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.

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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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. 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


. 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


. References..........................................................................................................................................................67

Lambert-Eaton Myasthenic Syndrome..................................................................................................................69

. Clinical.Information..............................................................................................................................................69

. Objectives............................................................................................................................................................70

. Intravenous.Immunoglobulin.for.LEMS...............................................................................................................70

. Summary.............................................................................................................................................................71


. References..........................................................................................................................................................71

Neuromyotonia (Isaacs’ Syndrome)...................................................................................................................... 7�

. Background.......................................................................................................................................................... 7�

. Intravenous.Immunoglobulin.for.Neuromyotonia................................................................................................7�

. Summary.............................................................................................................................................................7�


. References..........................................................................................................................................................7�

Inflammatory Myopathies......................................................................................................................................77

. Background..........................................................................................................................................................77

. Treatment.of.DM.and.PM...................................................................................................................................79

. Treatment.of.IBM................................................................................................................................................79

. Summary.............................................................................................................................................................80


. 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.


. References..........................................................................................................................................................87

Paraneoplastic Neurological Disorders.................................................................................................................90

. Introduction.........................................................................................................................................................90

. Clinical.Features..................................................................................................................................................90

. Pathogenesis.......................................................................................................................................................92

. Treatment.for.Paraneoplastic.Neurological.Disorders.........................................................................................92

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. Summary.............................................................................................................................................................93


. References..........................................................................................................................................................9�

Stiff-Person Syndrome............................................................................................................................................97

. Background..........................................................................................................................................................97

. Neurophysiology..................................................................................................................................................97

. Auto-Antibodies.and.Immunopathogenesis........................................................................................................98

. Therapies.............................................................................................................................................................98

. IVIG.in.SPS..........................................................................................................................................................98

. Summary.............................................................................................................................................................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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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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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

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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�


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


16


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


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


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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)...

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1729-3�.

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Basta. M,. Kirshbom. P,. Frank. MM,. Fries. LF.. . (1989)...

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Donkova.V,.Pashov.A,.Chevailler.A,.Mouthon.l,.Weill.B,.

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intravenous.immunoglobulin...Blood.101,.7�8-76�.

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immunoglobulin. abrogates. dendritic. cell. differentiation.

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�8,.3�97-3�02.

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Soluble. CD�,. CD8. and. HLA. molecules. in. commercial.

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19


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20


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21


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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


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�


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�


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


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


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.

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2.. .Arakawa.Y,.Yoshimura. M,. Kobayashi. S,. Ichihashi. K,.

Miyao.M,.Momoi.MY.and.Yanagisawa.M...The.use.of.

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Brain.&.Development.1993;.1�:.231-233.

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�.. .Asbury. AK.. . Diagnostic. considerations. in. Guillain-

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�.. .Asbury. AK.. . New. concepts. of. Guillain-Barré.

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6.. .Bril.V,.Use.WK,.Pearce.R,.Dhanani.A,.Sutton.D.and.

Kong.K...Pilot.trial.of.immunoglobulin.versus.plasma.

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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.

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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.

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28


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Brain.199�;.118:�77-�9�.

1�...Guillain-Barré. Syndrome. Steroid. Trial. . . Group...

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�90.

1�...Gurses.N,.Uysal.S,.Cetinkaya.F,. Islek. I,.Kalayci.AG...

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16...Madden.RDM,.Cornblath.DR,.Hughes.RAD,.Zielasek.

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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,.

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AC.. . Idiopathic. dysautonomia. treated. intravenous.

gammaglobulin...Lancet.1996;.3�7:.28-29.

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22...Hughes. RA,. Raphael. JC,. Swan. AV,. Doorn. PA...

Intravenous. immunoglobulin. for. Guillain-Barré.

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2�...Hughes.RAC,.Rees.JH...Clinical.and.epidemiological.

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2�...Hughes.RAC,. van.der.Meche.FGA.. .Corticosteroid.

treatment. for. Guillain-Barré. syndrome.. . Cochrane.

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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


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.

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�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-

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RAC.. . An. epidemiological. study. of. Guillain-Barré.

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Psychiatry.1988;.6�:.7�-77.

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Guillain-Barré. syndrome. in. children:. comparison.

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��...Singhi. SC,. Jayshree. M,. Singhi. P. Banerjee. S,.

Prabhakar. S.. . Intravenous. immunoglobulin. in. very.

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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.

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exchange.in.Guillain-Barré..syndrome...N.Engl.J.Med.

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�9...Van.Koningsveld.R,.van.Doom.PA,.Schmitz.PI,.et.al...

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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


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


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�


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.

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myositis.J.Neurol.Sci...2001;.18�:119-122.

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Immunosuppressive.treatment.for.multifocal.motor.

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demyelinating. polyneuropathy. Neurology.. . 1998;.

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�9...Hodgkinson.SJ,.Pollard.JD,.McLeod.JG...Cyclosporin.

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61.. .Gorson.KC,.Ropper.AH,.Clark.BD,.et.al.. .Treatment.

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62...Hadden.RD,.Sharrack.B,.Bensa.S,.et.al...Randomized.

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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


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.


�2


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�3

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��


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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


•..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.


�8


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.


�0


�.. .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


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

��


�.. .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


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


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


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.

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1�...Wolf.SM,.Rowland.LP,.Schotland.DL,.McKinney.AS,.

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21.. .Wakata.N,.Kiyozuka.T,.Konno.S,.Nakazora.H,.Nomoto.

N,.Sugimoto.H,.et.al..Autoimmune.thrombocytope-

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2�...Kister.I,.Gulati.S,.Boz.C,.Bergamaschi.R,.Piccolo.G,.

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MYASTHENIA GRAVIS

62


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MYASTHENIA GRAVIS

6�


6�...Chaudhry.V,. Cornblath. DR,. Griffin. JW,. O'Brien. R,.

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70...Kawaguchi.N,.Yoshiyama.Y,.Nemoto.Y,.Munakata.S,.

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76...Gajdos.P,.Chevret.S,.Clair.B,.Tranchant.C,.Chastang.

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MYASTHENIA GRAVIS

66


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


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.


72


�.. .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.


7�


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


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


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.


80


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


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.

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3.. .Gallardo.E,.Rojas-Garcia.R.&.de.Luna.N..Inflammation.

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�.. .Horneff.G,.Paetzke.I.&.Neuen-Jacob.E..Glycogenosis.

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myositis..Clin.Rheumatol.2001:20:�7-60.

�.. .Eisenberg. I,. Avidan. N,. Potikha.T,. et. al..The. UDP-

Nacetylglucosamine. 2-epimerase/N-acetylman-

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2001;29:83-87.

6.. .Dalakas. MC. Controlled. studies. with. high-dose.

intravenous. immunoglobulin. in. the. treatment. of.

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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-

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..

1�...Dalakas.MC,.Ilia.I,.Dambrosia.JM,.et.al..A.controlled.

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infusions.as. treatment. for.dermatomyositis..NEJM.

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16...Lang.BA,.Laxer.RM,.Murphy.G,.et.al..Treatment.of.

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82


19...Cherin. P. Pelletier. S,.Teixeira. A,. et. al.. Results. and.

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Rheum.2002:�6:�67-7�.

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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..

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2�...Danieli.MG,.Malcangi.G,.Palmieri.C,.et.al..Cyclosporin.

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2002:61:37-�1.

26...Cherin. P. Peitte. JC,.Wechsler. B,. et. al.. Intravenous.

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27.. .Jann.S,.Beretta.S,.Moggio.M.High-dose.intravenous.

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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.

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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.

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2001:�6:323-7.

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globulin..Neurology.1993:�3:876-879.

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body. myositis.. Rev. Rhum. Engl. Ed..

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immunoglobulin. for. dysphagia. of. inclusion. body.

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8�


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


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


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


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


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


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


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�


. 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.


96


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


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


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


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�


. 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.

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Gastaut. syndrome.. Epilepsia.. 1999.

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Pediatrics..1996;.97(3):.37�-9.

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EPILEPSY

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.

EPILEPSY

108


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


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.

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Opsoclonus-Myoclonus. Study. Group.. Clinical.

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AP.Griebel.ML,.Gumbinas.M,.Heydemann.PT,.Holt.

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Matthay. KK.. . Opsoclonus-myoclonus-ataxia.

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Long-term. neurologic. outcome. in. children. with.

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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


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�


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


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


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


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.

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noglobulin. treatment. in. multiple. sclerosis.. Effect. on.

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immunoglobulin.treatment.following.the.first.demyelin-

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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.

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Comi. G,. Filippi. M,. Barkhof. F,. et. al.. Interferon. beta. 1a.

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randomized,. double-blinded,. placebo-controlled. study..

Neurology.2000;��:Suppl.3:A8�-86.

Compston. A,. Coles. A.. Multiple. sclerosis.Lancet.

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koencephalitis. caused. by. CNS. infection. of. human.

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Fazekas. F,. Deisenhammer. F,. Strasser-Fuchs. S,. et. al..

Randomized. placebo-controlled. trial. of. monthly.

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remitting.multiple.sclerosis..Austrian.Immunoglobulin.in.

Multiple. Sclerosis. Study. Group.. Lancet. 1997;3�9:�89-

�93.

European. Study. Group. on. Interferon. Beta-1b. in.

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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.

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lin.in.secondary.progressive.multiple.sclerosis.(ESIMS)..

Mult.Scler.200�;11(�):�33-��0.

Goodin. DS,. Frohman. EM,. Garmany. GP,. et. al.. Disease.

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2002;�8:169-178.

Goodin. DS,. Arnason. BG,. Coyle. PK,. et. al..The. use. of.

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122


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immunoglobulin. in. secondary. progressive. multiple.

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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.

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�6.

Weinshenker.BG,.O’Brien.PC,.Patterson.TM,.Noseworthy.

JH,.Lucchinetti.CF,.Dodick.D,.et.al..A.randomized.trial.of.

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MULTIPLE SCLEROSIS

12�


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


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.

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1�...Okada.K,.Tsuji.S,.Tanaka.K...Intermittent.intravenous.

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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.

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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.

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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.

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Neurology.1998;�1:1219-20.

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2001;�0:121-127..

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MR,. Orr. P,. Ross. RT,. Power. C.. . Aboriginals. with.

multiple.sclerosis:.HLA.types.and.predominance.of.

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2�...Misu.T,.Fujihara.K,.Nakashima.I,.et.al...Pure.optico-

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2002;12�:2�60-68.

2�...Poser. CM,. Paty. DW,. Scheinberg. L,. et. al.. . New.

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31.

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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


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and.what.it.might.be...Lancet.2003;361:889-90.

31.. .Weinstock-Guttmann.B,.Ramanathan.M,.Lincoff.N,.

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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-

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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.

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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


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


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�


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

The Second Edition Expert Consensus Statements on the Use of IVIg in Neurology

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