were.the.
same.among.the.2.groups.but.the.regular.pulsed.corti-
costeroid. patients. had. less. disability,. lower. probability.
of. accumulating. sustained. disability,. lower. T1. lesion.
volume,.less.brain.atrophy.at.�.years...It.was.suggested.
that.regular.pulsed.corticosteroid.did.not.alter.mechanism.
initiating.relapses.in.MS,.but.reduced.consequences.of.
each. relapse. on. axons.. .Agents. that. prevent. disability.
due.to.progression.of.disease.
BEta-INtERfERONsFor. SPMS,. beta-interferon. may. help. to. slow. down.
progression. of. deficits. but. studies. are. controversial...
Anon.studied.718.patients.treated.with.beta-IFN1b...The.
trial. was. stopped. early. as. Rx. delayed. time. by. 9-12.
months.to.reach.a.sustained.increase.in.disability.(by.1.
Kurtzke.point)...Goodkin.et.al...carried.a.larger.study.of.
939.SPMS.patients.and.showed.no.benefit.on.disability,.
but. patients. had. longer. disease. duration. &. fewer.
relapses.in.the.2.years.before.study.during.trial.compared.
to. the. study. by. Anon.. . In. SPECTRIMS,. 618. SPMS.
patients. were. treated. with. beta-IFN1a. for. 3. years,.
results.showed.no.effect.on.disability,.but.again.patients.
were. older. with. longer. disease. duration. and. fewer.
relapses.than.those.of.first.study...Mitoxantrone
An. anthracenedione. which. suppresses.T. and. B. cells,.
induces. apoptosis. in. antigen. presenting. cells,. and.
deactivate. macrophages.. . A. double-blind. randomized.
trial. of. 19�. patients. with. worsening. RRMS. or. SPMS.
treated.with.mitoxantrone.or.placebo.3.monthly.for.2�.
months.showed.that.mitoxantrone.reduced.progression.
of.disability.and.clinical.exacerbation...Serious.potential.
side. effects. include. moderate. to. severe. heart. failure.
when.cumulative.dose.>.1�0mg/m2.and.hence.use. is.
limited. for. maximum. of. 3. years. at. current. dose,. birth.
defects. when. given. in. pregnancy. or. during. time. of.
conception.for.both.male.and.female.partners,.sterility.
which. may. be. permanent,. and. rarely. leukemia.. . It. is.
currently.recommended.for.use.as.induction.therapy.in.
very. active.disease.or. rescue. treatment. if. patients.do.
not.respond.to.beta-IFN.or.glatiramer.acetate...
OthER EMERGING tREatMENts. Natalizumab. is. a. humanized. monoclonal. antibody.
against. α�β1. integrin. (a. family. of. adhesion. molecules.
essential. in. cellular. interactions. of. immune. cells),. also.
called. very. late. antigen. �. (VLA�). VLA�. is. a. glycolipid.
which.is.an.important.mediator.of.cell.adhesion.and.tran-
sendothelial. migration,. and. regulates. activation. . of.
immune.cells.within. inflamed. tissue.. .A.double-blinded.
randomized. trial. of. 213. pts. with. RRMS. or. relapsing.
SPMS. treated. with. 3mg/kg. natalizumab. IV. or. 6mg/kg.
natalizumab. IV. or. placebo. every. 28. days. for. 6. months.
showed.that.treatment.was.associated.with.reduction.in.
number. of. new. enhancing. brain. lesions. over. the. 6.
months. period. and. reduction. in. number. of. clinical.
relapses.. .However,.such.differences.disappeared.upon.
additional.6.months’.follow-up.
. Alemtuzumab.is.humanised.antileucocyte.monoclonal.
antibody. (anti-CD�2),.which. reduces.cerebral. inflamma-
tion.in.SPMS.and.reduce.number.of.relapses.
ROLE Of IVIG IN MsAcuteattacksVisser.et.al.studied.whether.IVIG.combined.with.standard.
IVMP.offer.additional.benefits.to.IVMP.alone.in.recovery.
from.acute.attacks.of.MS...A.total.of.19.clinically.definite.
MS.patients.with.acute.attack.having.an. increase.of. at.
least.1.point.on.the.EDSS.were.randomized.to.the.IVIG-
IVMP.or.IVMP-placebo.arm...Both.groups.improved.one.
point.in.the.EDSS.�.weeks.after.starting.treatments,.also.
there.were.no.difference.in.secondary.outcome.measures.
including.EDSS.at.8.weeks,.time.to.improve.by.at.least.1.
EDSS.points,.difference.in.Scripps.score.and.ambulation.
index...They.concluded.that.IVIG-IVMP.was.not.superior.
to.IVMP.alone.in.treatment.of.moderate.to.severe.acute.
relapses.in.MS.
. Sorenson.et.al...performed.a.larger.study.involving.76.
MS.patients.with.acute.relapse.involving.visual.function,.
120
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
upper.limb.motor.function,.or.gait.with.symptoms.onset.
between.2�.hours.and.1�.days...IVIG.1g/kg.or.placebo.on.
(0.1%. human. albumin). was. administered. 2�. hours.
before. IVMP. 1g. daily. for. 3. days.. . Again. both. arms.
improved.without.difference.regarding.primary.endpoint.
of. the. mean. change. in. the. Z-score. of. the. individually.
chosen.targeted.neurological.deficit.from.baseline.to.12.
weeks.. . Hence. available. evidences. do. not. justify. use..
of. IVIG. as. add-on. therapy. to. IVMP. during. acute..
MS.attacks.
RRMsFazekas.et.al,.studied.1�8.patients.with.RRMS.who.were.
randomized.to.placebo.or.0.1�.–.0.2.g/kg.IVIG.monthly.for.
2.years.. . IVIG.group.had. improvement. in.the.change. in.
the.EDSS.compared.with.placebo.group,.and.benefits.in.
other. measures. including. number. of. relapses,. time.
between. relapses,.and.number.of.patients.with.clinical.
improvements.and.stability...Achiron.et.al...randomized.�0.
RRMS.patients.to.either.IVIG.0.�g/kg.monthly.for.2..years.
or.placebo,.and.noted.benefits.in.terms.of.yearly.relapse.
rate,.relapse-free.time,.and.time.to.first.relapse,.but.no.
difference. in. severity. of. relapse. and. MRI. parameters.
between. the. IVIG. and. placebo. groups.. . A. cross-over.
study.involving.26.patients.who.received.either.placebo.
or. IVIG.2g/kg.monthly. for.6.months. then.crossing.over.
found.reduction.in.relapse.rate.and.enhancing.lesions.on.
monthly.MRI.scans.with.IVIG.but.no.difference.in.other.
MRI.parameters.and.evoked.potentials.. .Most. recently,.
Achiron. et. al.. . randomized. 91. patients. having. the. first.
demyelinating.event.within.6.weeks.of.onset.of.neuro-
logical.symptoms.to.receive.IVIG.2g/kg.loading.or.placebo.
followed.by.boosters.0.�g/kg.once.every.6.weeks.for.one.
year.. . IVIG. treated. patients. had. lower. cumulative.
probability.of.developing.clinically.definite.MS.relative.to.
placebo.(rate.ratio.0.36)...Also.the.IVIG.group.had.reduced.
volume. and. number. of. T2W. lesion. and. volume. of.
enhancing.lesion.(Achiron.et.al.,.200�).
. Lewanska. et. al.. . performed. a. study. on. �9. RRMS.
patients.comparing.IVIG.at.0.2g/kg.and.0.�g/kg.monthly.
for.1.year...Both.dosages.were.associated.with.reduction.
in.relapse.rate.and.slowed.EDSS.progression.relative.to.
placebo. which. were. consistent. with. lower. increase. in.
T2W. lesion. load. changes,. cumulative. number. of..
new. T2W. lesions. and. cumulative. number. of..
enhancing.lesions.
. Achiron.et.al...retrospectively.studied.the.role.of.IVIg.
in.RRMS.patients.during.pregnancy.and.the.postpartum.
period.. . Patients. treated. continuously. with. IVIg. during.
gestation.and.the.postpartum.period.(0.�.g/kg/day.for.�.
days. within. 6-8. weeks. of. gestation. with. additional.
booster.doses.of.0.�.g/kg/day.once.every.6.weeks.until.
12.weeks.postpartum).had.reduced.relapse.rate.during.
pregnancy.and.post-partum.period.compared.to.patients.
without.IVIg.treatment...In.addition,.RRMS.patients.who.
received.IVIg.only.during.the.post-partum.period.(0.�.g/
kg/day.for.�.consecutive.days.within.the.first.week.after.
delivery.with.additional.booster.of. the.same.dose.at.6.
and.12.weeks.postpartum).also.had.a.decreased.relapse.
rate. compared. to. those. without. IVIg. treatment.. .The.
authors.concluded.that.for.RRMS.patients,.IVIg.treatment.
could.be.considered.as.an.optional.treatment.to.reduce.
the. incidence. of. pregnancy. and. postpartum-related.
relapses...
pROGREssIVE MsThe.European.Study.on.Immunoglobulin.in.MS.(ESIMS).
involved. 318. SPMS. patients. who. were. randomized. to.
monthly. IVIG. 1g/kg. or. placebo,. and. showed. that. no.
benefits. of. IVIG. on. the. primary. outcome. measure. of.
confirmed.deterioration.in.EDSS.and.secondary.outcome.
parameters. . including. time. to. EDSS. deterioration,.
relapse.rate,.proportion.of.relapse.free.patients,.change.
in.T2W. lesion. volume,. number. of. enhancing. lesions...
Interestingly. IVIG.therapy.was.associated.with.delayed.
loss. of. total. brain. volume. with. uncertain. significance...
Brain. volume. in. terms. of. a. partial. cerebral. fraction.
decreased. significantly. less. with. IVIG. than. placebo,.
primarily.seen.in.male.patients,.those.with.an.EDSS.of.6.
or.more,.and.patients.without.relapse.in.the.two.years.
before. trial.. . It. was. suggested. that. the. etiology. and.
potential. long-term.clinical. effects.of. this. lower. rate.of.
brain.volume.loss.with.IVIG.should.be.explored.further.
EXpERt CONsENsUsAccording.the.meta-analysis.of.the.largest.trials.of.IVIG.
in. RRMS,. IVIG. was. better. than. placebo. in. terms. of.
yearly. relapse.rate,. relapse-free.patients,.proportion.of.
121
MULTIPLE SCLEROSIS
patients.who.deteriorated.and.change.in.EDSS.score.
. Current. evidence. does. not. suggest. any. benefit. of.
IVIG.as.add-on.treatments.with.intravenous.pulse.corti-
costeroid.for.acute.attacks.of.MS...
. IVIG.may.be.considered.as.an.optional.treatment.to.
reduce. the. incidence. of. pregnancy. and. postpartum-
related.relapses.in.pregnant.RRMS.patients.with.a.high.
risk.of.relapse.
. IVIG. has. not. been. shown. to. confer. benefit. to.
primary.or.secondary.progressive.MS.patients.measured.
by.clinical.and.MRI.parameters.
REfERENCEsAchiron.A,.Gabbay.U,.Gilad.R,.et.al..Intravenous.immu-
noglobulin. treatment. in. multiple. sclerosis.. Effect. on.
relapses..Neurology.1998;�0:398-�02..
Achiron.A,.Kishner.I,.Sarova-Pinhas.I,.et.al..Intravenous.
immunoglobulin.treatment.following.the.first.demyelin-
ating.event.suggestive.of.multiple.sclerosis..Arch.Neurol.
200�;61:1�1�-1�20.
Achiron.A,.Kishner.I,.Dolev.M,.et.al..Effect.of.intravenous.
immunoglobulin. treatment. on. pregnancy. and.
postpartum-related. relapses. in. multiple. sclerosis.. J.
Neurol.200�;2�1:1133-1137.
Beck. RW,. Cleary. PA,. Anderson. MM. Jr,. et. al.. A.
randomized,. controlled. trial. of. corticosteroids. in. the.
treatment. of. acute. optic. neuritis.. N. Eng. J. Med.
1992;326:�81-�88.
Comi. G,. Filippi. M,. Barkhof. F,. et. al.. Interferon. beta. 1a.
(Rebif). in. patients. with. acute. neurological. syndromes.
suggestive. of. multiple. sclerosis:. a. multi-center,.
randomized,. double-blinded,. placebo-controlled. study..
Neurology.2000;��:Suppl.3:A8�-86.
Compston. A,. Coles. A.. Multiple. sclerosis.Lancet.
2002;3�9:1221-1231.
Challoner.PB,.Smith.KT,.Parker.JD,.et.al..Subacute.leu-
koencephalitis. caused. by. CNS. infection. of. human.
herpesvirus.6.in.multiple.sclerosis..Proc.Natl.Acad.Sci.U.
S.A.199�;92:7��0-7���.
Dean.G..Annual.incidence,.prevalence,.and.mortality.of.
multiple. sclerosis. in. white. South-African. born. and. in.
white.immigrants.to.South.Africa..BMJ.
Fazekas. F,. Deisenhammer. F,. Strasser-Fuchs. S,. et. al..
Randomized. placebo-controlled. trial. of. monthly.
intravenous. immunoglobulin. therapy. in. relapsing-
remitting.multiple.sclerosis..Austrian.Immunoglobulin.in.
Multiple. Sclerosis. Study. Group.. Lancet. 1997;3�9:�89-
�93.
European. Study. Group. on. Interferon. Beta-1b. in.
Secondary. Progressive. MS.. Placebo-controlled.
multicenter. randomized. trial. of. interferon. beta-1b. in.
treatment.of.secondary.progressive.multiple.sclerosis..
Lancet.1998;3�2:1�91-1�97.
Fazekas. F,. Sorenson. PS,. Filippi. M,. et. al.. MRI. results.
from.the.European.study.on.intravenous.immunoglobu-
lin.in.secondary.progressive.multiple.sclerosis.(ESIMS)..
Mult.Scler.200�;11(�):�33-��0.
Goodin. DS,. Frohman. EM,. Garmany. GP,. et. al.. Disease.
modifying.therapies.in.multiple.sclerosis..Report.of.the.
Therapeutics.and.Technology.Assessment.Subcommittee.
of. the. American. Academy. of. Neurology. and. the. MS.
Council. for. Clinical. Practice. Guidelines.. Neurology.
2002;�8:169-178.
Goodin. DS,. Arnason. BG,. Coyle. PK,. et. al..The. use. of.
mitoxantrone.(Novantrone).for.the.treatment.of.multiple.
sclerosis:. report. of. the. Therapeutics. and. Technology.
Assessment.Subcommittee.of. the.American.Academy.
of.Neurology..Neurology.2003;61:1332-1338.
122
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
Hommes.OR,.Sorenson.PS,.Fazekas.F,.et.al..Intravenous.
immunoglobulin. in. secondary. progressive. multiple.
sclerosis:. randomized. placebo-controlled. trial.. Lancet.
200�;36�:11�9-11�6.
Jacobs.LD,.Cookfair.DL,.Rudick.RA,.et.al..Intramuscular.
interferon.beta-1a. for. disease.progression. in. relapsing.
multiple.sclerosis..Ann.Neurol.1996;39:28�-29�.
Jacobs. LD,. Beck. RW,. Simon. JH,. et. al.. Intramuscular.
interferon. beta-1a. therapy. during. a. first. demyelinating.
event. in. multiple. sclerosis.. CHAMPS. Study. Group.. N.
Eng.J.Med.2000;3�3:898-90�.
Jersild. C,. Fog.T,. Hansen. GS,. et. al.. Histocompatibility.
determinants.in.multiple.sclerosis,.with.special.reference.
to.clinical.course..Lancet.1973;2:123�-1237..
Kappos. L,. Polman. C,. Pozzilli. C,. et. al.. The. European.
Study.Group.in.Interferon.b-1b.in.Secondary.Progressive.
MS..Final.analysis.of.the.European.multicenter.trial.on.
IFN. 1b. in. secondary. progressive. MS.. Neurology.
2001;�7:1969-197�.
Keegan. M,. Pineda. AA,. McClelland. RL,. Darby. CH,.
Rodriguez. M,. Weinshenker. BG.. Plasma. exchange. for.
severe. attacks. of. CNS. demyelination:. predictors. of.
response..Neurology.2002;�8:1�3-6.
Keegan. M,. Konig. F,. Bitsch. A,. et. al.. Multiple. sclerosis.
pathological. subtype. predicts. response. to. therapeutic.
plasma.exchange..Neurology.200�(Suppl.�):A2�9.
Lassmann. H.. Axonal. injury. in. multiple. sclerosis.. J.
Neurol.Neurosurg.Psychiatry.2003;7�:69�-697.
Lewanska.M,.Siger-Zajdel.M,.Selmaj.K..No.difference.in.
efficacy.of.two.different.doses.of.intravenous.immuno-
globulins. in. MS:. clinical. and. MRI. assessment.. Eur. J.
Neurol.2002;9:�6�-�72.
Lucchinetti.CF,.Bruck.W,.Parisi.J,.et.al..Heterogeneity.of.
multiple.sclerosis.lesions:.implications.for.the.pathogen-
esis.of.demyelination..Ann.Neurol.2000;�7:707-717.
McDonald..WI,.Compston.A,.Edan.G,.et.al..Recommended.
diagnostic.criteria.for.multiple.sclerosis:.guidelines.from.
the. international. panel. on. the. diagnosis. of. multiple.
sclerosis.(2001)..Ann.Neurol.�0:121-127..
North. American. Study. Group. on. Interferon. beta-1b. in.
Secondary. Progressive. MS.. Interferon. beta-1b. in.
secondary. progressive. MS:. results. from. a. 3-year.
controlled.study..Neurology.200�;63:1788-179�
Noseworthy. JH,. Lucchinetti. CF,. Rodriguez. M,.
Weinshenker. BG.. Mutliple. sclerosis.. N. Eng. J. Med.
2000;3�3:938-9�2.
Poser.CM,.Paty.DW,.Scheinberg.L,.et.al..New.diagnostic.
criteria. for. multiple. sclerosis:. guidelines. for. research.
protocols.(1983)..Ann.Neurol.133:227-31.
Piddlesden.SJ,.Lassmann.H,.Zimprich.F,.et.al..The.demy-
elinating.potential.of.antibodies. to.myelin.oligodendro-
cyte. glycoprotein. is. related. to. their. ability. to. fix.
complement..Am.J.Pathol.1993;1�3:���-�6�.
Prevention.of.Relapses.and.Disability.by.Interferon.beta.
-1a. Subcutaneously. in. Multiple. Sclerosis. (PRISMS).
Study. Group.. Randomized. double-blind. placebo-
controlled. study. of. interferon. beta-1a. in. relapsing/
remitting. multiple. sclerosis.. Lancet. 1998;3�2:1�98-
1�0�.
.
Rieckmann. P,. Toyka. KV,. Bassetti. C,. et. al.. Multiple.
Sclerosis.Therapy.Consensus.Group..Escalating. immu-
notherapy. of. multiple. sclerosis. –. new. aspects. and.
practical.application..J.Neurol.200�;2�1:1329-1339.
123
Secondary. Progressive. Efficacy. Clinical. Trial. of.
Recombinant. Interferon-beta-1a. in. MS. (SPECTRIMS).
Study.Group..Randomized. controlled. trial. of. interferon.
beta-1a. in. secondary. progressive. MS:. clinical. results..
Neurology.2001;�6:1�96-1�0�.
Siriam. S,. Stratton. CW,. Yao. SY,. et. al.. Chlamydia.
pneumoniae.infection.of.the.central.nervous.system.in.
multiple.sclerosis..Ann.Neurol.1999;�6:6-1�.
Sorenson.PS,.Wanscher.B,.Jensen.CV,.et.al..Intravenous.
immunoglobulin. G. reduces. MRI. activity. in. relapsing.
multiple.sclerosis..Neurology.1998;�0:1273-1281.
Steinman.L..Multiple.sclerosis:.a.coordinated.immuno-
logical. attack. against. myelin. in. the. central. nervous.
system..Cell.1996;8�:299-302.
Storch. MK,. Piddlesden. S,. Haltia. M,. et. al.. Multiple.
sclerosis:.in.situ.evidence.for.antibody-.and.complement-
mediated.demyelination..Ann.Neurol.1998;�3:�6�-�71.
Trapp. BD,. Peterson. J,. Ransohoff. RM,. et. al.. Axonal.
transaction. in.the. lesion.of.multiple.sclerosis..N.Eng.J.
Med.1998;338:278-28�.
The. IFNB. Multiple. Sclerosis. Study. Group.. Interferon.
beta-1b. is. effective. in. relapsing-remitting. multiple.
sclerosis..I..Clinical.results.of.a.multicenter,.randomized,.
double-blind,. placebo-controlled. trial.. Neurology.
1993;�3:6��-661.
Weinshenker. BG,. Bass. B,. Rice. GP,. et. al..The. natural.
history. of. multiple. sclerosis:. a. geographically. based.
study..I..Clinical.course.and.disability..Brain.1989;112:133-
�6.
Weinshenker.BG,.O’Brien.PC,.Patterson.TM,.Noseworthy.
JH,.Lucchinetti.CF,.Dodick.D,.et.al..A.randomized.trial.of.
plasma. exchange. in. acute. central. nervous. system.
inflammatory.disease..Ann.Neurol.1999;�6(6):878-86.
MULTIPLE SCLEROSIS
12�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
NEUROMYELITIS OPTICAINtROdUCtIONNeuromyelitis. optica. (NMO). is. an. idiopathic. inflamma-
tory.demyelinating.disorder.characterized.by.monophasic.
or. relapsing. attacks. of. optic. neuritis. (ON). and. acute.
transverse. myelitis. (ATM). (Wingerchuk. et. al.,. 2007)...
Acute. partial. transverse. myelitis. (APTM). affecting. part.
of. cross. section. of. spinal. cord. within. one. vertebral.
segment.longitudinally.associated.with.good.recovery.is.
the. typical. spinal. involvement. in. classical.MS. (Kidd.et.
al.,.1993;.Bakshi.et.al.,.1998).
. OSMS.is.more.common. in.Asians. (Yu.et.al.,.1989;.
Kira. 2003),. and. at. least. some. of. these. patients. are.
actually. suffering. from. NMO. (Lennon. et. al.,. 200�;.
Wingerchuk. et. al.,. 2007;. Matsuoka. et. al.,. 2007)...
Immunogenetic. factors. might. explain. this. ethnic.
difference.in.susceptibility.to.develop.OSMS...Classical.
MS. is. associated. with. HLA-DRB1*1�01. allele. while.
OSMS. is. associated. with. HLA-DPB1*0�01. allele.
(Yanmasaki.et.al.,.1999)...Similarly,.Canadian.aboriginals.
had.an.aggressive.form.of.MS.with.frequent.optic.nerve.
and.spinal.cord.involvement.compatible.with.OSMS.or.
NMO.which.did.not.respond.to.conventional. therapies.
for.classical.MS,.and.they.did.not.possess.HLA.alleles.
known.to.be.associated.with.classical.MS.(Mirsattari.et.
al.,.2001)...Recently,.it.was.reported.that.IIDD.patients.
with. fulminant. attacks. were. clinically. and. immunoge-
netically.distinct. from.those.without. fulminant.attacks,.
and.features.of.OSMS.or.NMO.were.mostly.shared.by.
patients. with. fulminant. attacks.. .The. GG. homozygous.
and. G. alleles. of. the. CTLA�. gene. A/G. coding. single.
nucleotide.polymorphism.at.position.�9.in.exon.1.were.
significantly. more. common. in. patients. with. fulminant.
attacks.than.those.without.(Fukazawa.et.al.,.200�).
CLINICaL fEatUREsTypical.ATM.in.NMO.is.severe.causing.profound.sensory.
and.motor.deficits.affecting.whole.cross.section.of.spinal.
cord.associated.with.cord.swelling.and.subsequent.cord.
atrophy,. though. mild. cases. were. noted. as. well.
(Wingerchuk.et.al.,.1999)...Weinshenker.considered.the.
most. . characteristic. finding. in. NMO. was. central-
enhancing,. longitudinally. extensive. signal. abnormality.
over.3.or.more.vertebral.segments.on.MRI.in.the.setting.
of.acute.myelitis.(Weinshenker.2003)...Recent.evidence.
suggests.that.classical.MS.and.NMO.are.distinct.entities.
with. different. immunopathogenetic. mechanisms. (de.
Seze.et.al.,.2003;.Lennon.et.al.,.200�;.Correate.and.Fiol,.
200�)...In.comparison.to.classical.MS,.NMO.patients.are.
predominantly. female. with. older. onset. age,. and.
associated. with. lower. frequency. of. cerebrospinal. fluid.
12�
NEUROMYELITIS OPTICA
(CSF). oligoclonal. bands. (OCB). and. worse. neurological.
prognosis.(de.Seze.et.al.,.2003;.Ghezzi.et.al.,.200�).
pathOLOGY aNd pathOGENEsIs Pathologically. NMO. is. characterized. by. presence. of.
necrosis.of.grey.and.white.matter,.perivascular.immuno-
globulin.deposition.and.marked.complement.activation,.
vascular.proliferation.and.hyalinization,.eosinophilic.and.
neutrophilic.infiltration.(Lucchinetti.et.al.,.2002)...Humoral.
immunity. probably. played. an. important. role. in. the.
pathogenesis.of.NMO.(Lucchinetti.et.al.,.2002;.Lennon.
et. al.,. 200�;. Correate. and. Fiol,. 200�).. . Lennon. and.
colleagues.discovered.an.IgG.autoantibody.that.specifi-
cally.bound.to.an.autoantigen.in.or.near.the.blood-brain.
barrier. in. microvessels,. pia,. subpia. and.Virchow-Robin.
space.of.the.CNS.in.sera.of..73%.patients.with.definite.
NMO. or. high. risk. for. NMO,. but. not. in. classical. MS.
(Lennon. et. al.,. 200�).. .The.prominent. immunoglobulin.
deposition.and.complement.activation.in.a.unique.peri-
vascular. pattern. observed. in. affected. tissues. of. NMO.
patients. supported. the. hypothesis. that. this. NMO-IgG.
was.directly.involved.its.pathogenesis.
. Interestingly,. this. NMO-IgG. were. also. detected. in.
�8%.of.Japanese.opticospinal.multiple.sclerosis.(OSMS).
patients,. supporting. the. view. that. OSMS. in. Asians.
might.be.the.same.as.NMO.in.Causacians. (Lennon.et.
al.,.200�)...In.addition,.sixteen.(��.7%).of.3�.patients.at.
high. risk. for. NMO,. including. those. with. one. attack. of.
ATM.extending.over.3.or.more.vertebral.segments.lon-
gitudinally. or. recurrent. optic. neuritis. without. myelitis,.
were. seropositive. for. the. NMO-IgG. (Lennon. et. al.,.
200�).. .Together.with.patients.with.recurrent. longitudi-
nally.extensive.transverse.myelitis.(LETM).without.optic.
neuritis,these.patients.are.likely.having.restricted.forms.
of.NMO.(Lennon.et.al.,.200�;.Chan.et.al.,.200�),.which.
also. belong. to. the. spectrum. of. NMO. disorders.
(Wingerchuk.et.al.,.2007)...
. The. autoantigen. targeted. by. this. NMO-IgG. is.
identified.to.be.the.aquaporin-�.water.channel.(Lennon.
et.al.,.200�),.which.is.the.most.abundant.water.channel.
in. the. CNS. and. is. expressed. by. astrocytes. predomi-
nantly. at. the. astrocytic. foot. processes.. . AQP�. plays.
important.role.in.water.homeostasis.between.the.blood.
and. the.brain,. and.between.brain. and. the.CSF.. .Most.
recently.Hinson.and.colleagues.showed.that.serum.IgG.
from. NMO. patients. bind. to. extracellular. domain. of.
AQP�. expressed. on. surface. membrane. of. HEK. cells.
transfected. with. AQP�. fused. with. green. fluorescent.
protein. (GFP),. induce. endocytosis. and. degradation. of.
AQP�,.and.initiate.complement.activation...The.authors.
proposed.that.IgG.targeting.astrocytic.processes.around.
nodes. of. Ranvier. could. initiate. demyelination.. .These.
support.that.AQP�.autoantibody.is.directly.pathogenic.in.
NMO.by. initiating. inflammatory.demyelination. (Hinson.
et.al...2007)...
tREatMENtAcute. attack. of. ATM. or. ON. should. be. treated. with.
intravenous. pulse. methylprednisolone. (Wingerchuk. et.
al.,.2007)...Vigorous.plasmapheresis.should.be.performed.
if. recovery.from.severe.attacks.of. inflammatory.demy-
elination. after. pulse. steroid. was. unsatisfactory.
(Weinshenker.et.al.,.1999;.Keegan.et.al.,.2002).. .Early.
plasmapheresis.is.recommended.especially.for.patients.
with.severe.cervical.myelitis.at.risk.of.respiratory.insuf-
ficiency.(Wingerchuk.et.al.,.2007)...
. Maintenance. immunosuppressive. therapy. is.
recommended.for.reducing.relapse.frequency.in.NMO...
Systemic. corticosteroids. in. combination. with. azathio-
prine.were. reported.effective. in.NMO. (Mandler.et. al.,.
1998).while.disease.modifying.agents.for.classical.MS.
does. not. seem. to. be. effective. (Wenshenker. and.
Wingerchuk,. 200�).. . Cree. and. colleagues. studied. 8.
patients.with.worsening.NMO.treated.with.rituximab.to.
achieve.B.cell.depletion...Six.of.the.eight.patients.were.
relapse. free.and. the.median.attack. rate.declined. from.
2.6.attacks/patient/year.to.0.attacks/patient/year...Seven.
of. eight. patients. experienced. substantial. recovery. of.
neurologic. function. over. 1. year. of. average. follow-up.
with.pretreatment.median.EDSS.score.being.7.�,.and.at.
follow-up. examination. �.�. (Cree. et. al.,. 200�)...
Mitoxantrone. (Weinstock-Guttmann. et. al.,. 2006). and.
mycophenolate. mofetil. (Falcini. et. al.,. 2006). have. also.
been.reported.efficacious.in.inducing.clinical.remission.
in.NMO.patients.who.do.not.respond.to.other.immuno-
suppressants.therapy.
126
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
RoLEofIVIGINNMoThere. is.no. randomized.controlled. trials.on.efficacy.of.
IVIG. in. NMO.. . Case. reports. suggested. that. monthly.
intravenous.immunoglobulin.might.also.be.efficacious.in.
preventing.relapses.and.promoting.neurological.recovery.
in. NMO.. . Bakker. and. Metz. reported. 2. NMO. patients.
who.responded.to.IVIG...A.�2-year-old.woman.with.a.23.
year.history.of.NMO.which.was.actively. relapsing.and.
unresponsive. to. daily. corticosteroid. and. azathioprine.
was.given.monthly.IVIG.for.�.�.years,.during.which.time.
she.had.no.relapse...Another.�8-year-old.woman.with.3.
year. history. of.NMO.had.�. attacks. during. the. first. 16.
months. of. disease.. . IVIG. was. given. monthly. and. she.
had.complete.cessation.of.relapses.and.significant.neu-
rological. improvement. over. 1. year. of. IVIG. therapy.
(Bakker. and. Metz,. 200�).. . Okada. and. colleagues.
reported..that. intermittent.IVIG.successfully.prevented.
relapses.of.NMO. in. a.�0-year-old.woman.seropositive.
for.AQP�.autoantibody.who.continued.to.relapse.despite.
beta-interferon. . and.azathioprine.. .She.had.no. relapse.
for.more.than.�.years.after.initiation.of.monthly.IVIG.(0.�.
g/kg/day.for.one.day).(Okada.et.al.,.2007).
EXpERt CONsENsUsWithout. large. scale. randomized. controlled. trials,. the.
efficacy. of. IVIG. in. NMO. is. uncertain.. . Anecdotal.
evidence. from. case. reports. suggested. that. in. some.
NMO.patients.unresponsive. to. corticosteroid. and.aza-
thioprine,. IVIG.might. reduce.relapse.rate.and.promote.
neurological.recovery.
REfERENCEs1.. .Bakker. J,. Metz. L.. . Devic’s. neuromyelitis. optica.
treated. with. intravenous. gamma. globulin. (IVIG)...
Can.J.Neurol.Sci.200�;31(2):26�-7.
2.. .Bakshi.R,.Kinkel.PR,.Mechtler.LL,.Bates.VE,.Lindsay.
BD,.Esposito.SE,.et.al...Magnetic.resonance.imaging.
findings.in.22.cases.of.myelitis:.comparison.between.
patients.with.and.without.multiple.sclerosis...Eur.J.
Neurol.1998;�:3�-�8.
3.. .Berman.M,.Feldman.S,.Alter.M,.Zilber.N,.Kahana.E...
Acute. transverse. myelitis:. incidence. and. etiologic.
considerations...Neurology.1981;31:966-71.
�.. .Chan. KH,.Tsang. KL,. Fong. GCY,. et. al.. . Idiopathic.
severe. recurrent. transverse. myelitis:. a. restricted.
variant.of.neuromyelitis.optica...Clin.Neuro.Neurosurg.
200�;107(2):132-�.
�.. .Cordonnier. D,. de. Seze. J,. Breteau. G,. Ferriby. D,.
Michelin. E,. Stojkovic. T,. Pruvo. JP,. Vermersch. P...
Prospective.study.of.patients.presenting.with.acute.
partial. transverse. myelopathy.. . J. Neurol.
2003;1�0(12):1��7-�2.
6.. .Cree.BA,.Lamb.S,.Morgan.K,.et.al.. .An.open. label.
study. of. the. effects. of. rituximab. in. neuromyelitis.
optica...Neurology.200�;12:6�(7):1270-1272.
7.. .Jorge.Correate,.Marcela.Fiol...Activation.of.humoral.
immunity. and. eosinophils. in. neuromyelitis. optica...
Neurology.200�;63:2263-70.
8.. .de.Seze.J,.Lebrun.C,.Stoikovic.T,.Ferriby.D,.Chatel.M,.
Vermersch. P.. . Is. Devic’s. neuromyelitis. optica. a.
separate.disease?.A.comparative.study.with.multiple.
sclerosis...Mult.Scler.2003;9:�21-2�.
9.. .Falcini. F,. Trapani. S,. Ricci. L,. et. al.. . Sustained.
improvement.of.a.girl.affected.with.Devic’s.disease.
over. 2. years. of. mycophenolate. mofetil. treatment...
Rheumatology.2006;��:913-91�.
10...Fukazawa.T,.Kikuchi.S,.Niino.M,.Yabe.I,.Miyagishi.R,.
Fukaura.H,.Hamada.T,.Tashiro.K,.Sasaki.H.. .Attack-
related. severity:. a. key. factor. in. understanding. the.
spectrum.of. idiopathic. inflammatory.demyelinating.
disorders...J.Neurol.Sci.200�;22�(1-2):71-8.
11.. .Ghezzi. A,. Bergamaschi. R,. Martinelli. V,.Trojano. M,.
Tola. MR,. Merelli. E,. Mancardi. L,. Gallo. P,. Filippi. M,.
Zaffaroni.M,.Comi.G...Clinical.characteristics,.course.
and. prognosis. of. relapsing. Devic’s. Neuromyelitis.
Optica...J.Neurol.200�;2�1(1):�7-�2.
127
NEUROMYELITIS OPTICA
12...Hinson. SR,. Pittock. SJ,. Lucchinetti. CF,. Roemer. SF,.
Fryer.JP,.Kryzer.TJ,.Lennon.VA...Pathogenic.potential.
of.IgG.binding.to.water.channel.extracellular.domain.
in.neuromyelitis.optica...Neurology.2007;69:1-11.
13...Jeffery. DR,. Mandler. RN,. Davis. LE.. . Transverse.
myelitis:.retrospective.analysis.of.33.cases,.with.dif-
ferentiation. of. cases. associated. with. multiple.
sclerosis. and. parainfectious. events.. . Arch. Neurol.
1993;�0:�32-3�.
1�...Jun-ichi. Kira.. . Multiple. sclerosis. in. the. Japanese.
population...Lancet.Neurology.2003;2:117-27.
1�...Okada.K,.Tsuji.S,.Tanaka.K...Intermittent.intravenous.
immunoglobulin. successfully. prevent. relapses. of.
neuromyelitis. optica.. . Intern. Med. 2007;�6:1671-
1672.
16...Keegan. M,. Pineda. AA,. McClelland. RL,. Darby. CH,.
Rodriguez. M,.Weinshenker. BG.. . Plasma. exchange.
for.severe.attacks.of.CNS.demyelination:.predictors.
of.response...Neurology.2002;�8:1�3-6.
17.. .Kidd. D,.Thorpe. JWm.Thompson. AJ,. et. al.. . Spinal.
cord.MRI.using.multi-array.coils.and.fast.spin.echo.
II.. . Findings. in. multiple. sclerosis.. . Neurology.
1993;�3:2632-7.
18...Lennon.VA,.Wingerchuk.DM,.Kryzer.TJ,.Pittock.SJ,.
Lucchinetti. CF,. Kazuo. Fujihara,. Ichiro. Nakashima,.
Weinshenker.BG...A.serum.autoantibody.marker.of.
neuromyelitis. optica:. distinction. from. multiple.
sclerosis...Lancet.200�;36�:2106-12..
19...Lucchinetti.CF,.Mandler.RN,.McGavern.D,.et.al.. .A.
role.for.humoral.mechanisms.in.the.pathogenesis.of.
Devic’s. neuromyelitis. optica.. . Brain. 2002;12�:.
1��0-61.
20...Mandler.RN,.Ahmed.N,.Dencoff.JE...Devic’s.neuro-
myelitis.optica:.a.prospective.study.of.seven.patients.
treated. with. prednisolone. and. azathioprine...
Neurology.1998;�1:1219-20.
21.. .McDonald. WI,. Compston. A,. Edan. G,. et. al...
Recommended. diagnostic. criteria. for. multiple.
sclerosis:.guidelines.from.the.international.panel.on.
the. diagnosis. of. multiple. sclerosis.. . Ann. Neurol.
2001;�0:121-127..
22...Mirsattari.SM,.Johnston.JB,.McKenna.R,.Del.Bigio.
MR,. Orr. P,. Ross. RT,. Power. C.. . Aboriginals. with.
multiple.sclerosis:.HLA.types.and.predominance.of.
neuromyelitis.optica...Neurology.2001;�6:317-23.
23...Misra. UK,. Kalita. J,. Kumar. S.. . A. clinical,. MRI. and.
neurophysiological. study. of. acute. transverse.
myelitis...J.Neurol.Sci.1996;138:1�0-6.
2�...Misu.T,.Fujihara.K,.Nakashima.I,.et.al...Pure.optico-
spinal. form. of. multiple. sclerosis. in. Japan.. . Brain.
2002;12�:2�60-68.
2�...Poser. CM,. Paty. DW,. Scheinberg. L,. et. al.. . New.
diagnostic. criteria. for.multiple. sclerosis:. guidelines.
for. research. protocols.. . Ann. Neurol. 1983;133:227-
31.
26...Matsuoka.T,.Matsushita.T,.Kawano.Y,.Osoegawa.M,.
Ochi.H,.et.al...Heterogeneity.of.aquaporin-�.autoim-
munity.and.spinal.cord.lesions.in.multiple.sclerosis.
in.Japanese...Brain.2007;130:1206-1223.
27.. .Transverse. myelitis. consortium. working. group...
Proposed.diagnostic.criteria.and.nosology.of.acute.
transverse.myelitis...Neurology.2002;�9(�):�99-�0�.
28...Tippet. DS,. Fishman. PS,. Panitch. HS.. . Relapsing.
transverse.myelitis...Neurology.1991;�1:703-6.
29...Weinshenker. BG,. O’Brien. PC,. Patterson. TM,.
Noseworthy.JH,.Lucchinetti.CF,.Dodick.D,.et.al.. .A.
randomized.trial.of.plasma.exchange.in.acute.central.
nervous.system.inflammatory.disease...Ann.Neurol.
1999;�6(6):878-86.
128
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
30...Weinshenker. BG.. . Neuromyelitis. optica:. what. is. it.
and.what.it.might.be...Lancet.2003;361:889-90.
31.. .Weinstock-Guttmann.B,.Ramanathan.M,.Lincoff.N,.
et. al.. . Study. of. mitoxantrone. for. the. treatment. of.
recurrent.neuromyelitis.optica.(Devic.disease)...Arch.
Neurol.2006;63:9�7-963.
32...Wingerchuk. DM,. Hogancamp. WF,. O’Brien. PC,.
Weinshenker.BG...The.clinical.course.of.neuromyeli-
tis. optica. (Devic’s. syndrome).. . Neurology.
1999;�3:1107-1�.
33...Wingerchuk.DM,.Lennon.VA,.Lucchinetti.CF,.Pittock.
SJ,.Weinshenker.BG...The.spectrum.of.neuromyeli-
tis.optica...Lancet.Neurol.2007;6:80�-81�.
3�...Yamasaki. K,. Horiuchi. I,. Minohara. M,. Kawano. Y,.
Ohyagi.Y,.Yamada.T,.Mihara.F,.Ito.H,.Nishimura.Y,.Kira.
J.. . HLA-DPB1*0�01-associated. with. opticospinal.
multiple.sclerosis:.clinical,.neuroimaging.and.immu-
nogenetic.studies...Brain.1999;122:1689-96.
3�...Yu.YL,. Hawkins. BR,. Ho. HC,. Huang. CY.. . Multiple.
sclerosis. among. Chinese. in. Hong. Kong.. . Brain.
1989;112:1���-67.
129
APPENDICESappENdIX aTerms. of. reference. and. membership. of. the..Scientific.Committee..
tERMSofREfERENCEThe.Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.Board.was.launched.at.the.�th.International.Symposium.on.IVIg.conference.in.September.2003.. The. Advisory. Board. is. an. autonomous. body. of.neurologists.drawn.from.across.the.Asia.Pacific.region...There. are. 11. members. who. are. experts. in. their. field;.they. represent. Australia,. New. Zealand,. Hong. Kong,.Singapore,.Thailand,.India,.Taiwan,.Malaysia.and.the.UK...The. membership. of. this. board. represents. around. half.the.world’s.population.. The.charter.of.the.Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.Board.includes.the.development.of.expert. consensus. statements,. using. evidence. based.medicine. approach. for. the. use. of. IVIg. in. neurological.practice,.the.development.of.an.educational.program.for.the.Asia.Pacific.region.and.the.creation.of.an.Asia.Pacific.IVIg.conference.
appENdIX BIn. the. production. of. the. first. edition,. relevant. articles.were.summarized.by.the.Advisory.Board.over.a.two.day.meeting.in.Singapore.in.December.2003...A.decision.on.
the. format. of. the. statements. was. decided. at. that.meeting...The.decision.was.to.provide.a.background.on.the.relevant.disorder,.with.a.summary.of.the.diagnostic.process.and.differential.diagnosis...The.statement.was.to.include.a.review.of.the.literature.for.all.treatments.and.a.detailed.review.of.IVIg.in.the.relevant.condition...Members.of. the. Asia. Pacific. . Immunoglobulins. in. Neurology.Advisory.Board.were.assigned.topics.for.review.. The.statements.were.prepared.by.Board.Members.and.circulated.for.comment.to.all.members.of.the.Board...Comments.were.received.and.revisions.of.the.statements.then.proceeded...A.teleconference.in.February.200�.and.then.a.formal.meeting.in.June.200�.were.scheduled...At.the.June.200�.meeting,.the.statements.were.reviewed.in.an.open.forum.and.revisions.were.made.. .An.expert.consensus. statement. was. then. formulated. for. each.review.. .The.consensus.statements.were.circulated. for.comment.again.and.a.final.teleconference.in.late.October.200�.ratified.the.statements. In. the. production. of. the. second. edition,. Board.Members. updated. their. respective. topics. based. on.extensive. reviews. of. relevant. literature. published. from.200�.to.2007..These.revisions.were.discussed.at.a.two.-day. meeting. in. Singapore. in. 2007.. Additional. contents.were.discussed.at.a.follow.up.meeting.in.Hong.Kong.in.August. 2007.. Final. adjustments. to. the. text. of. each.chapter. were. incorporated. in. October. 2008,. prior..to.publication.
APPENDICES
130
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
appENdIX CLiterature.Review.on.the.use.of.IVIg.in.NeurologySearch.Strategy.and.Results. Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.Board. members. of. INDAPS. undertook. the. literature.review.on.which.the.Consensus.Statements.are.based.
2.1SEARCHStRAtEGyThe. OVID. interface. was. used. to. search. the. following.electronic.databases:
◊.PREMEDLINE.◊.MEDLINE.–1966-2003.and.2003.-.Oct.2008◊.Cochrane.Database◊.Review.of.article.citations.and.Cochrane.Reviews... for.relevant.additional.citations
•.EMBASE-1993-2003.and.2003.-.Oct.2008•.Elsevier.Science.B.V,.2003.and.2008
2.2SEARCHtERMSOver.�0016.abstracts.obtained.with.search.terms..Terms.used.to.identify.relevant.citations.included:Immunoglobulins.-.IntravenousImmunoglobulinImmunoglobulin.-.Drug.AdministrationImmunoglobulin.-.Adverse.Drug.ReactionImmunoglobulin.-.Clinical.Trial.Immunoglobulin.-.Drug.DoseImmunoglobulin.-.Intravenous.Drug.AdministrationDemyeliating.Autoimmune.Diseases,.CNS.or.Dymelinating.DiseaseLambert.Eaton.Myasthenic.Syndrome.or.Eaton.Lambert.SyndromeLeukoencephalitis,.Acute.Haemmorrhagic.or.Eaton.Lambert.SyndromeLeukoencephalitis,.Acute.Haemorrhagic.or.EncephalomyelitisMyasthenia.Gravis.PolyradiculoneuropathyStiff-Person.SyndromeStiff.Man.SyndromeBrain.DiseaseBrain.DiseasesCentral.Nervous.System.InfectionsCentral.Nervous.InfectionEncephalomyelitis
Spinal.Cord.DiseasesSpinal.Cord.DiseaseParaneoplastic.SyndromesNervous.SystemParaneoplastic.SyndromeFatigue.SyndromeChronic.Chronic.Fatigue.SyndromeMotor.Neurone.DiseaseNeuromuscular.Junction.DiseaseNeuromuscular.Junction.DisorderPeripheral.Nervous.System.DiseasePeripheral.NeuropathyIsaacs.SyndromeMyokymiaVasculitisCentral.Nervous.SystemBrain.Vasculitis.Uveomeningoencephalitic.SyndromeMeningoencephalitisAutoimmune.DiseaseImmunoglobulins
2.3SEARCHfINDINGSCitations.were.screened.and.selected.using.the.process.outlined.in.Appendix.C...The.search.retrieved.over.�0016.citations. of. which. in. excess. of. . 900. citations. were.utilised.to.perform.the.literature.analysis.
131
a/prof andrew J Kornberg (Chair)Director.of.Neurology.Royal.Children’s.Hospital.Flemington.Road.Parkville.Victoria,.Australia.30�2
prof Marinos C dalakas, M.d. Chair,.Clinical.Neuroscience..Neurouomuscular.DiseasesImperial.College.London,.U.K
dr Woon Chee YeeConsultant.NeurologistNational.Neuroscience.InstituteSingapore
prof Edward ByrneExecutive.Dean.Faculty.of.Biomedical.SciencesUniversity.CollegeLondon,.U.K..
a/prof Ching-piao tsaiPresident,.Taiwan.Neurological.Society,.Neurological.InstituteNational.Yang-Ming.University.and.Taipei.Veterans.General.Hospital.Taipei.Taiwan
dr Koon ho ChanSpecialist.NeurologistUniversity.Department.of.MedicineQueen.Mary.HospitalThe.University.of.Hong.Kong
dr Rawiphan WitoonpanichConsultant.NeurologistDivision.of.NeurologyRamathibodi.Hospital.Mahidol.University.Bangkok,.Thailand
MEMBERSHIP OFSCIENTIFIC COMMITTEE
MEMBERSHIP OF SCIENTIFIC COMMITTEE
132
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
dr david hutchinsonConsultant.NeurologistDepartment.of.NeurologyAuckland.District.Health.Board.Auckland,.New.Zealand
prof John pollard Director.of.NeurologyBrain.Mind.Research.Institute.University.of.SydneyNSW,.Australia
dr Vrajesh UdaniConsultant.NeurologistPaediatrics.&.Neurology.PD.Hinduja.National.HospitalMumbai,.India
dr santhi datuk puvanarajah.Consultant.Neurologist. . . .Division.of.NeurologyKuala.Lumpur.HospitalKuala.Lumpur,.Malaysia
133
COMMENTARY ON INTERPRETATION OF PUBLICATIONS REVIEWEDThe.literature.review.considered.all.relevant.studies.and.commentaries.published.in.English.from.1966.onwards...The.integration. of. Evidenced. Based. Medicine. (EBM). into. clinical. practice. includes. the. integration. of. individual. clinical.expertise,.best.available.external.clinical.evidence.from.systemic.review.and.patient.values.and.expectations..EBM.alone.is.never.sufficient.to.make.a.clinical.decision..Decisions.must.always.trade.the.benefits,.risks,.inconvenience.and.costs.associated.with.alternative.management.strategies,.and.in.doing.so,.consider.the.patient's.values.
13�
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGYEXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
ACKNOWLEDGEMENTS
The.Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.Board.wishes.to.acknowledge.the.following:
•.CSL.Bioplasma.for.supporting.the.development.of.the.Asia. Pacific. Immunoglobulins. in. Neurology.Advisory.Board. and. ensuring. that. it. remains. autonomous..and.independent
•.Our.families.for.giving.each.of.us.their.unfailing.under-standing. and. patience. during. the. course. of. the. last..�. years.. The. writing. of. these. statements. and. the.planning.of.the.INDAPS.conferences.is.testament.to.their.support.
13�
WAIVER OF LIABILITY
The.information.contained.in.this.document.is.intended.to. serve. as. a. guideline. only.. Neither. the. contributing.authors,.the.Asia.Pacific.Immunoglobulins.in.Neurology.Advisory.Board.or.CSL.Bioplasma.shall.be.liable.for.any.actions,.claims,.damages,.costs.or.obligations.that.may.arise. from. the. inappropriate. use. or. misuse. of. the.material.contained.in.this.document.
WAIVER OF LIABILITY