The Second Edition Expert Consensus Statements On The Use of IVIg in Neurology

SECOND EDITION
Prepared by the Asia Pacific Immunoglobulins in Neurology Advisory Board Revised November 2008
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGY

EXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
2nd EDITION PREPARED BY THE ASIA PACIFIC IMMUNOGLOBULINS IN NEUROLOGY ADVISORY BOARD
NOVEMBER 2008
BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGY EXPERT CONSENSUS STATEMENTS ON THE USE OF IVIG IN NEUROLOGY
Copyright Asia Pacific Immunoglobulins in Neurology Advisory Board Inc. Apart from any fair dealing for the use of private study, research, criticism, or review as permitted under the Copyright Act, no part of this book may be transmitted or reproduced in any form, electronic or mechanical, or by any information storage and retrieval system, without the written permission of the publishers. This publication has been made possible by an unrestricted educational grant from CSL Bioplasma.

TABLE OF CONTENTS
TABLE OF CONTENTS
Foreword.................................................................................................................................................................. 10. The Mechanism of Action of Intravenous Immunoglobulin in the Treatment of Autoimmune Neurological Diseases................................................................................................................................................................... 1.. . . . . . . . . . . . . . . . . . . . Abstract............................................................................................................................................................... 1 Introduction......................................................................................................................................................... 1. References.......................................................................................................................................................... 18 Introduction.........................................................................................................................................................22 Treatment.in.GBS................................................................................................................................................23 Expert.Consensus...............................................................................................................................................26 References..........................................................................................................................................................27 Introduction.........................................................................................................................................................31 Diagnosis.............................................................................................................................................................31 Differential.Diagnosis..........................................................................................................................................32 . Natural.History....................................................................................................................................................32 . Pathogenesis.......................................................................................................................................................32 Treatment............................................................................................................................................................33 Suggested.Approach.to.Management................................................................................................................3 Expert.Consensus...............................................................................................................................................3 References..........................................................................................................................................................3 Definition.............................................................................................................................................................39 Diagnosis.............................................................................................................................................................39

Guillain-Barr Syndrome........................................................................................................................................22
Chronic Inflammatory Demyelinating Polyneuropathy.......................................................................................31
Multifocal Motor Neuropathy................................................................................................................................39.. .
. . . . . . . . . . . . . . . . . . .
Pathogenesis.......................................................................................................................................................0 Natural.History....................................................................................................................................................0 . Pathology.............................................................................................................................................................0 Treatment............................................................................................................................................................0 Summary.............................................................................................................................................................1 Expert.Consensus...............................................................................................................................................1 References..........................................................................................................................................................2 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 Neuralgic.Amyotrophy/Brachial.Neuritis..............................................................................................................1.
IgM Paraproteinemic Neuropathies........................................................................................................................
Brachial and Lumbosacral Plexopathies...............................................................................................................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 Clinical.Information............................................................................................................................................... Objectives...........................................................................................................................................................8 . Intravenous.Immunoglobulin.for.MG.Exacerbations.and.Myasthenic.Crisis......................................................8.. . Intravenous.Immunoglobulin.for.MG.with.Worsening.Weakness.......................................................................9. Intravenous.Immunoglobulin.for.Moderate.to.Severe.Stable.MG......................................................................9 Summary.............................................................................................................................................................60 Expert.Consensus...............................................................................................................................................60 References..........................................................................................................................................................60
Myasthenia Gravis. ................................................................................................................................................. .
TABLE OF CONTENTS
Amyotrophic Lateral Sclerosis...............................................................................................................................66 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical.Information..............................................................................................................................................66. IVIG.as.Maintenance.Therapy..............................................................................................................................67.. Objective.............................................................................................................................................................67 Summary.............................................................................................................................................................67 Expert.Consensus...............................................................................................................................................67 References..........................................................................................................................................................67 Clinical.Information..............................................................................................................................................69 Objectives...........................................................................................................................................................70 . Intravenous.Immunoglobulin.for.LEMS. .............................................................................................................70 . Summary.............................................................................................................................................................71 Expert.Consensus...............................................................................................................................................71 References..........................................................................................................................................................71 Background.......................................................................................................................................................... 7 Intravenous.Immunoglobulin.for.Neuromyotonia................................................................................................7 Summary.............................................................................................................................................................7 Expert.Consensus...............................................................................................................................................7 References..........................................................................................................................................................7 Background..........................................................................................................................................................77 Treatment.of.DM.and.PM...................................................................................................................................79 Treatment.of.IBM................................................................................................................................................79 Summary.............................................................................................................................................................80 Expert.Consensus...............................................................................................................................................81 References..........................................................................................................................................................81 Background..........................................................................................................................................................8 Etiology,.Pathophysiology.and.Laboratory.Observations....................................................................................8. Chronic.Fatigue.Syndrome..................................................................................................................................8. Therapy.in.CFS....................................................................................................................................................8. IVIG.in.CFS..........................................................................................................................................................86. Expert.Consensus...............................................................................................................................................87 References..........................................................................................................................................................87 Introduction.........................................................................................................................................................90 Clinical.Features..................................................................................................................................................90 Pathogenesis.......................................................................................................................................................92 Treatment.for.Paraneoplastic.Neurological.Disorders.........................................................................................92
Lambert-Eaton Myasthenic Syndrome.................................................................................................................69 .
Neuromyotonia (Isaacs Syndrome)...................................................................................................................... 7
Inflammatory Myopathies......................................................................................................................................77
Chronic Fatigue Syndrome.....................................................................................................................................8
Paraneoplastic Neurological Disorders.................................................................................................................90
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary.............................................................................................................................................................93 Expert.Consensus...............................................................................................................................................9 References..........................................................................................................................................................9 Background..........................................................................................................................................................97 Neurophysiology..................................................................................................................................................97 Auto-Antibodies.and.Immunopathogenesis........................................................................................................98 Therapies.............................................................................................................................................................98 IVIG.in.SPS..........................................................................................................................................................98 Summary.............................................................................................................................................................99 Expert.Consensus...............................................................................................................................................99 References..........................................................................................................................................................99 Background........................................................................................................................................................ 101 Intractable.Epilepsies........................................................................................................................................ 101 Basis.for.Using.Immunomodulation.................................................................................................................. 102 IVIG.in.Epilepsy................................................................................................................................................. 103 Summary........................................................................................................................................................... 10.. Expert.Consensus............................................................................................................................................. 10 References........................................................................................................................................................ 10 Background........................................................................................................................................................ 108 Conventional.Management............................................................................................................................... 109 IVIG.in.OMA...................................................................................................................................................... 109 Summary........................................................................................................................................................... 109 Expert.Consensus..............................................................................................................................................110 References.........................................................................................................................................................110 Clinical.Features................................................................................................................................................ 112. Etiology. ............................................................................................................................................................ 112. . Pathogenesis..................................................................................................................................................... 112. Diagnosis........................................................................................................................................................... 113. Treatment.......................................................................................................................................................... 113. Role.of.IVIG.in.Adem. ....................................................................................................................................... 113. . Expert.Consensus............................................................................................................................................. 11. References........................................................................................................................................................ 11
Stiff-Person Syndrome............................................................................................................................................97
Epilepsy.................................................................................................................................................................. 101
OpsoclonusMyoclonusAtaxia........................................................................................................................... 108
Acute Disseminated Encephalomyelitis.............................................................................................................. 112.
TABLE OF CONTENTS
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 Introduction....................................................................................................................................................... 12. Clinical.Features................................................................................................................................................ 12. Pathology.and.Pathogenesis............................................................................................................................. 12. Treatment.......................................................................................................................................................... 12. Expert.Consensus............................................................................................................................................. 126. References........................................................................................................................................................ 126. Appendix.A........................................................................................................................................................ 129 Appendix.B........................................................................................................................................................ 129.. Appendix.C........................................................................................................................................................ 130
Neuromyelitis Optica............................................................................................................................................ 12.
Appendices............................................................................................................................................................ 129 .
Membership of Scientific Committee................................................................................................................. 131. Commentary on Interpretation of Publications Reviewed. .............................................................................. 133. . Acknowledgements.............................................................................................................................................. 13. . Waiver of Liability................................................................................................................................................. 13 .
FOREWORD
BRINGING 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. patients. preference,. clinicians. . experience,. and. most. importantly,. the. availability. . of. resources. and. therapies. must. also. be. taken. into.account. In. the. Asia. Pacific,. where. half. of. the. worlds. 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. regions. 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:
10
FOREWORD
. . . . . . . . .
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
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.
. 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-Barr.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.
A/Prof.Andrew.J..Kornberg Chairman,. Asia. Pacific. Immunoglobulins. in. Neurology. Advisory.Board November.2008
11
WaIVER Of LIaBILItY
The.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.
COMMENtaRY ON thE INtERpREtatION Of pUBLICatIONs REVIEWEd

This. 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 tERMINOLOGY

Standards. 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. AIDP. ALS. . CIDP. Acute.Inflammatory.Demyelinating. Polyneuropathy Amyotrophic.Lateral.Sclerosis Chronic.Inflammatory.Demyelinating. Polyneuropathy
CREAN Chronic.relapsing.experimental.. autoimmuneneuritis DM.. EAN. EBM. GBS. IBM. IV. . IVIg. . LEMS. MMN. MRC. Dermatomyositis Experimental.autoimmune.neuritis Evidence.Based.Medicine Guillain-Barr.syndrome Inclusion.body.myositis Intravenous Intravenous.Immunoglobulin Lambert-Eaton.Myasthenic.Syndrome Multifocal.Motor.Neuropathy Medical.Research.Council
These. consensus. statements. are. based. on. evidence. base.literature.research.and.expert.opinion... he.continuing. T development.of.knowledge,.opinion.and.practice.necessitates.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..Kornberg Chairman,.Asia.Pacific.Immunoglobulins.in.Neurology. Advisory.Board Department.of.Neurology Royal.Childrens.Hospital Parkville.Victoria.302 Australia andrew@kornberg.md
12
FOREWORD
NHMRC. National.Health.and.Medical.Research.Council PE. . PM.. Plasma.exchange Polymyositis
BIBLIOGRaphY aNd LItERatURE REVIEW

Please.see.Appendix.C LEVELS of EVIDENCE RAtINGS I. Evidence.obtained.from.a.systematic.review.of.all. relevant.randomised.controlled.trials. II. Evidence.obtained.from.at.least.one.properly. designed.randomised.controlled.trial.
IIIi..Evidence.obtained.from.well.designed.pseudorandomised.controlled.trials.(alternate.location.or. some.other.method). IIIii.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.
SouRCE:.NHMRC.1999.A Guide to the Development, Implementation and Evaluation of Clinical Practice Guidelines. National.Health.and.Medical.Research.Council,.Canberra.
13
THE MECHANISM OF ACTION OF INTRAVENOUS IMMUNOGLOBULIN IN THE TREATMENT OF AUTOIMMUNE NEUROLOGICAL DISEASES
aBstRaCt
Intravenous.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-Barr. 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. complementmediated. 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.
1
INtROdUCtION
Intravenous.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. 200a,b),. those. relevant. to. the. efficacy. of. the. drug. in. autoimmune. neuromuscular. disorders.include.the.following:.
pROpOsEd MEChaNIsMs Of aCtION Of IVIG aNd thEIR RELEVaNCE IN thE REspECtIVE aUtOIMMUNE NEUROMUsCULaR dIsEasEs
ACtIoNS of IVIG NEuRoMuSCuLAR DISEASES
1.. . ffect.on.autoantibodies.by: E . .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.. .nhibition.of.complement.binding.and.prevention.of. I Membranolytic.Attack.Complex.(MAC).formation 3.. . c.Receptor.modulation.and.blockade.on.invaded. F macrophages .. . uppression.of.pathogenic.cytokines.and.adhesion. S molecules .. Modulation.of.T.cell.function
a). . yasthenia.gravis;.b).LEMS;.c).stiff-person. M syndrome;.d).autoimmune.demyelinating.neuropathies.(CIDP ,.GBS,.MMN)
a). . ermatomyositis;.b).Guillain-Barr.syndrome;.c). D CIDP;.d).Myasthenia.gravis a). . uillain-Barr.syndrome;.b).CIDP;.c).Inflammatory. G myopathies a). .nflammatory.myopathies;.b)..Demyelinating.neuI ropathies;.c)..Myasthenia.gravis a). . uillain-Barr.syndrome;.b)..CIDP;.c).inflammatory. G myopathies
6.. Possible.effect.on.remyelination
a). Guillain-Barr.syndrome;.b).CIDP
1. EffECt oN AutoANtIBoDIES The.IgG.of.normal.humans.contains.low.titer.antibodies. against. a. wide. spectrum. of. human. proteins,. and. antiidiotypic. antibodies. directed. against. F,. the. antigenbinding.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. antiidiotypic.specificities...The.idiotypic.antibodies.have.the. potential.to.bind.to.and.neutralize.pathogenic.autoantibodies,. thereby. preventing. their. interaction. with. the. autoantigen.. .This. effect. has. been. shown. experimentally,.when.extracted.F(')2.fragments.of.IVIg.bound.to. and. neutralized. known. autoantibodies,. such. as. antiDNA,.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.dosedependent. protection. of. cytotoxicity. induced. by. GBS. sera.(Zhang.et.al.200)...Additionally,.the.F()2,.but.not. the. Fc. portion. of. the. IgG,. within. the. IVIg. preparations. inhibits. the. binding. of. anti-. GM1. antibodies. to. GM1coated.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.
1
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.autoantibodies. 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. INHIBItIoN of CoMPLEMENt BINDING AND PREVENtIoN of MEMBRANoLytIC AttACk CoMPLEx (MAC) foRMAtIoN The. 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. complementdependent.Forssman.shock.by.inhibiting.the.uptake.of. complement. C3. and. C. fragments. to. the. endothelial. cells.(Basta.et.al.1989)...In.patients.with.dermatomyositis,.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.Cb. 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.
16
targeted. tissues. (Dalakas. 1999b).. . A. complementinhibiting. 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.cytotoxicity.induced.by.the.GBS.sera.(Zhang.et.al.200). 3. MoDuLAtIoN oR BLoCkADE of fC RECEPtoRS oN MACRoPHAGES There.are.specific.Fc.receptors.for.each.class.of.immunoglobulin...IgG.molecules.bind.through.their.Fc.region. of. Fc. receptors. on. hematopoietic. cells,. such. as. macrophages.. . FcR. 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.FcR.receptors. determines.the.final.immune.response;.overexpression. of.FcR.I.and.FcR.III.favor.activation,.whereas.overexpression.of.FcR.II.infers.inhibition.of.phagocytosis.and. interception. of. antibody-dependent. cell-mediated. cytotoxicity.(Kazatchkine.and.Kaveri.2001;.Samuelsson.et.al. 2001)...IVIg.upregulates.the.inhibitory.FcR.II.receptors. and.modulates.the.FcR.II/.FcR.III.ratio.on.macrophages. (Samuelsson.et.al.2001)...An.increase.in.the.number.of. monocytes.bearing.the.FcR.II.inhibitory.receptors.and. an.increase.in.the.FcR.II/.FcR.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. be.determined. 4. SuPPRESSIoN of PAtHoGENIC CytokINES AND otHER IMMuNoREGuLAtoRy MoLECuLES In.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,.metalcells. unable. to. exert. . their. action. (Dalakas. 1997b;. 1998b),. remains. to. .
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-,. IL1,. TGF-,. 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.neuromuscular.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 to AutoIMMuNE NEuRoMuSCuLAR DISEASES a) 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.1.helix.of.the.HLAI.molecule.(Kaveri.et.al.,.1996)...These.antibodies.bind.to. soluble. and. membrane-associated. HLA-I. . antigen. and. may. theoretically. have. an. effect. on. inhibiting. CD8mediated. cytotoxicity,. a. process. relevant. to. several.Tcell-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. demonstrated. 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.downregulated. 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.
17
REfERENCEs
Abe.Y,. Horiuchi.A,. Miyake. M,. Kimura. S.. . (199).. .Anticytokine.nature.of.natural.human.immunoglobulin:.one. possible.mechanism.of.the.clinical.effect.of.intravenous. immunoglobulin.therapy...Immunol.Rev.139,.-19... Amemiya.K,.Semino-Mora.C,.Granger.RP ,.Dalakas.MC.. . (2000)..Downregulation.of.TGF-1.mRNA.and.protein.in. the.muscles.of.patients.with.inflammatory.myopathies. after. treatment. with. high-dose. intravenous. immunoglobulin...Clin.Immunol.9,.99-10.
B . ayry. J,. Lacroix-Desmazes. S,. Delignat. S,. Mouthon. L,. Weill.B,.Kazatchkine.MD,.Kaveri.SV...(2003b)...Intravenous. immunoglobulin. abrogates. dendritic. cell. differentiation. induced.by.interferon-.present.in.serum.from.patients. with. systemic. lupus. erythematosus.. . Arthritis. Rheum. 8,.397-302. Blasczyk. R,. Westhoff. V,. Grosse-Wilde. H.. . (1993).. . Soluble. CD,. CD8. and. HLA. molecules. in. commercial. immunoglobulin.preparations...Lancet.31,.789-790. Buchwald.B,.Ahangari.R,.Weishaupt.A,.Toyka.KV...(2002).. .
Ankrust.P ,.Muller.F ,.Svenson.M,.Nordoy.I,.Bendtzen.K,. Froland. SS.. . (1999).. . Administration. of. intravenous. immunoglobulin.(IVIg).in.vivo.downregulatory.effects.on. the.IL -1.system...Clin.Exp.Immunol.11,.136-13.
Intravenous. immunoglobulins. neutralize. blocking. antibodies. in. Guillain-Barr. syndrome.. .Ann. Neurol. 1,. 673-680. Choi.Y,. Dalakas. MC.. . Expression. of. matrix. metallopro-
Bain.PG,.Motomura.M,.Newsom-Davis.J,.et.al..(1996).. . Effects. of. intravenous. immunoglobulin. on. muscle. weakness. and. calcium-channel. autoantibodies. in. the. Lambert-Eaton. myasthenic. syndrome.. . Neurology. 7:678-83. Basta. M,. Dalakas. MC.. . (199). High-dose. intravenous. immunoglobulin. exerts. its. beneficial. effect. in. patients. with.dermatomyositis.by.blocking.endomysial.deposition. of. activated. complement. fragments.. . J. Clin. Invest. 9,. 1729-3. Basta.M,.Illa.I,.Dalakas.MC...(1996)...Increased.in.vitro. uptake.of.the.complement.C3b.in.the.serum.of.patients. with. Guillain. Barre. syndrome,. myasthenia. gravis. and. dermatomyositis...J.Neuroimmunol.71,.227-229. Basta. M,. Kirshbom. P Frank. MM,. Fries. LF . (1989).. ,. .. . Mechanisms. of. therapeutic. effect. of. high-dose. intravenous. immunoglobulin.. . J. Clin. Invest. 8,. 1971981. Bayry. J,. Lacroix-Desmazes. S,. Carbonneil. C,. Misra. N,. Donkova.V,.Pashov.A,.Chevailler.A,.Mouthon.l,.Weill.B,. Bruneval. P Kazatchkine. MD,. Kaveri. SV.. . (2003a).. ,. . Inhibition.of.maturation.and.function.of.dendritic.cells.by. intravenous.immunoglobulin...Blood.101,.78-76.
18
teinases. in. the. muscle. of. patients. with. Inflammatory. Myopathies...Neurology..2000;:6-71. Creange.A,.Gregson.NA,.Hughes.RA...(2003)...Intravenous. immunoglobulin. modulates. lymphocyte. CD. and. monocyte. FCgammaRII. expression. in. patients. with. chronic. inflammatory. neuropathies.. . J. Neuroimmunol. 13,.91-9. Dalakas. MC.. . (1991).. . Polymyositis,. dermatomyositis. and.inclusion-body.myositis...N.Engl.J.Med.32,.187198... Dalakas.MC...A. herapeutic..Approach.to.Immunotherapy. T in. Inflammatory. Myopathies.. . In:. D.A.Drachman. (ed).. . Immunosuppressive. treatment. for. Neurologists,. . American.Academy.of.Neurology.Lecture.Series,.27:396;1993. D . alakas.MC...(199c)...Basic.aspects.of.neuroimmunology. as. they. relate. to. immunotherapeutic. targets:. present. and. future. prospects.. . Ann. Neurol. 37,. . (S).2-13. D . alakas. MC.. . (1997b).. . Intravenous. immunoglobulin. therapy.for.neurological.diseases...Ann.Intern.Med.126,. 721-730...
Dalakas. MC.. . (1998b).. . Mechanism. of. action. of. intravenous. immunoglobulin. and. therapeutic. considerations. in. the. Treatment. of. autoimmune. neurologic. diseases...Neurology.1(Suppl),.S2-S8. D . alakas. MC.. . (1999b).. . Intravenous. immunoglobulin. in. the.treatment.of.autoimmune.neuromuscular.diseases:. present. status. and. practical. therapeutic. guidelines.. . Muscle.Nerve.22,.179-197 .
Dalakas. MC,. Quarles. RH,. Farrer. RG,. Dambrosia. J,. Soueidan. S,. Stein. DP Cupler. EJ,. Sekul. EA,. Otero. C.. ,. . (1996)...A.controlled.study.of.intravenous.immunoglobulin.in.demyelinating.neuropathy.with.IgM.gammopathy.. . Ann.Neurol.0,.792-79. Dalakas. MC,. Hohlfeld. R.. . (2003b).. . Polymyositis. and. dermatomyositis...Lancet.362,.971-982. Damas.JK,.Gullestad.L,.Aass.H,.et.al..(2001)...Enhanced.
Dalakas. MC,. Fujii. M,. Li. M,. et. al.. (2001).. . High-dose. intravenous.immunoglobulin.for.Stiff-Person.Syndrome.. . N.Engl.J.of.Med.3:1870-1876. Dalakas.MC...(2002a)...Blockade.of.blocking.antibodies. in. Guillain-Barr. syndromes:.unblocking. the. mystery. of. action. of. intravenous. immunoglobulin.. . Ann. Neurol. 1,.667-669. Dalakas. MC.. . (2002b).. . Mechanisms. of. action. of. IVIg. and.therapeutic.considerations.in.the.treatment.of.acute. and. chronic. demyelinating. neuropathies.. . Neurology. . 9(Suppl.6),.S13-21. Dalakas.MC...(200a)...Intravenous.Immunoglobulin.in. autoimmune. neuromuscular. Diseases.. . JAMA.. . 291:2367-237. Dalakas.MC.(200b)...The.use.of.intravenous.immunoglobulin. in. the. treatment. of. autoimmune. Neurological. Disorders:.Evidence-based.indications.and.safety.profile.. . Pharmacol.Therapeutics.102:177-193.
gene.expression.of.chemokines.and.their.corresponding. receptors. in. mononuclear. blood. cells. in. chronic. heart. failure--modulatory.effect.of.intravenous.immunoglobulin...J.Am.Coll.Cardiol...38:187-93. De. Bleecker. JL,. De. Paepe. B,.Vanwalleghem. IE,. et. al.. (2002)...Differential.expression.of.chemokines.in.inflammatory.myopathies...Neurology.2;8:1779-8. Diegel.M...Rankin.B.Bolen.J...Dubois.P ,.Kiener.P ...(199).. . Cross.linking.of.Fc.receptor.to.surface.immunoglobulin. on.B.cells.provides.on.inhibitory.signal.that.closes.the. plasma.membrane.calcium.channel...J.Biol.Chem.269,. 1109-1116. Dietrich.G,.Kazatchkine.MD...(1990)...Normal.immunoglobulin. G. (IgG). for. therapeutic. use. (intravenous. Ig). contains. anti-idiotypic. specificities. against. an. immunodominant,.disease-associated,.cross-reactive.idiotype.of. human. anti-thyroglobulin. autoantibodies.. . J. Clin. Invest. 8,.620-9. Dwyer. JM.. . Manipulating. the. immune. system. with.
Dalakas.MC...(200c)...Fifth.International.Symposium.of. IVIg:.IVIg.in.the.third.millennium...Dalakas.MC,.Spath.PJ. (Eds).UK...Parthenon.Publishers. Dalakas. MC,. Illa. I,. Dambrosia. JM,. Soueidan. SA,. Stein. DP Otero. C,. Dinsmore. ST,. McCrosky. S.. . (1993).. . A. ,. controlled.trial.of.high-dose.intravenous.immunoglobulin. infusions. as. treatment. for. dermatomyositis.. . N. Engl. J. Med.329,.1993-2000.
immune.globulin...(1992)...N.Engl.J.Med..326,107-16. Gabriel.CM,.Gregson.NA,.Redford.EJ,.Davies.M,.Smith. KJ.. . RAC. Hughes.. . (1997).. . Human. immunoglobulin. ameliorates.rat.experimental.allergic.neuritis...Brain.120,. 133-10. Greenberg. SA,. Pinkus. JL,. Pinkus. GS,. et. al.. (200).. . Interferon-alpha/beta-mediated. innate. immune. mechanisms.in.dermatomyositis...Ann.Neurol.7:66-78.
19
Illa.I,.Ortiz.N,.Gallard.E,.Juarez.C,.Grau.JM,.Dalakas.MC.. . Acute.axonal.Guillain.Barr.syndrome.with.IgG.antibodies. against. motor. axons. following. parenteral. injection. of. gangliosides...Ann.Neurol.38:218-22;199.
Malik. U.. . Oleksowicz. L,. Latov. N,. Cardo. LJ.. . (1996).. . Intravenous.y-globulin.inhibits.binding.of.anti-GMI.to.its. target.antigen...Ann.Neurol.39,136-139. Marchalonis. JJ,. Kaymaz. H,. Dedeoglu. F Schluter. SF ,. ,.
Jacobs. BC,. O'Hanlon. GM,. Bullens. RW,. et. al.. (2003).. . Immunoglobulins. inhibit. pathophysiological. effects. of. anti-GQ1b-positive. sera. at. motor. nerve. terminals. through. inhibition. of. antibody. binding.. . Brain. 126:. 2220-3.
Yocum. DE,. Edmundson.AB.. . (1992).. . Human. autoantibodies.reactive.with.synthetic.autoantigens.from.T.cell. receptor.V. chain.. . Proc. Natl. Acad. Sci. USA. 89,. 3323329. Prasad. NK,. Papoff. G,. Zeuner. A,. et. al.. . Therapeutic.
Kaveri.S,.Vassilev.T,.Hurex.V,.Lengagne.R,.Lefranc.C,.Cot. S,.Pouletty.P ,.Glotz.P ,.Kazatchkine.MD.(1996).Antibodies. to.a.conserved.region.of.HLA.class.I.molecules,.capable. of.modulating.CD8.T.cell-mediated.function,.are.present. in.pooled.normal.immunoglobulin.for.therapeutic.use...J. Clin.Invest.97 ,.868-869. Kazatchkine. MD,.Dietrich.G,.Hurez,.V,.Ronda.N,.Bellon. B,. Rossi. F Kaveri. SV.. . (199).. . V. region-mediated. ,. selection. of. autoreactive. repertoires. by. intravenous. immunoglobulin...Immunol.Rev.139,.79-107 . Kazatchkine.MD,.Kaveri.SV...(2001)...Immunomodulation. of. autoimmune. and. inflammatory. diseases. with. intravenous.immune.globulin...N.Engl.J.Med.3,.777. Kieseier. BC,. Clements. JM,. Pischel. HB,. et. al.. (1998).. . MMP-9. and. MMP-7. are. expressed. in. experimental. autoimmune. neuritis. and. the. Guillain-Barre. syndrome.. . Ann.Neurol...1998.3:27-3. Kieseier.BC,.Dalakas.MC,.Hartung.HP ...(2002)...Immune. mechanisms. in. chronic. inflammatory. demyelinating. neuropathy...Neurology.9(Suppl.6),.S7-12. Koffman.BM,.Dalakas.MC...(1997)...Effect.of.high-dose. intravenous. immunoglobulin. on. serum. chemistry,. hematology. and. lymphocyte. subpopulations:.
preparations. of. normal. polyspecific. IgG. (IVIg). induce. apoptosis. in. human. lymphocytes. and. monocytes:. a. novel. mechanism. of. action. of. IVIg. involving. the. Fas. apoptotic.pathway...J.Immunol.1998;161:3781-3790. Raju.R,.Dalakas.MC.(200)...Gene.expression.profile.in. the.muscles.of.patients.with.inflammatory.myopathies:. effect. of. therapy. with. IVIg. and. biologic. validation. of. clinical.relevant.genes...Brain.128:1887-96. Renaud. S,. Hays. AP Brannagan.TH. 3rd,. et. al.. (200).. ,. . Gene.expression.profiling.in.chronic.inflammatory.demyelinating.polyneuropathy..J.Neuroimmunol.19(1-2):2031... Rigal.D,.Vermot-Desroches.C,.Heitz.S,.Bernaud.J,.Alfonsi. F ,.Monier.JC...(199)...Effect.of.IVIg.in.peripheral.blood. B,. NK,. and. T. cell. subpopulations. in. women. with. recurrent. spontaneous. abortions:. . specific. effect. on. LFA-1.and.CD6.molecules...Clin.Immunol.Immunopathol. 71,.309-1. Roux.KH,.Tankersley.DL...(1990)...A.view.of.the.human. idiotypic. repertoire.. . Electron. microscopic. and. immunologic. analyses. of. spontaneous. idiotype--antiidiotype.dimers.in.pooled.human.IgG...J.Immunol.1,. 1387-92. Samuelsson. A,.Towers.TL,. Ravetch. JV.. . (2001).. . Antiinflammatory. activity. of. IVIG. mediated. through. the. inhibitory.Fc.receptor...Science.291,.8-86.
assessments. based. on. controlled. treatment. trials. in. patients.with.neurological.diseases...Muscle.Nerve.20,. 1102-1107 .
20
Sekul. EA,. Cupler. EJ,. Dalakas. MC.. . (199).. . Aseptic. meningitis.associated.with.high-dose.intravenous.immunoglobulin. therapy:. frequency. and. risk. factors.. . Ann. Intern.Med.121,.29-62. 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.13,.203-21. Svenson.M,.Hansen.MB,.Bendtzen.K...(1993)...Binding. of.cytokines.to.pharmaceutically.prepared.human.immunoglobulin...J.Clin.Invest.92,.233-9. Takei. S,. Arora. YK,. Walker. SM.. . (1993).. . Intravenous. immunoglobulin. contains. specific. antibodies. inhibitory. of.activation.of.T.cells.by.staphylococcal.toxin.superantigens...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. Theilers. 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. immunoglobulin...Science.282,..90-93. Yu. Z,. Lennon.VA.. . (1999).. . Mechanism. of. intravenous. immune. globulin. therapy. in. antibody-mediated. autoimmune.diseases...N.Engl.J.Med.30,.227-228. Yuki. N,. Miyaga. F . (1996).. . Possible. mechanism. of. .. intravenous. immunoglobulin. treatment. on. anti-GM1. antibody-mediated.neuropathies...J.Neurol.Sci.139,160162. 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.
21
GUILLAIN-BARR SYNDROME
INtROdUCtION
The. Guillain-Barr. 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.polyradiculoneuropathy,. 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.complications. 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.

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.distinguished.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. pharyngocervico-brachial. variant,. pure. sensory. GBS. and. acute. pandysautonomia. . Significant. advances. have. been. made. in. understanding. 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.antiGDIa/anti-GM1.ganglioside.IgG.with.AMAN2...Specific. antecedent.infections,.namely.Campylobacter.jejuni.(C.. . jejuni),.Mycoplasma.pneumoniae,.Epstein-Barr.virus.and.
subtypes. of. the. disease .. . The. most. common. form,. classic.GBS.(or.acute.inflammatory.demyelinating.polyneuropathy,.AIDP),.is.characterized.by.segmental.demy22
cytomegalovirus,. have. been. associated. with. GBS. in. a. case.control.study27...Similarly,.C...jejuni.and.Haemophilus. influenza. (H.. . influenza). have. been. associated. with. MFS .. . In. the. case. of. C.. . jejuni. infections,. the.
29
immunoabsorption,.which.is.not.generally.available,.has. not. revealed. clear. benefit. in. two. studies8,. 19.. .They. will. not.be.discussed.further.in.this.review. CoRtICoStERoID tHERAPy The. 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.methylprednisolone. 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,.methylprednisolone.and.oral.prednisone.or.prednisolone,.and. including.these.two.trials,.found.no.significant.difference. in. outcome. between. the. patients. receiving. corticosteroid.and.control.patients2. PLASMA ExCHANGE Following. 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. substantiated.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.. . Metaanalysis.by.a.Cochrane.systemic.review.of.six.PE.trials. showed. results. consistent. with. these. two. leading. studies0...In.addition,.there.was.evidence.from.some.of. these. studies. that. PE. treatment. reduced. the. cost. of. treatment.for.GBS.compared.to.supportive.care. IVIG Case. reports. that. IVIG. improved. patients. with. chronic. inflammatory. demyelinating. polyneuropathy. led. to. its.
23
association.of.infection.with.GBS.was.further.correlated. with. raised. anti-GM1b. and. anti-GalNac-GD1a. IgG. antibodies...Ganglioside-like.epitopes.reactive.with.antiGM1.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. polyneuropathy.. . 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 GBs
Three.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. demonstrated. a. beneficial. effect. from. steroid. therapy.. .Two. other. treatments,. interferon-beta. and. immunoabsorption,. have. also. been. studied. in. GBS.. . Interferon-beta. showed. no. benefit. in. a. small. randomized. trial ,. while.
38
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.versions ,.updating.an.

23
updated. Cochrane. review23. identified. three. additional. trials8,.3,.1.to.the.three.above,.but.one.of.these1.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.immunoabsorption...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. trial7.. . 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. IVIG in Combination Treatments i.. . omparison of combined PE and IVIG with PE alone C 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.. . omparison of combined methylprednisolone and C IVIG with IVIG alone A. recent. trial. compared. combined. IV. methylprednisolone. and. IVIG. treatment. with. IVIG. alone. in. GBS,. following. a. pilot. study. that. suggested. it. may. have. a.
earlier. version22. and. a. review. from. the. Quality. . Standards. Subcommittee. of. the. American. Academy. . of.Neurology26. a. omparison of IVIG with placebo or supportive C treatment only No. trials. comparing. IVIG. with. placebo. were. identified.. . Two. trials. comparing. IVIG. with. supportive. treatment. alone1,.30.and.three.related.studies.involving.retrospective.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. omparison of IVIG with Plasma Exchange (PE) C 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.
2
beneficial.effect...However,.the.double-blind,.controlled. randomised. trial. did. not. show. a. significant. difference. between.the.two.treatments8.
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
d. Further Issues of IVIG treatment in GBS i.. . elapse, R lack of response or worsening following IVIG About. 10%. of. GBS. patients. treated. with. IVIG. demonstrated.secondary.worsening.after.a.period.of.stabilization. and. improvement.. . Such. relapses. appeared. to. be. associated. with. a. more. prolonged. progression. of. the. disease.. . They. responded. again. to. a. second. similar. treatment0. . 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. treatment
1,. 28,. 30,.3,.
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. .
...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. nontreatment,.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 . comparing. IVIG. plus. dexamethasone. with.
1
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.. .VIG in mild GBS. I IVIG in GBS lasting longer than two weeks
2
good. prognosis,. the. value. of. IVIG. in. such. cases. . remains.unresolved. . Anecdotal.reports.of.good.response.of.acute.dysau20,.33
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 in GBS i.. . E P 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.. .ntolerance.or.serious.side.effects.of.IVIG.use I
tonomia.to.IVIG.are.documented
EXpERt CONsENsUs
a. IVIG use in GBS i.. . BS with significant or severe involvement seen G 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.. . ild GBS M 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.deterioration. 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.
26
3.. . ack.of.availability.of.IVIG.with.PE.available L ii. Steroid Steroids. should. not. be. used. in. GBS. and. are. . not.recommended..The.combination.of.methylprednisolone.and.IVIG.is.also.not.recommended. c. ecommended dose and duration of infusion of R IVIG in GBS 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. ecommended treatment for early relapse or R lack of response 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. Combination therapy Sequential.treatment.with.PE.followed.by.IVIG.does.not. have. a. superior. effect. to. either. treatment. given. alone. and.is.not.recommended.
REfERENCEs
1.. . gboola. O. and. Blott. M,. . Guillain. Barr. disease. in. A pregnancy. treated. with. intravenous. immunoglobulin...J.Obstetrics.Gynaecology.2000;.20:3-36. 2.. .Arakawa Y,. Yoshimura. M,. Kobayashi. S,. Ichihashi. K,. . Miyao.M,.Momoi.MY.and.Yanagisawa.M...The.use.of. intravenous.immunoglobulin.in.Miller.Fisher.syndrome.. . Brain.&.Development.1993;.1:.231-233. 3.. . sbury. AK. and. Cornblath. DR,. . Assessment. of. A current. diagnostic. criteria. for. Guillain-Barr syndrome...Ann.Neurol.1990;.27(suppl):S21-S2. .. . sbury. AK.. . Diagnostic. considerations. in. GuillainA Barr.syndrome...Ann.Neurol.1981;.9:.Suppl:.1-. .. . sbury. AK.. . New. concepts. of. Guillain-Barr. A syndrome...J.Child.Neurol.2000;.1:.183-191. 6.. . ril.V,.Use.WK,.Pearce.R,.Dhanani.A,.Sutton.D.and. B Kong.K...Pilot.trial.of.immunoglobulin.versus.plasma. exchange. in. patients. with. Guillain-Barr. syndrome.. . Neurology.1996;.6:100-103. 7 . han.LY,. sui.MH,.Leung. N...Guillain-Barr.syndrome. .. C T T in. pregnancy.. . Acta. Obstet. Gynecol. Scand. 200;. 83:319-32. 8.. . iener.H-C,.Haupt.WF D ,.Kloss.TM,.Rosenow.F ,.Philipp. T,. Koeppen. S.. . A. preliminary,. randomized. study. comparing. intravenous. immunoglobulin,. plasma. exchange,. and. immune. absorption. in. Guillain-Barr. syndrome.. . European. Neurology. . 2001;. 6:. 107109... 9.. . ait. G,. Gull. I,. Kupferminc. M,. Shenhav. M,. Gold. R,. F Jaffa. A. and. Lessing. JB.. . Intravenous. immune. globulins.in.Guillain-Barr.syndrome.in.pregnancy...J. Obstetrics.Gynaecology.1998;.18:78-79.
27
10... easby.TE,. Gilbert. JJ,. Brown.WF Bolton. CF Hahn. F ,. ,. AF Koopman.WF Zochodne. DW.. . An. acute. axonal. ,. ,. form. of. Guillain-Barr. polyneuropathy.. . Brain. 1986;. 109:.111-1126. 11.. French. Cooperative. Group. in. Plasma. Exchange. in. . Guillain-Barr. Syndrome.. . Efficiency. of. plasma. exchange. in. Guillain-Barr. . syndrome:. role. of. replacement.fluids...Ann.Neurol.1987;.22:.73-761. 12... rench. Cooperative. Group. in. Plasma. Exchange. in. F Guillain-Barr. . Syndrome.. . Plasma. exchange. in. Guillain-Barr. syndrome:. one. year. follow-up.. . Ann. Neurol.1992;.32:.9-97 . 13... riffin. JW,. Li. CY,. HoTW,. et. al.. . Guillain-Barr. G syndrome.in.northern.China...The.spectrum.of.neuropathological. changes. in. clinically. defined. cases.. . Brain.199;.118:77-9.
18... afer-Macko. CE,. Sheikh. KA,. Li. CY,. et. al.. . Immune. H attack.on.the.Schwann.cell.surface.in.acute.inflammatory. demyelinating. polyneuropathy.. .Ann. Neurol. 1996;.39:.627-637 . 19... aupt.WF Rosenow. F van. der.Ven. C,. Borberg. H,. H ,. ,. Pawlik. G.. . Sequential. treatment. of. Guillain-Barr. syndrome. with. extracorporeal. elimination. and. intravenous. immunoglobulin.. . J. Neurol. Sci. 1996;. 137:1-19. 20... eafield.MT,.Gammage.MD,.Nightingale.S,.Williams. H AC.. . Idiopathic. dysautonomia. treated. intravenous. gammaglobulin...Lancet.1996;.37:.28-29. 21.. . ughes.RAC,.Newsom-Davis.JM,.Perkin.GD,.Pierce. H JM.. . Controlled. trial. of. prednisolone. in. acute. polyneuropathy...Lancet.1978;.2:70-73. 22... ughes. RA,. Raphael. JC,. Swan. AV,. Doorn. PA.. H .
1... uillain-Barr. Syndrome. Steroid. Trial. . . Group.. G . Double-blind.trial.of.intravenous.methylprednisolone. in. Guillain-Barr. syndrome.. . Lancet. 1993;. 31:8690.
Intravenous. immunoglobulin. for. Guillain-Barr. syndrome...Cochrane.Database.Syst.Rev...2001;(2): CD002063. 23... ughes. RA,. Raphael. JC,. Swan. AV,. Doorn. PA.. H .
1... urses. N,. Uysal. S,. Cetinkaya. F Islek. I,. Kalayci.AG.. G ,. . Intravenous. immunoglobulin. treatment. in. children. with. Guillain-Barr. syndrome.. . Scand. J. Infect. Dis. 199;.27:.21-23.
Intravenous. immunoglobulin. for. Guillain-Barr. syndrome...Cochrane.Database.Syst.Rev...200;(1): CD002063..and.2006;.(1):CD002063. 2... ughes.RAC,.Rees.JH...Clinical.and.epidemiological. H
16... adden.RDM,.Cornblath.DR,.Hughes.RAD,.Zielasek. M J,. Hartung. H-RToyka. KV,. Swan.AV,. and. the. Plasma. Exchange/Snadoglobulin. Guillain-Barr. Syndrome. Trial. Group.. . Electrophysiological. Classification. of. Guillain-Barre. Syndrome:. Clinical. Associations. and. Outcome...Ann.Neurol.1998;.:780-788. 17 . afer-Macko.C,.Hsieh.ST,.Li.CY,.et.al...Acute.motor. .. H axonal. neuropathy:. an. antibody-mediated. attack. on. axolemma...Ann.Neurol.1996;.0:.63-6.
features. of. Guillain-Barr. syndrome.. . J. Infect. Dis. 1997;.176(suppl2):.S92-S98. 2... ughes. RAC,. van. der. Meche. FGA.. . Corticosteroid. H treatment. for. Guillain-Barr. syndrome.. . Cochrane. Database. Syst. Rev. 2000;(2):CD0016.. . Update. in. Cochrane.Database.Syst.Rev.2000;(3):CD0016. 26... ughes. RAC,.Wijdicks. EFM,. Barohn. R,. Benson. E,. H Cornblath. DR,. Hahn. AF Meythaler. JM,. Miller. RG,. ,. Sladky. JT. and. Stevens. JC.. . Practice. parameter:. Immunotherapy. for. Guillain-Barr. syndrome. Neurology.2003;.61:.736-70.
28
27 . acobs. BC,. Rothbarth. PH,. van. der. Meche. FG,. .. J Herbrink.P.Schmitz.PI,.de.Klerk.MA,.van.Doom.PA.. . The. spectrum. of. antecedent. infections. in. GuillainBarr.syndrome...A.case.control.study...Neurology. 1998;.1:.1110-111. 28... anra.G,.Ozon.A,.Vaisar.J,.Castagna.L,.Secmeer.G,. K Topaloglu.H...Intravenous.immunoglobulin.treatment. in. children. with. Guillain. Barr. syndrome.. . Eur. J. Paediatr.Neurol.1997;.1:7-12. 29... oga. M,. Gilbert. M,. Li. J,. Koike. S,. Takahashi. M,. K Furukawa.K,.Hirata.K,.Yuki.N...Antecedent.infections. in. Fisher. syndrome:. a. common. pathogenesis. of. molecular.mimicry...Neurology.200;.6:160-1611. 30... orinthenberg.R,.Schessl.J,.Kirschner.J,.Monting.JS.. K . Intravenously. administered. immunoglobulin. in. the. treatment. of. childhood. Guillain-Barr. syndrome:. a. randomized.trial...Pediatrics.200;.116:8-1. 31.. . uijckx.GJ,.Vles.J,.de.Baets.M,.Buchwald.B,.Troost. L J...Guillain-Barr.syndrome.in.a.mother.and.newborn. child...Lancet.1997;.39:27 . 32... cKhann. GM,. Cornblath. DR,. Griffin. JW,. et. al.. M . Acute.motor.axonal.neuropathy:.a.frequent.cause.of. acute. flaccid. paralysis. in. China.. .Ann. Neurol. 1993;. 33:333-32. 33... ericle.RA.and.Triggs.WJ...Treatment.of.acute.panM dyautonomia. with. intravenous. immunoglobulin.. . J. Neurol.Neurosurg.Psychiatry.1997;.62:29-31. 3... ishimoto.Y,. Koga. M,. Kamijo. M,. Hirata. K,.Yuki. N.. N . Immunoglobulin. improves. a. model. of. acute. motor. axonal. neuropathy. by. preventing. axonal. degeneration...Neurology.200;.62:.1939-19. 3... omura. T,. Hamaguchi. K,. Hosakawa. T,. Hattori. T,. N Satou.T,. Mannen.T,. et. al.. . A. randomized. controlled. trial. comparing. intravenous. immunoglobulin. and. plasmapheresis. in. Guillain-Barr. syndrome.. . Neurological.Therapeutics.2001;.18:.69-81.
36... lasma. Exchange/Sandoglobulin. Guillain-Barr. P Syndrome.Trial. Group.. . Randomised. trial. of. plasma. exchange,. intravenous. immunoglobulin,. and. combined. treatments. in. Guillain-Barr. syndrome.. . Lancet.1997;.39:.22-230. 37 . revots. DR,. Sutler. RW.. . Assessment. of. Guillain.. P Barr. syndrome. mortality. and. morbidity. in. the. United.States:.implications.for.acute.flaccid.paralysis. surveillance...J.Infect.Dis.1997;.17(suppl.1):.S11S1. 38... ritchard.J,.Gray.IA,.Idrissoya.ZR,.Lecky.BR,.Sutton. P IJ,.Swan.AV,.Willison.HJ,.Winer.JB,.Hughes.RA...A. randomized.controlled.trial.of.recombinant.interferonbeta. 1a. in. Guillain-Barr. syndrome.. . Neurology. 2003;.61:1282-128. 39... aphael.JC,.Chevret.S,.Harboun.M,.Jars-Guincestre. R MC;. French. Guillain-Barr. 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... aphael. J-C,. Chevret. S,. Hughes. RAC,. Annane. D.. R . Plasma. exchange. for. Guillain-Barr. syndrome. (Cochrane.review)...Cochrane.Database.of.Systemic. Reviews.2...Oxford:.Update.Software,.2001. 1.. Raphael. JC,. Masson. C,. Morice. V,. et. al.. . . Le. . syndrome.de.Guillain-Barre:.etude.retrospective.de. 233.observations...Sem.Hop.Paris.198;.60:.2326. 2... ees. JH,. Thompson. RD,. Smeeton. NC,. Hughes. R RAC.. . An. epidemiological. study. of. Guillain-Barr. syndrome.in.south.east.England...J.Neurol.Neurosurg. Psychiatry.1988;.6:.7-77 . 3... hahar. E. and. Leiderman. M.. . Outcome. of. severe. S Guillain-Barr. syndrome. in. children:. comparison. between. untreated. cases. versus. gamma-globulin. therapy...Clin.Neuropharmacol...2003;.26.(2):.8-87 .
29
... inghi. SC,. Jayshree. M,. Singhi. P. Banerjee. S,. S Prabhakar. S.. . Intravenous. immunoglobulin. in. very. severe.childhood.Guillain-Barr.syndrome...AnnTrop. Paediatr...1999;.19:.167-17. ... he. Guillain-Barr. Syndrome. Study. Group.. T . Plasmapheresis.and.acute.Guillain-Barr.syndrome.. . Neurology.198;.3:.1096-110. 6... he.Italian.Guillain-Barr.Study.Group...The.prognosis. T and. main. prognostic. indicators. of. Guillain-Barr. . syndrome:. a. multicentre. prospective. study. of. 297. patients...Brain.1996;.119:.203-2061. 7 Van. der. Meche. FGA,. Schmitz. PIM. and. the. Dutch. .. . Guillain-Barr. Study. Group.. . A. randomized. trial. comparing.intravenous.immune.globulin.and.plasma. exchange.in.Guillain-Barr..syndrome...N.Engl.J.Med. 1992;.326:.1123-1129. 8... an. Koningsveld. R,. Schmitz. PIM,. van. der. Meche. V FGA,.Visser. LH,. Meulstee. J,. van. Doom. PA;. Dutch. GBS. study. group.. . Effect. of. methylprednisolone. when.added.to.standard.treatment.with.intravenous. immunoglobulin. for. Guillain-Barr. syndrome:. randomised.trial...Lancet.200;363:192-196. 9... an.Koningsveld.R,.van.Doom.PA,.Schmitz.PI,.et.al.. V . Mild. forms. of. Guillain. Barr. syndrome. in. an. epidemiologic. survey. in. the. Netherlands.. . Neurology. 2000;.:.620-62. 0... isser. LH,. van. der. Meche. FG,. Meulstee. J,. van. V Doom.PA...Risk.factors.for.treatment.related.clinical. fluctuations. in. Guillain-Barr. syndrome.. . Dutch. Guillain-Barr. . study. group.. . J. Neurol. Neurosurg. Psychiatry.1998;.6:.22-2.
1.. . ang.R,.Feng.A,.Sun.W,.Wen.Z...Intravenous.immuW noglobulin.in.children.with.Guillain-Barr.syndrome.. . Jounal. of. Applied. Clinical. Pediatrics. 2001;. . 16:223-22. 2... illison. HJ,. Yuki. N.. Peripheral. neuropathies. and. W antiglycolipid. antibodies.. Brain. 2002;. 12:. . 291-.262.
30
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

INtROdUCtION
Chronic.inflammatory.demyelinating.neuropathy.(CIDP). is. an. acquired. sensorimotor. polyneuropathy. characterised. by. a. progressive. or. relapsing/remitting. course,. evidence. of. demyelination. on. electrophysiological. or. pathological. studies,. and. response. to. immunomodulatory.therapies...There.is.no.specific.diagnostic.test.but. the. characteristic. clinical. and. laboratory. findings. help. distinguish. this. disorder. from. other. immune. mediated. neuropathic.syndromes. 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.. . symmetric. presentation-MADSAM. or. the. LewisA Sumner.syndrome 3.. Pure.motor.CIDP . .. Pure.sensory.CIDP . .. . ocal.presentation.i.e...one.or.more.nerves.or.a.focal. F 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.. .Atleast.0%.prolongation.of.distal.motor.latency.or . 2.. . t.least.30%.reduction.of.motor.conduction.velocity,. A or
31
dIaGNOsIs
Accurate. 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-Barr. syndrome. of. subacute. onset. or. when. recurrent.. . Diagnostic. criteria. have.been.proposed.by.several.groups.which.describe. characteristic.clinical,.electrophysiological.and.histological. 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.. .
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 . istal.CMAP.duration.of.at.least.9ms.in.at.least.one. .. D nerve.+at.least.one.other.demyelinating.parameter. in.at.least.one.other.nerve... . In.practice.a.diagnosis.of.CIDP.may.be.made.when.
NatURaL hIstORY
The. 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. CIDP.is.a.relatively.rare.disease.in.childhood...As.a.
a.patient.presents.with.a.polyneuropathy.or.polyradiculoneuropathy.which.evolves.subacutely.over.more.than. .weeks. or.chronically.over.many.months. and.electrophysiological. 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.immunotherapy 6. . Nerve. biopsy. is. not. considered. mandatory. for. diagnosis.by.most.groups11,12.but.it.is.a.useful.procedure. when.doubt.concerning.diagnosis.remains...Since.cerebrospinal. 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.
patients.over.6.years18. 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 .
pathOGENEsIs
CIDP. 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. metalloproteinases. 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.
dIffERENtIaL dIaGNOsIs
1.. . ereditary. demyelinating. neuropathies. when. no. H family.history.available 2.. Neuropathies.associated.with.malignancy.including. . POEMS.syndrome 3.. IgM. monoclonal. gammopathy. with. antibodies. . . to.MAG. .. . etabolic. causes. of. demyelinating. neuropathy. M (diabetes,. uraemia,. hypothyroidism,. acromegaly).. . However.diabetes.and.CIDP.may.coexist. .. . rug.induced.demyelinating.neuropathies.including. D amiodorone,.perhexiline.maleate,.n-hexane 6.. .nfective.disorders.including.HIV.and.Lyme.disease I 7 Recurrent.Guillain.Barr.syndrome... .. 8.. Multifocal.motor.neuropathy.with.conduction.block
32
tREatMENt
CoRtICoStERoIDS Beginning.with.the.renowned.work.of.Austin .many.non.
.28
PLASMA ExCHANGE Several.uncontrolled.studies.have.reported.at.least.short. term.benefit.from.plasma.exchange37-1...Two.controlled. trials. subsequently. confirmed. its. efficacy.. . Dyck. and. colleagues2. 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. complications.and.is.contraindicated.in.children.and.patients.with. cardiovascular.instability. INtRAVENouS IMMuNoGLoBuLIN Four. randomised. placebo. controlled. trials. have. been. performed. using. IVIg. in. CIDP. of. which. 3. have. shown. the.efficacy.of.this.treatment3,.6-9...A.Cochrane.review,. has. confirmed. the. favourable. effect. of. IVIg0.. . 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. weeks1-3.. . 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.
33
randomised.studies.have.shown.the.efficacy.of.corticosteroid.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. healthrelated. 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.
3
administer . 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.contemplated .
3
significant. short. term. difference. between. IVIg. . and. plasma. exchange. or. between. IVIg. and. . oral.prednisone33... IMMuNoSuPPRESSIVE AGENtS No.controlled.trials.have.been.reported.for.any.immunosuppressive. 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. AzAtHIoPRINE Azathioprine.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. MyCoPHENoLAtE Several. uncontrolled. studies. of. small. numbers. of. patients.have.examined.the.effect.of.Mycophenolate.in. CIDP . Whereas. a. beneficial. effect. was. reported. by. .. some6,.no.benefit.was.reported.by.others7...A.controlled. trial.of.adequate.power.is.urgently.needed. CyCLoPHoSPHAMIDE A.series.of.1.patients.reported.by.Good.and.colleagues8. 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.neurologists. are. reluctant. to. use. this. drug. because. of. the. risk. of. serious. adverse. events. including. marrow. suppression,. bladder. toxicity,. cancer,. infertility. . and.alopecia. CyCLoSPoRIN A This.drug.which.acts.upon.T.cell.activation.and.cytokine. production.has.been.reported.to.be.effective.in.treatment. resistant.CIDP.in.anecdotal.series9.60... he.recommended. T
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. hepatotoxity,.anorexia,.gum.hypertrophy,.hirsuitism.and.neurotoxicity. INtERfERoN An. 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 MaNaGEMENt

INDuCtIoN of REMISSIoN For.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... MAINtENANCE tREAtMENt There. 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.corticosteroid,. as. the. case. may. be.. . Others. introduce. second.line.therapies.usually.a.combination.of.corticosteroid.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.
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.
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. 3mg/day.and.the.dose.progressively.reduced.according. to. clinical. improvement.. . Some. patients. can. be. maintained. on. low. dose. steroid. and. immunosuppression. 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.
REfERENCEs
1.. . esearch.criteria.for.diagnosis.of.chronic.inflammaR tory. demyelinating. polyneuropathy. (CIDP).. . Report. from. an. Ad. Hoc. Subcommittee. of. the. American. Academy.of.Neurology.AIDS.Task.Force..Neurology.. . 1991;.1:617-618. 2.. . icolas. G,. Maisonobe. T,. Le. Forestier. N,. et. al.. N . Proposed. revised. electrophysiological. criteria. for. chronic. inflammatory. demyelinating. polyradiculoneuropathy.Muscle.Nerve...2002;.2:26-30. 3.. . an.den.Bergh.PY,.Pieret.F V ...Electrodiagnostic.criteria. for. acute. and. chronic. inflammatory. demyelinating. polyradiculoneuropathy. Muscle. Nerve.. . 200;. 29:6-7. .. . cCombe. PA,. Pollard. JD,. McLeod. JG.. . Chronic. M inflammatory.demyelinating.polyradiculoneuropathy.. . A.clinical.and.electrophysiological.study.of.92.cases. Brain...1987;.110.(.Pt.6):1617-1630. .. . arohn. RJ,. Kissel. JT,.Warmolts. JR,. et. al.. . Chronic. B inflammatory.demyelinating.polyradiculoneuropathy.. . Clinical. characteristics,. course,. and. recommendations. for. diagnostic. criteria. Arch. Neurol.. . 1989;. 6:878-88. 6.. .Hughes .RA,.Bouche.P ,.Cornblath.DR,.et.al...European.
EXpERt CONsENsUs
In.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.immunosuppression. can. lead. to. a. reduction. of. the. expensive. treatments. over. time.. .Trials. addressing. this. issue. are.
Federation.of.Neurological.Societies/Peripheral.Nerve. Society.guideline.on.management.of.chronic.inflammatory.demyelinating.polyradiculoneuropathy:.report. of. a. joint. task. force. of. the. European. Federation. of. Neurological. Societies. and. the. Peripheral. Nerve. Society.Eur.J.Neurol...2006;.13:326-332. 7 . an.Doorn.PA...Treatment.of.Guillain-Barr.syndrome. .. v and.CIDP.J.Peripher.Nerv.Syst...200;.10:113-127 .
3
8.. . atov. N.. . Diagnosis. of. CIDP. Neurology.. . 2002;. L . 9:S2-S6. 9.. . agda. P Latov. N,. Brannagan. TH,. III,. et. al.. M ,. . Comparison. of. electrodiagnostic. abnormalities. and. criteria.in.a.cohort.of.patients.with.chronic.inflammatory. demyelinating. polyneuropathy. Arch. Neurol.. . 2003;.60:17-179. 10... oller. H,. Kieseier. BC,. Jander. S,. et. al.. . Chronic. K inflammatory.demyelinating.polyneuropathy.N.Engl. J.Med...200;.32:133-136. 11.. . olenaar. DS,. Vermeulen. M,. de. HR.. . Diagnostic. M value.of.sural.nerve.biopsy.in.chronic.inflammatory. demyelinating. polyneuropathy. J. Neurol. Neurosurg. Psychiatry...1998;.6:8-89. 12... aperstein. DS,. Katz. JS,. Amato. AA,. et. al.. . Clinical. S spectrum. of. chronic. acquired. demyelinating. polyneuropathies.Muscle.Nerve...2001;.2:311-32. 13... unn. MP Manji. H,. Choudhary. PP et. al.. . Chronic. L ,. ,. inflammatory. demyelinating. polyradiculoneuropathy:. a. prevalence. study. in. south. east. England.. . J. Neurol.Neurosurg.Psychiatry...1999;.66:677-680 1... cLeod.JG,.Pollard.JD,.Macaskill.P M ,.et.al...Prevalence. of.chronic.inflammatory.demyelinating.polyneuropathy. in. New. South. Wales,. Australia.. . Ann. Neurol.. . 1999;.6:910-913.
18... attori. N,. Misu. K,. Koike. H,. et. al.. . Age. of. onset. H influences. clinical. features. of. chronic. inflammatory. demyelinating. polyneuropathy. J. Neurol. Sci.. . 2001;. 18:7-63. 19... an. WX,. Taylor. J,. Ndrias-Kauba. S,. et. al.. . Passive. Y transfer. of. demyelination. by. serum. or. IgG. from. chronic.inflammatory.demyelinating.polyneuropathy. patients.Ann.Neurol...2000;.7:76-77. 20... oyka. KV,. Gold. R.. . The. pathogenesis. of. CIDP:. T rationale. for. treatment. with. immunomodulatory. agents.Neurology...2003;.60:S2-S7 . 21.. Spies.JM,.Westland.KW,.Bonner.JG,.et.al...Intraneural. . activated. T. cells. cause. focal. breakdown. of. the. blood-nerve.barrier.Brain..199;.118.(.Pt.):87-868. 22... athey. EK,. Pollard. JD,.Armati. PJ.. .TNF. alpha,. IFN. M gamma. and. IL-2. mRNA. expression. in. CIDP. sural. nerve.biopsies.J.Neurol.Sci...1999;.163:7-2. 23... an.WX,.Archelos.JJ,.Hartung.HP Y ,.et.al...P0.protein. is.a.target.antigen.in.chronic.inflammatory.demyelinating. polyradiculoneuropathy. Ann. Neurol.. . 2001;. 0:286-292. 2... abriel.CM,.Gregson.NA,.Hughes.RA..Anti-PMP22. G antibodies.in.patients.with.inflammatory.neuropathy. J.Neuroimmunol...2000;.10:139-16. 2... elendez-Vasquez.C,.Redford.J,.Choudhary.PP M ,.et.al.. .
1...Dyck .PJ,.Lais.AC,.Ohta.M,.et.al..Chronic.inflammtory. polyradiculoneuropathy.. Mayo. Clinic. Proceedings.. . 197;.0:621-61.
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16... cCombe. PA,. Pollard. JD,. McLeod. JG.. . Chronic. M inflammatory.demyelinating.polyradiculoneuropathy.. . A.clinical.and.electrophysiological.study.of.92.cases. Brain...1987;.110.(.Pt.6):1617-1630. 17 . ouchard.C,.Lacroix.C,.Plante.V,.et.al..Clinicopathologic. .. B findings.and.prognosis.of.chronic.inflammatory.demyelinating.polyneuropathy.Neurology...1999;.2:98-03.
36
Characterisation. of. autoantibodies. to. peripheral. myelin. protein. 22. in. patients. with. hereditary. and. acquired. neuropathies. J. Neuroimmunol.. . 2000;. 10:1-163. 27 Hughes.RA,.Allen.D,.Makowska.A,.et.al...Pathogenesis. .... of.chronic.inflammatory.demyelinating.polyradiculoneuropathy.J.Peripher.Nerv.Syst...2006;.11:30-6.
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relapsing.and.chronic.progressive.idiopathic.inflammatory.polyneuropathy.by.plasma.exchange.J.Neurol. Sci...1981;.2:69-78. 0... ollard.JD,.McLeod.JG,.Gatenby.P P ,.et.al...Prediction. of.response.to.plasma.exchange.in.chronic.relapsing. polyneuropathy...A.clinico-pathological.correlation.J. Neurol.Sci...1983;.8:269-287 . 1.. . robel. CJ,. Watson. D.. . Plasmapheresis. in. chronic. W demyelinating.polyneuropathy.N.Engl.J.Med...1992;. 326:1089-1090. 2... yck.PJ,.Daube.J,.O'Brien.P D ,.et.al...Plasma.exchange. in.chronic.inflammatory.demyelinating.polyradiculoneuropathy.N.Engl.J.Med...1986;.31:61-6. 3... ahn.AF H ,.Bolton.CF ,.Pillay.N,.et.al...Plasma-exchange.
3... cCrone.P M ,.Chisholm.D,.Knapp.M,.et.al...Cost-utility. analysis.of.intravenous.immunoglobulin.and.prednisolone. for. chronic. inflammatory. demyelinating. polyradiculoneuropathy.Eur.J.Neurol...2003;.10:687-69.
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3... ehndiratta. MM,. Hughes. RA.. . Corticosteroids. for. M chronic. inflammatory. demyelinating. polyradiculoneuropathy. Cochrane. Database. Syst. Rev.. . 2002;. CD002062.
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37
6... an. Doorn. PA,. Brand.A,. Strengers. PF et. al.. . Highv ,. dose. intravenous. immunoglobulin. treatment. in. chronic. inflammatory. demyelinating. polyneuropathy:. a. double-blind,. placebo-controlled,. crossover. study.Neurology...1990;.0:209-212.
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7 . hompson. N,. Choudhary. P Hughes. RA,. et. al.. . A. .. T ,. novel.trial.design.to.study.the.effect.of.intravenous. immunoglobulin. in. chronic. inflammatory. demyelinating. polyradiculoneuropathy. J. Neurol.. . 1996;. 23:280-28. 8... endell. JR,. Barohn. RJ,. Freimer. ML,. et. al.. M . Randomized. controlled. trial. of. IVIg. in. untreated. chronic. inflammatory. demyelinating. polyradiculoneuropathy.Neurology...2001;.6:-9. 9... ahn.AF H ,.Bolton.CF ,.Zochodne.D,.et.al...Intravenous. immunoglobulin. treatment. in. chronic. inflammatory. demyelinating. polyneuropathy.. . A. double-blind,. placebo-controlled,. cross-over. study. Brain.. . 1996;. 119.(.Pt.):1067-1077 . 0... an.Schaik.IN,.Winer.JB,.de.Haan.R,.et.al...Intravenous. v immunoglobulin.for.chronic.inflammatory.demyelinating. polyradiculoneuropathy:. a. systematic. review. Lancet.Neurol..2002;.1:91-98. 1.. . houdhary.PP C ,.Hughes.RA...Long-term.treatment.of. chronic. inflammatory. demyelinating. polyradiculoneuropathy. with. plasma. exchange. or. intravenous. immunoglobulin.QJM...199;.88:93-02. 2... an.Doorn.PA,.Vermeulen.M,.Brand.A,.et.al...Intravenous. v immunoglobulin. treatment. in. patients. with. chronic. inflammatory. demyelinating. polyneuropathy.. . Clinical. and. laboratory. characteristics. associated. with. improvement.Arch.Neurol...1991;.8:217-220. 3... iles. CM,. Brown. P Chapel. H,. et. al.. . Intravenous. W ,. immunoglobulin.in.neurological.disease:.a.specialist. review. J. Neurol. Neurosurg. Psychiatry.. . 2002;. 72:0-8.
38
azathioprine. and.prednisone. in. chronic. inflammatory-demyelinating. polyneuropathy. Neurology.. . 198;. 3:1173-1176. 6...MowzoonN,.Sussman. ,.Bradley,. G...Mycophenolate. . A W (CellCept). treatment. of. myasthenia. gravis,. chronic. inflammatory. polyneuropathy. and. inclusion. body. myositis.J.Neurol.Sci...2001;.18:119-122. 7 . mapathi. T,. Hughes. RA,. Nobile-Orazio. E,. et. al.. .. U . Immunosuppressive.treatment.for.multifocal.motor. neuropathy. Cochrane. Database. Syst. Rev.. . 2002;CD003217 . 8... ood. JL,. Chehrenama. M,. Mayer. RF et. al.. . Pulse. G ,. cyclophosphamide. therapy. in. chronic. inflammatory. demyelinating. polyneuropathy. Neurology.. . 1998;. 1:173-1738. 9... odgkinson.SJ,.Pollard.JD,.McLeod.JG...Cyclosporin. H A.in.the.treatment.of.chronic.demyelinating.polyradiculoneuropathy. J. Neurol. Neurosurg. Psychiatry.. . 1990;.3:327-330. 60... arnett.MH,.Pollard.JD,.Davies.L,.et.al...Cyclosporin. B A. in. resistant. chronic. inflammatory. demyelinating. polyradiculoneuropathy. Muscle. Nerve.. . 1998;. 21:-60. 61.. . orson.KC,.Ropper.AH,.Clark.BD,.et.al...Treatment. G of.chronic.inflammatory.demyelinating.polyneuropathy.with.interferon-alpha.2a.Neurology...1998;.0:887 . 62... adden.RD,.Sharrack.B,.Bensa.S,.et.al...Randomized. H trial. of. interferon. beta-1a. in. chronic. inflammatory. demyelinating. polyradiculoneuropath. Neurology.. . 1999;.3:7-61.
MULTIFOCAL MOTOR NEUROPATHY

dEfINItION
Multifocal.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.pattern ...Upper.motor.neuron.signs.do.not.
1,2
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.supramaximal.stimulation. . However.Pakiam.and.Parry8.have.described.patients.
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)
dIaGNOsIs
The. 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.
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.
39
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.disease ...However.the.role.
1
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 hIstORY
MMN. 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.deterioration. correlates. with. reduced. distal. CMAP. amplitude. presumably. because. of. progressive. axonal. degeneration22...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.deterioration.may.relate.to.question.of.dosage23-2...
of. antiganglioside. antibodies. in. MMN. remains. to. . be.defined... . Hence. the. diagnosis. is. usually. made. in. a. patient. with.the.appropriate.clinical.features.and.electrophysiological. 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...
pathOLOGY
In.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.
pathOGENEsIs
The. 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.
0
tREatMENt
INtRAVENouS IMMuNoGLoBuLIN Four. 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.
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. cases
22,38
immunosuppressive. agent. in. MMN. alone. or. in. combination. with. IVIg2.. . Because. of. the. well. known. adverse. effects. of. cyclophosphamide. its. use. in. MMN. should.be.considered.only.in.severely.affected.cases. IMMuNoSuPPRESSIVE AGENtS Several.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. cyclophosphamide.the.lack.of.controlled.studies.and.its.adverse.effect. profile.have.limited.its.use.in.MMN. otHER tHERAPIES Patients. with. MMN. may. worsen. following. treatment. with. corticosteroids7. and. plasma. exchange8. and. their. use.is.not.indicated...Improvement.has.been.described. in. small. numbers. of. patients. following. interferon-beta. 1a.therapy9...Benefit.has.also.been.reported.in.a.small. group. of. patients. following. the. use. of. the. B. cell. (antiCD20).monoclonal.antibody,.Rituximab0-2.
.. . 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. degeneration23.. . A. previous. study. has. correlated. clinical. improvement.with.reduction.of.conduction.block.in.neurophysiological. studies ,. but. another. long. term. study.
30
reported. that. conduction. block. improved. in. some. nerves.but.become.apparent.in.others.during.treatment. with.IVIg38...A.report.of.progressive.axonal.loss.despite. therapy . is. consistent. with. those. studies. showing.
22
continued. clinical. deterioration inadequate.dosage. DoSAGE
22,28,38,0
. but. may. reflect.
sUMMaRY
Because.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.
Treatment.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. immunosuppressive. 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.
EXpERt CONsENsUs
IVIg. 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.
1
REfERENCEs
1.. .Nobile-Orazio E,. Cappellari. A,. Meucci. N,. et. al.. . . Multifocal. motor. neuropathy:. clinical. and. immunological.features.and.response.to.IVIg.in.relation.to.the. presence. and. degree. of. motor. conduction. block.. . J. Neurol.Neurosurg.Psychiatry...2002;.72:761-766. 2.. . obile-Orazio.E,.Casellato.C,.Di. roia.A...Neuropathies. N T associated.with.IgG.and.IgA.monoclonal.gammopathy.. Rev.Neurol.(Paris)...2002;.18:979-987 . 3.. . aylor.BV,.Willison.HJ...Multifocal.Motor.Neuropathy. T and.Conduction.Block.ed.,.200:2277-2298 .. . arry. GJ.. . Motor. neuropathy. with. multifocal. P conduction. block.. . Semin. Neurol.. . 1993;. 13:26927. .. . rarup.C,.Stewart.JD,.Sumner.AJ,.et.al...A.syndrome. K of.asymmetric.limb.weakness.with.motor.conduction. block...Neurology...1990;.0:118-127 . 6.. . hee. EK,. England. JD,. Sumner. AJ.. . A. computer. R simulation.of.conduction.block:.effects.produced.by. actual. block. versus. interphase. cancellation.. . Ann. Neurol...1990;.28:16-16. 7 . feiffer. G,. Wicklein. EM,. Wittig. K.. . Sensitivity. and. .. P specificity.of.different.conduction.block.criteria...Clin. Neurophysiol...2000;.111:1388-139. 8.. . akiam.AS,.Parry.GJ...Multifocal.motor.neuropathy. P without. overt. conduction. block.. . Muscle. Nerve.. . 1998;.21:23-2. 9.. . atz. JS,. Saperstein. DS,. Gronseth. G,. et. al.. . Distal. K acquired. demyelinating. symmetric. neuropathy.. . Neurology...2000;.:61-620.
11.. . ornberg.AJ,.Pestronk.A,.Bieser.K,.et.al...The.clinical. K correlates. of. high-titer. IgG. anti-GM1. antibodies.. . Ann.Neurol...199;.3:23-237 . 12... ouche. P Moulonguet.A,.Younes-Chennoufi.AB,. et. B ,. al.. . Multifocal. motor. neuropathy. with. conduction. block:. a. study. of. 2. patients.. . J. Neurol. Neurosurg. Psychiatry...199;.9:38-. 13... estronk. A,. Li. F Griffin. J,. et. al.. . Polyneuropathy. P ,. syndromes. associated. with. serum. antibodies. to. sulfatide. and. myelin-associated. glycoprotein.. . Neurology...1991;.1:37-362. 1... illison. HJ.. .The. immunobiology. of. Guillain-Barr. W syndromes.. . J. Peripher. Nerv. Syst.. . 200;. 10:9112. 1... iernan. MC,. Guglielmi. JM,. Kaji. R,. et. al.. . Evidence. K for.axonal.membrane.hyperpolarization.in.multifocal. motor. neuropathy. with. conduction. block.. . Brain.. . 2002;.12:66-67. 16... irota.N,.Kaji.R,.Bostock.H,.et.al...The.physiological. H effect.of.anti-GM1.antibodies.on.saltatory.conduction. and.transmembrane.currents.in.single.motor.axons.. . Brain...1997;.120.(.Pt.12):219-2169. 17 . akigawa.T,.Yasuda.H,.Kikkawa.R,.et.al...Antibodies. .. T against.GM1.ganglioside.affect.K+.and.Na+.currents. in.isolated.rat.myelinated.nerve.fibers...Ann.Neurol.. . 199;.37:36-2. 18... antoro.M,.Uncini.A,.Corbo.M,.et.al...Experimental. S conduction. block. induced. by. serum. from. a. patient. with. anti-GM1. antibodies.. . Ann. Neurol.. . 1992;. 31:38-390. 19... arvey.GK,.Gold.R,.Hartung.HP H ,.et.al...Non-neural-
10... odera. H,. Bostock. H,. Izumi. Y,. et. al.. . ActivityN dependent. conduction. block. in. multifocal. motor. neuropathy:. magnetic. fatigue. test.. . Neurology.. . 2006;.67:280-287 .
specific.T.lymphocytes.can.orchestrate.inflammatory. peripheral. neuropathy.. . Brain.. . 199;. 118. (. Pt. ):1263-1272.
2
20... aylor. BV,. Dyck. PJ,. Engelstad. J,. et. al.. . Multifocal. T motor.neuropathy:.pathologic.alterations.at.the.site. of. conduction. block.. . J. Neuropathol. Exp. Neurol.. . 200;.63:129-137 . 21.. . an.Asseldonk.JT,.Van.den.Berg.LH,.Kalmijn.S,.et.al.. V . Axon.loss.is.an.important.determinant.of.weakness. in.multifocal.motor.neuropathy...J.Neurol.Neurosurg. Psychiatry...2006;.77:73-77 . 22... erenghi.F T ,.Cappellari.A,.Bersano.A,.et.al...How.long. is. IVIg. effective. in. multifocal. motor. neuropathy?.. . Neurology...200;.62:666-668. 23... ucic.S,.Black.KR,.Chong.PS,.et.al...Multifocal.motor. V neuropathy:.decrease.in.conduction.blocks.and.reinnervation. with. long-term. IVIg.. . Neurology.. . 200;. 63:126-1269. 2... an. Schaik. IN,. Bouche. P Illa. I,. et. al.. . European. v ,. Federation. of. Neurological. Societies/Peripheral. Nerve. Society. guideline. on. management. of. multifocal. motor. neuropathy.. . Eur. J. Neurol.. . 2006;. 13:802-808. 2... ross. D,. Drake. E.. . Multifocal. motot. neuropathies. C with. conduction. block;. long. term. follow. up. of. ten. patients.treated.with.IVIg...Rev.Neurol.(Paris)...2006;. 162S1:36-30. 26... uer.RN,.Bell.RB,.Lee.MA...Neuropathy.with.onion. A bulb. formations. and. pure. motor. manifestations.. . Can.J.Neurol.Sci...1989;.16:19-197 . 27 . aji.R,.Oka.N,.Tsuji.T,.et.al...Pathological.findings.at. .. K the. site. of. conduction. block. in. multifocal. motor. neuropathy...Ann.Neurol...1993;.33:12-18.
29... an. den. Berg. LH,. Kerkhoff. H,. Oey. PL,. et. al.. V . Treatment.of.multifocal.motor.neuropathy.with.high. dose.intravenous.immunoglobulins:.a.double.blind,. placebo. controlled. study.. . J. Neurol. Neurosurg. Psychiatry...199;.9:28-22. 30... ederico.P F ,.Zochodne.DW,.Hahn.AF ,.et.al...Multifocal. motor. neuropathy. improved. by. IVIg:. randomized,. double-blind,. placebo-controlled. study.. . Neurology.. . 2000;.:126-1262. 31.. . eger.JM,.Chassande.B,.Musset.L,.et.al...Intravenous. L immunoglobulin. therapy. in. multifocal. motor. neuropathy:. a. double-blind,. placebo-controlled. study...Brain...2001;.12:1-13. 32... haudhry. V,. Corse. AM,. Cornblath. DR,. et. al.. C . Multifocal. motor. neuropathy:. response. to. human. immune.globulin...Ann.Neurol...1993;.33:237-22. 33... obile-Orazio.E,.Meucci.N,.Barbieri.S,.et.al...HighN dose. intravenous. immunoglobulin. therapy. in. multifocal. motor. neuropathy.. . Neurology.. . 1993;. 3:37-. 3... omi. G,. Amadio. S,. Galardi. G,. et. al.. . Clinical. and. C neurophysiological. assessment. of. immunoglobulin. therapy. in. five. patients. with. multifocal. motor. neuropathy...J.Neurol.Neurosurg.Psychiatry...199;. 7.Suppl:3-37 . 3... zulay. JP Blin. O,. Pouget. J,. et. al.. . Intravenous. A ,. immunoglobulin. treatment. in. patients. with. motor. neuron. syndromes. associated. with. anti-GM1. antibodies:.a.double-blind,.placebo-controlled.study.. . Neurology...199;.:29-32. 36... eucci.N,.Cappellari.A,.Barbieri.S,.et.al...Long.term. M
28... zulay.JP A ,.Rihet.P ,.Pouget.J,.et.al...Long.term.follow. up.of.multifocal.motor.neuropathy.with.conduction. block. under. treatment.. J. Neurol. Neurosurg. Psychiatry...1997;.62:391-39.
effect. of. intravenous. immunoglobulins. and. oral. cyclophosphamide. in. multifocal. motor. neuropathy.. . J.Neurol.Neurosurg.Psychiatry...1997;.63:76-769.
3
37 . an. den. Berg. LH,. Franssen. H,. Wokke. JH.. .. V . Improvement.of.multifocal.motor.neuropathy.during. long-term. weekly. treatment. with. human. immunoglobulin...Neurology...199;.:987-988. 38... an.den.Berg-Vos.RM,.Franssen.H,.Wokke.JH,.et.al.. V . Multifocal.motor.neuropathy:.long-term.clinical.and. electrophysiological. assessment. of. intravenous. immunoglobulin. maintenance. treatment.. . Brain.. . 2002;.12:187-1886. 39... an. Doorn. PA,. van. der. Meche. FG.. . IVIg. treatment. v improves.multifocal.motor.neuropathy:.easy.to.start. but. difficult. to. stop.. . Neurology.. . 2000;. :126127 . 0... an.den.Berg.LH,.Franssen.H,.Wokke.JH...The.longV term.effect.of.intravenous.immunoglobulin.treatment. in.multifocal.motor.neuropathy...Brain...1998;.121.(. Pt.3):21-28. 1.. . an.den.Berg-Vos.RM,.Franssen.H,.Wokke.JH,.et.al.. V . Multifocal.motor.neuropathy:.diagnostic.criteria.that. predict.the.response.to.immunoglobulin.treatment.. . Ann.Neurol...2000;.8:919-926. 2... mapathi. T,. Hughes. RA,. Nobile-Orazio. E,. et. al.. U . Immunosuppressive.treatment.for.multifocal.motor. neuropathy.. . Cochrane. Database. Syst. Rev.. . 2002;CD003217 . 3... eldman. EL,. Bromberg. MB,. Albers. JW,. et. al.. F . Immunosuppressive. treatment. in. multifocal. motor. neuropathy...Ann.Neurol...1991;.30:397-01. ... estronk.A,.Cornblath.DR,.Ilyas.AA,.et.al...A.treatable. P multifocal.motor.neuropathy.with.antibodies.to.GM1. ganglioside...Ann.Neurol...1988;.2:73-78. ... an.E,.Lynn.DJ,.Amato.AA,.et.al...Immunosuppressive. T treatment.of.motor.neuron.syndromes...Attempts.to. distinguish.a.treatable.disorder...Arch.Neurol...199;. 1:19-200.
6... estronk. A,. Lopate. G,. Kornberg. AJ,. et. al.. . Distal. P 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 . onaghy.M,.Mills.KR,.Boniface.SJ,.et.al...Pure.motor. .. D demyelinating.neuropathy:.deterioration.after.steroid. treatment.and.improvement.with.intravenous.immunoglobulin.. . J. Neurol. Neurosurg. Psychiatry.. . 199;. 7:778-783. 8... arpo.M,.Cappellari.A,.Mora.G,.et.al...Deterioration. C of. multifocal. motor. neuropathy. after. plasma. exchange...Neurology...1998;.0:180-182. 9... artina.IS,.van.Doorn.PA,.Schmitz.PI,.et.al...Chronic. M motor. neuropathies:. response. to. interferon-beta1a. after. failure. of. conventional. therapies.. . J. Neurol. Neurosurg.Psychiatry...1999;.66:197-201. 0... evine.TD,. Pestronk. A.. . IgM. antibody-related. polyL neuropathies:. B-cell. depletion. chemotherapy. using. Rituximab...Neurology...1999;.2:1701-170. 1.. . estronk.A,.Florence.J,.Miller.T,.et.al...Treatment.of. P IgM. antibody. associated. polyneuropathies. using. rituximab.. . J. Neurol. Neurosurg. Psychiatry.. . 2003;. 7:8-89. 2... uegg. SJ,. Fuhr. P Steck. AJ.. . Rituximab. stabilizes. R ,. multifocal. motor. neuropathy. increasingly. less. responsive. to. IVIg.. . Neurology.. . 200;. 63:21782179.

IGM PARAPROTEINEMIC NEUROPATHIES

INtROdUCtION
The.association.of.paraproteins.with.peripheral.neuropathies. was. first. described. with. multiple. myeloma. and. subsequently. with. Waldenstrms. 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. . 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.
dEfINItION
Neuropathies.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).
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.gammopathies. were. associated. with. malignant. lymphoproliferative.diseases1.
GENERaL INfORMatION
It.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...
pathOGENEsIs
Pathogenetically,.damage.to.nerve.tissue.by.paraproteins. is.thought.to.occur.by.the.following.mechanisms1:... irectly,.if.having.properties.of.antibodies.specific.for. D a.myelin.or.axonal.component..gangliosides,.sulfated. glycosphingolipids.&.glycoprotein.antigens

.. myloid. A
by-product.
deposition.
(causing. .
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:.. oot.numbness,.paresthesias,.imbalance,.gait.ataxia,. F dysesthesias.or.lancinating.pains .. eakness.of.distal.leg.muscles.and.variable.atrophy,. W as.illness.advances IgM neuropathies.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.neuropathies.. . IgM. demyelinating. neuropathies. form. a. distinct.subset.with.the.following.features:.. haracterized. by. slowly. progressive,. mainly. distal,. C 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.
non-specific.damage) .. ocal.ischemia.due.to.serum.hyperviscosity.(causing. L 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. (polyneuropathy,. organomegaly,. endocrinopathy,. M. band. and. skin.changes).syndrome.have.an.uncertain.causal.relationship.with.neuropathies...
CLINICaL pREsENtatION
Paraproteinemic. 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:-
SyStEMIC DISoRDER Multiple.myeloma. Waldenstrms.macroglobulinemia. Osteosclerotic.myeloma. Primary.NF-amyloidosis. Cryoglobulinemia. POEMS.syndrome. CANOMAD.syndrome.
tyPE of IMMuNoGLoBuLIN & LIGHt CHAIN CLASS 10%.show.IgM./.IgG-. IgM-. 8%.IgG./.IgA-. IgG/IgA-..;.initial.feature.in.1%. IgM.or.IgG. IgG/IgA-.. IgM.
tyPE of PoLyNEuRoPAtHy
Axonal Demyelinating Demyelinating Axonal Axonal Mixed.demyelinating.&.axonal.picture Mixed.demyelinating.&.axonal.picture
6
.. ore.than.0%.are.associated.with.antibodies.against. M myelin-associated.glycoprotein.(MAG).and.sphingoglycolipids. and. are. more. commonly. associated. with. kappa.than.lambda.light.chains ..IgM .neuropathies.associated.with.anti-GM 1.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. .. erve. conduction. studies. shows. sensory. fibres. that. N are. severely. affected. with. conduction. velocity. . slowing. (without. block). that. is. more. diffuse. and. distally.predominant .. ess. L 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.paraproteins.. . Electrophysiologically,. focal. blocks. of. conduction.in.motor.nerves.may.be.detected...
most.compelling.reason.for.ordering.a.nerve.biopsy.will. be.to.rule.out.amyloid.deposition...
OBJECtIVEs
To. 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. immunosuppressive.regimes...Most.case.series.are.small.(1.. .patients).and.include.diverse.groups.of.patients.with. conventional.immunotherapies...Peer-reviewed.publications. 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 NEUROpathIEs

In.an.open.study.in.1990, Cook et al1.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, Lger et al2. in. an. open-label. IVIG. study,. reported. six. out. of. 13. patients. (6%),. who. demonstrated. 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.neuromuscular. symptoms. at. baseline,. three. months. and. at.
7
INVEstIGatIONs
The.important.principle.in.investigating.paraproteinemic. patients.is.to.differentiate.the.malignant.from.the.nonmalignant.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.immunoglobulin. 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.workup. but. also. provides. a. correlation. with. patients. symptoms.for.prognosis.and.symptom.clarification...The.
treatments.end...Only.2.out.of.11.patients.demonstrated. 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] . Gorson et al20.in 1997.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. -. subcutaneously. 3. MU/ m.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-. 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. -. . conducted. by. the. same. group. of. investigators,. . found. no. benefit. from. interferon. treatment.. . [Level.II.evidence]
A.case.report.by.Ponsford et al in 2000.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.. .gM. neuropathies,. with. or. without. reactivity. to. I 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.conservatively.and.treated.only.symptomatically.for.paresthesiae. 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.. . hose. IgG & IgA monoclonal gammopathies. T fulfilling. criteria. for. demyelinating. neuropathy. are. best. treated. like. idiopathic. CIDP. with. conventional. immunomodulating. therapies. such. as. corticosteroids,. plasma. exchange. and. IVIG.. . (Please. refer. to. section.on.CIDP)
8
3.. .n. those. patients. where. PpN are detected with I multiple myeloma, amyloidosis or Waldenstrms macroglobulinemia,.treatment.should.be.directed. at. the. underlying. disease.. . Most. disappointingly,. these. neuropathies. often. remain. recalcitrant. to. treatment...IVIG.is.not.indicated.here. .. . or.those.paraproteinemic.neuropathies.associated. F with.Type.II./.III.Cryoglobulinemia.due.to.Hepatitis.C. virus.infection,.it.is.recommended.that.they.receive. interferon. -. . (with. or. without. ribavirin). for. . 6..12.months
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.paraproteinemic.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.paraproteinemic.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...
OthER IMMUNOsUppREsaNts BEING CONsIdEREd

In.recent.times,.the.following.drugs.have.been.tested.as. alternative. treatment. options. for. refractory. cases. but. their.efficacy.remains.open.to.debate:..Mycophenolate mofetil.(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. . . ituximab..Humanized.monoclonal.antibody.against. R CD20. antigen. has. been. used. especially. for. Waldenstrms.macroglobulinemia.with.IgM-related. neuropathies. that. show. moderate. to. severe. disability...Weekly.infusions.of.37mg/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 . . ludarabine. . fluorinated. purine. analogue. shows. F promising.results.in.various.low.grade.lymphoproliferative. conditions. including. IgM-secreting. plasma. cell. dyscrasias.. . Intravenous. (IV). Fludarabine. was. given.at.2mg/m2.daily.for..days.every...6.weeks. for.6.months.7... . . ladribine. . a. purine. nucleoside. analogue;. in. C combination. with. IVIG. infusion. has. been. used. 1.. . While. the. M-protein. levels. reduced,. IVIG. was. required.to.maintain.the.clinical.remission...
REfERENCEs:
1.. . ook. D,. Dalakas. M,. Galdi. A,. et. al.. . High. dose. C intravenous. immunoglobulin. in. the. treatment. of. demyelinating. 0:212-21. 2.. . ger. JM,. Ben. Younces-Chennoufi. A,. Chassande. L 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.. . alakas. MC,. Quarles. RH,. Farrer. RC,. et. al.. . A. D controlled. study. of. intravenous. immunoglobulin. in. demyelinating. neuropathy. with. IgM. gammopathy.. . Ann.Neurol.1996;.0():792-79. .. . llie.E,.Vital.A,.Steck.A,.et.al...Neuropathy.associated. E with. benign. anti-myelin-associated. glycoprotein. IgM. gammopathy:. Clinical,. immunological,. neurophysiological,.pathological.findings.and.response.to. treatment.in.33.cases...J.Neurol.1996;.23:3-3. neuropathy. associated. with. monoclonal. gammopathy.. . Neurology. 1990;. .
9
.. . ariette. X,. Chastang. C,. Clavelou. P et. al.. . A. M ,. randomized.trial.comparing.interferon.(IFN)...and. intravenous. immunoglobulin. in. polyneuropathy. associated.with.monoclonal.IgM...J.Neurol.Neurosurg. Psychiatry.1997;.63:28-3. 6.. . opper. &. Gorson.. . Neuropathies. associated. with. R Paraproteinemia...NEJM.1998;.338(22):.1601..1607 . 7 . ilson. HC,. Lunn. MPT,. Schey. S. &. Hughes. RAC.. .. W . Successful. treatment. of. IgM. paraproteinemic. neuropathy. with. fludarabine.. . J. Neurol. Neurosurg. Psychiatry.1999;66:7.-.80. 8.. . evine.TD.&.Pestronk.A...IgM.antibody-related.polyL neuropathies:. B-cell. depletion. chemotherapy. using. Rituximab...Neurology.1999;2:1701..170. 9.. . obile-Orazio. E,. Meucci. N,. Baldini. L,. Di. Troia. A,. N 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... issel. JT,. Mendell. JR.. . Neuropathies. Associated. K with. Monoclonal. Gammopathies.. . Diagnosis. and. Management. of. Peripheral. Nerve. Disorders. 2001. Oxford.University.Press,.Inc.:272.-.291. 11.. . aperstein. DS,. Amato. AA,. Katz. JS,. Barohn. RJ.. S . Immune-Mediated.Polyneuropathies...Neuromuscular. Diseases.2001.Butterworth-Heinemann:.17..167 . 12... icklund. MP. &. Kissel. JT.. . Paraproteinemic. W Neuropathy...Current.treatment.Options.in.Neurology. 2001;.3.:17.-.16. 13... omi.et.al...for.the.Inflammatory.Neuropathy.Cause. C and. Treatment. Group.. . A. randomized. trail. of. intravenous. immunoglobulin. in. IgM. paraproteins. associated.demyelinating.neuropathy...J...Neurology. 2002;.29:.1370..1377 .
1... hosh.A,.Littlewood.T.&.Donaghy.M...Cladribine.in. G the. treatment. of. IgM. paraproteinemic. neuropathy.. . Neurology.2002;9:1290..1291. 1... letz. MWR,. Duda. PW,. Kappos. L. &. Steck. AJ.. P . Immune-mediated. neuropathies:. etiology. and. pathogenic. relationship. to. again. processes.. . J.. . of. Neuroimmunology.2003;137:1-11.. 16... orson. KC,. Amato. A. &. Ropper. AH.. . Efficacy. of. G mycophenolate. mofetil. in. patients. with. chronic. immune.demyelinating.polyneuropathy...Neurology. 200;.63:71..717 . 17 .Monaco Turri.E,.Zanusso.G,.Maistrello.B... reatment. .. .S,. T of. inflammatory. and. paraproteinemic. neuropathies.. . Curr. Drug.Targets. Immune. Endocr. Metabol. Disord.. . 200.Jun;..(2):11..18...Review. 18... .Kumar,.A.Verma,.D.Kishore,.LD.Parhi,.D.Joshi,.S. P Misra.. . Polyneuropathy. with. Osteosclerotic. Myeloma..POEMS.Syndrome.JAPI..Dec.200;.Vol.. . 2:.997-998. 19... oint.Task.Force.of.the.EFNS.and.PNS...Guideline.on. J management. of. paraproteinemic. demyelinating. neuropathies.. . J. Peripher. Nerv. Syst.. . 2006. Mar;. . 11.(1):.9..19. 20... orson. KC,. Allam. G,. Ropper. AH.. . Chronic. inflamG 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. paraproteinsassociated.peripheral.neuropathy.(Review).2007 .
0
BRACHIAL AND LUMBOSACRAL PLEXOPATHIES

NEURaLGIC aMYOtROphY/BRaChIaL NEURItIs
BACkGRouND Neuralgic. 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.continuously.present.and.may.last.several.weeks... he.weakness,. T wasting.and.sensory.loss.are.often.very.patchy.in.distribution,. 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.
1
pathOGENEtIC MEChaNIsMs IN NEURaLGIC aMYOtROphY

Two. 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...
having.conduction.block.and.no.pain.may.not.be.distinguished.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 pLEXOpathY

Diabetic. lumbosacral. plexopathy. is. a. distinct. complication. 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.
tREatMENt Of NEURaLGIC aMYOtROphY

CoNVENtIoNAL tHERAPy Conventional. treatment. of. neuralgic. amyotrophy. has. generally.been.conservative,.based.on.the.understanding. of. a. relatively. benign. prognosis.. . Patients. have. generally. been. offered. symptomatic. treatments,. especially.pain.relief.during.the.acute.phase,.with.rehabilitative. 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 IVIG

With. 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.
2
IdIOpathIC LUMBOsaCRaL pLEXOpathY

A.syndrome.similar.to.diabetic.lumbosacral.plexopathy,. but. unassociated. with. diabetes. mellitus. is. also. recognized.and.referred.to.as.idiopathic,.primary.or.nondiabetic. 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.
pathOGENEtIC MEChaNIsMs Of dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathY

Pathological.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. indistinguishable,. raising. the. question. whether. the. two. disorders.have.a.similar.pathogenetic.mechanism.
largest. of. these. series. reported. five. patients. in. whom. response.to.IVIG.was.suggested.by.the.temporal.relationship. 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. nonhereditary.forms.of.neuralgic.amyotrophy....
thERapY IN dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathY

Although.controlled.trials.with.IVIG.and.methylprednisolone.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.cyclosporine. . 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.
REfERENCEs
1.. . rdolino.G,.Barbieri.S,.Priori.A...High.dose.intravenous. A immune. globulin. in. the. treatment. of. hereditary. recurrent. brachial. plexus. neuropathy.. . J. Neurol. Neuorsurg.Psychiat.2003;.7:0-1. 2.. . usimano.MD,.Bilbao.JM,.Cohen.SM...Hypertrophic. C brachial.plexus.neuritis:.A.pathological.study.of.two. cases...Ann.Neurol.1988;.2:61-622. 3.. . yck. PJB,. Engelstad. J,. Norell. J,. Dyck. PJ.. D . Microvasculitis.in.non-diabetic.lumbosacral.radiculoplexus.neuropathy.(LSRPN):.Similarity.to.the.diabetic. variety. (DLSRPN).. . J. Peripheral. Nervous. System. 2001...6: .. . yck. PJB,. Norell. JE,. Dyck. PJ.. . Microvasculitis. and. D ischemia. in. diabetic. lumbosacral. radiculoplexus. neuropathy...Neurology.1999;.3:2113-2121.
3
.. . yck.PJ,.Windebank.AJ...Diabetic.and.non-diabetic. D lumbosacral. radiculoplexus. neuropathies:. new. insights.into.pathophysiology.and.treatment...Muscle. Nerve.2002...2:77-91.
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... uarez.GA,.Giannini.C,.Bosch.EP S ,.Barohn.RJ,.Wodak.
6.. . ilho.FJA,.Nathan.BM,.Palmert.MR,.Katirji.B...Diabetic. F amyotrophy. in. an. adolescent. responsive. to. intravenous. immunoglobulin.. . Muscle. Nerve. 200.. . 32:818-820. 7 . ollinger. P Sturzenegger. M.. . Chronic. progressive. .. H ,. primary. lumbosacral. plexus. neuritis:. MRI. findings. and.response.to.immunoglobulin.therapy...J.Neurol. 2000...27:13-1.
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 ...20:2-26. 16... an.Alfen.N,.van.Engelen.BG...The.clinical.spectrum. v
8.. .noue. C,. Hayashi. A,.Yoshizawa.T,. Sato. A,. Shoji. S.. I . 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,. anaka.F T ,.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.. . lewelyn. JG,. Thomas. PK,. King. RHM.. . Epineurial. L microvasculitis. in. proximal. diabetic. neuropathy.. . J. Neurol.1998...2:19-16. 12... ark. DH,. Park. YK,. Kim. JH.. . Intravenous. immunoP globulin. therapy. for. idiopathic. postoperative. lumbosacral. plexopathy.. . J. Clin. Neurosci.. . 200.. . 12:313-31.
of.neuralgic.amyotrophy.in.26.cases...Brain.2006.. . 129:38-0. 17 . erma. A,. Bradley. WG.. . High. dose. intravenous. .. V immunoglobulin. therapy. in. chronic. progressive. lumbosacral. plexopathy.. . Neurology. 199.. . :2820. 18... ochodne.DW,.Isaac.D,.Jones.C...Failure.of.immuZ notherapy. to. prevent,. arrest. or. reverse. diabetic. lumbosacral. plexopathy. Acta. Neurol. Scand. 2003.. 107:299-301.

MYASTHENIA GRAVIS
MYASTHENIA GRAVIS
CLINICaL INfORMatION
Myasthenia. gravis. (MG). is. an. autoimmune. disease. associated.with.the.presence.of.antibodies.to.the.acetylcholine. receptors. (AChR). at. the. neuromuscular. junction..However,.these.antibodies.cannot.be.detected. in.up.to.20%.of.patients.with.generalized.MG.(seronegative. MG) .. Recently,. antibodies. to. muscle-specific.
1
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.seronegative.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.

tyrosine. kinase. (MuSK),. a. surface. membrane. receptor. essential. for. the. development. of. the. neuromuscular. junction.(by.mediating.agrin-induced.clustering.of.AChR. during. synapse. formation ),. were. found. in. 70%. of. 2.
2
seronegative.generalized.MG.patients.in.one.series.and. 37 .%.of.32.such.patients.in.another.series ...Antibodies.

3,.
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.
other.autoantibodies.and.autoimmune.diseases1,e.g.,. systemic.lupus.erythematosus16-18,.hypothyroidism.and. hyperthyroidism16,. 19,. 20,. autoimmune. thrombocytopenic. purpura. and. autoimmune. hemolytic. anemia ,.
21
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. muscles3...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. assay0,. 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. exacerbations...The.clinical.features.of.drug-induced.myasthenic. syndrome. are. similar. to. idiopathic. MG. and. serum.

scleroderma ,. multiple. sclerosis

22 26.
23,. 2
,. neuromyotonia
2,.
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.characteristic. 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)
39 37 ,.38
,.single-fiber.electromyography.(SFEMG)
38,.
. and. serum. AChR. antibodies0.. . 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. cholinesterase.inhibitor,.can.be.given.at.a.dose.of.0..mg..intravenously. 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.
6
.. .
Normal. AChR. antibody. concentrations. do. not. exclude.
MYASTHENIA GRAVIS
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.immunosuppressive. therapy.. . In. such. cases,. it. may. be. argued. that.the.drug.unmasked.a.pre-existing.immune-mediated. disorder.of.the.neuromuscular.junction6. . Available. therapies. include. symptomatic. treatment. with. cholinesterase. inhibitors. such. as. pyridostigmine,. specific. treatment. with. immunosuppressive. drugs. particularly.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) ...This.can.be.achieved.
7
treated. with. prednisolone3.. . Limited. evidence. from. randomised. controlled. trials. suggests. that. corticosteroid. 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. failures8.. . 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. medication9.. . 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.corticosteroid.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.
7
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. benefit8,. 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. immunosuppressive.treatment.for.MG.in.spite.of.their.side.effects2.. . In. observational. studies,. remission. or. marked. improvement. was. seen. in. the. majority. of. patients.
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.neuromuscular. 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.
OBJECtIVEs
To.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 CRIsIs

IVIG VERSuS PE Efficacy.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.immunosuppressive. treatment. before. randomization,. those. drugs. were.continued.without.any.change.in.dosage..Eightyseven. 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.participants. (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.
8
MYASTHENIA GRAVIS
IVIG VERSuS MEtHyLPREDNISoLoNE There.has.been.one.RCT.by.Schuchardt.(Schuchardt.et. al,.2002.unpublished.data).comparing.IVIG.to.oral.methylprednisolone...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.underpowered.in.relation.to.the.study.objectives. HIGH DoSE VERSuS LoW DoSE IVIG One. 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.seventythree.patients.aged.1-8.years.with.acute.MG.exacerbation.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.
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 MG

IVIG VERSuS PE There. 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. IVIG VERSuS PLACEBo One.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. IVIG AS MAINtENANCE tHERAPy Two.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.
9
INtRaVENOUs IMMUNOGLOBULIN fOR MG WIth WORsENING WEaKNEss

IVIG VERSuS PLACEBo A.recent.randomized,.placebo-controlled,.masked.study. by.Zinman.et.al.was.aimed.to.determine.the.effectiveness. 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.
difficult. to. deduce. from. these. uncontrolled. studies. whether.there.is.a.drug.sparing.effect.
2.. . iyanage.Y,.Hoch.W,.Beeson.D,.Vincent.A..The.agrin/ L muscle-specific. kinase. pathway:. new. targets. for. autoimmune.and.genetic.disorders.at.the.neuromuscular.junction..Muscle.Nerve.2002;2(1):-16. 3.. . och.W,. McConville. J,. Helms. S,. Newsom-Davis. J,. H 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. .. . anders.DB,.El-Salem.K,.Massey.JM,.McConville.J,. S Vincent.A..Clinical.aspects.of.MuSK.antibody.positive. seronegative.MG..Neurology.2003;60(12):1978-80. .. . hang.X,.Yang.M,.Xu.J,.Zhang.M,.Lang.B,.Wang.W,. Z et. al.. Clinical. and. serological. study. of. myasthenia. gravis.in.HuBei.Province,.China..J.Neurol.Neurosurg. Psychiatry.2007;78():386-90. 6.. . eh. JH,. Chen. WH,. Chiu. HC,. Vincent. A.. Low. Y frequency.of.MuSK.antibody.in.generalized.seronegative.myasthenia.gravis.among.Chinese..Neurology. 200;62(11):2131-2. 7 . ee.JY,.Sung.JJ,.Cho.JY,.Oh.DH,.Kim.HJ,.Park.JH,. .. L et. al.. MuSK. antibody-positive,. seronegative. myasthenia. gravis. in. Korea.. J. Clin. Neurosci. 2006;13(3):33-. 8.. . hta.K,.Shigemoto.K,.Kubo.S,.Maruyama.N,.Abe.Y,. O Ueda. N,. et. al.. MuSK. antibodies. in. AChR. Ab-seropositive. MG. vs. AChR. Ab-seronegative. MG.. Neurology.200;62(11):2132-3. 9.. . irmanns. B,. Brenner. T,. Abramsky. O,. Steiner. I.. B
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 . . ..g/kg/day.for.3-.days.(a.total.dose.of.1.2.g/kg.is. 0 as.effective.as.2.g/kg) . . .g/kg/day.for.1-2.days.(a.total.dose.of.1.g/kg.is.as. 1 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 CONsENsUs
1.. .VIG.is.recommended.for.myasthenia.gravis.exacerI bations,.myasthenic.crisis.and.patients.with.severe. weakness.poorly.controlled.with.other.agents.or.in. lieu.of.PE. 2.. . .dose.of.IVIG.of.1.g/kg.for.1.day.can.be.used.in.the. A treatment.of.MG.exacerbations.
REfERENCEs
1.. . ossman.S,. incent.A,.Newsom-Davis.J..Myasthenia. M V gravis. without. acetylcholine-receptor. antibody:. a. distinct.disease.entity..Lancet.1986;1(873):116-9.
Seronegative. myasthenia. gravis:. clinical. features,. response.to.therapy.and.synthesis.of.acetylcholine. receptor. antibodies. in. vitro.. J. Neurol. Sci. 1991;102(2):18-9.
60
MYASTHENIA GRAVIS
10... voli. A,. Batocchi. AP Lo. Monaco. M,. Servidei. S,. E ,. Padua. L,. Majolini. L,. et. al.. Clinical. heterogeneity. of. seronegative. myasthenia. gravis.. Neuromuscul. Disord.1996;6(3):1-61. 11.. . voli.A,.Tonali.PA,.Padua.L,.Monaco.ML,.Scuderi.F E ,. Batocchi.AP ,.et.al..Clinical.correlates.with.anti-MuSK. antibodies. in. generalized. seronegative. myasthenia. gravis..Brain.2003;126(Pt.10):230-11. 12... incent. A,. McConville. J,. Farrugia. ME,. NewsomV Davis. J.. Seronegative. myasthenia. gravis.. Semin. Neurol.200;2(1):12-33. 13... rachman. DB,. Angus. CW,. Adams. RN,. Michelson. D JD,. Hoffman. GJ.. Myasthenic. antibodies. cross-link. acetylcholine.receptors.to.accelerate.degradation..N. Engl.J.Med.1978;298(20):1116-22. 1... rachman. DB,. Adams. RN,. Josifek. LF Self. SG.. D ,. Functional.activities.of.autoantibodies.to.acetylcholine.receptors.and.the.clinical.severity.of.myasthenia. gravis..N.Engl.J.Med.1982;307(13):769-7. 1... olf.SM,.Rowland.LP W ,.Schotland.DL,.McKinney.AS,. Hoefer. PF Aranow. H,. Jr.. Myasthenia. as. an. ,. autoimmune.disease:.clinical.aspects..Ann.N.Y.Acad. Sci.1966;13(1):17-3. 16... onana.MF Z ,.Reyes.E,.Weisman.AK..Coexistence.of. four.autoimmune.diseases.in.one.patient:.the.kaleidoscope. of. autoimmunity.. J. Clin. Rheumatol. 2002;8(6):322-. 17 . thoeger.Z,.Neiman.A,.Elbirt.D,.Zinger.H,.Magen.E,. .. S Burstein.R,.et.al..High.prevalence.of.systemic.lupus. erythematosus. in. 78. myasthenia. gravis. patients:. a. clinical. and. serologic. study.. Am. J. Med. Sci. 2006;331(1):-9.
18...wadate. H,. Kobayashi. H,. Shio. K,. Noguchi. E,. I Watanabe. K,. Sasajima.T,. et. al.. A. case. of. systemic. lupus. erythematosus. complicated. by. pure. red. cell. aplasia. and. idiopathic. portal. hypertension. after. thymectomy..Mod.Rheumatol.2006;16(2):109-12. 19... atanakorn. D,. Vejjajiva. A.. Long-term. follow-up. of. R myasthenia. gravis. patients. with. hyperthyroidism.. Acta.Neurol.Scand.2002;106(2):93-8. 20... oth. C,. McDonald. D,. Oger. J,. Brownell. K.. T Acetylcholine. receptor. antibodies. in. myasthenia. gravis. are. associated. with. greater. risk. of. diabetes. and. thyroid. disease.. Acta. Neurol. Scand. 2006;11(2):12-32. 21.. Wakata.N,.Kiyozuka.T,.Konno.S,.Nakazora.H,.Nomoto. . N,.Sugimoto.H,.et.al..Autoimmune.thrombocytopenic. purpura,. autoimmune. hemolytic. anemia. and. gastric.cancer.appeared.in.a.patient.with.myasthenia. gravis..Intern.Med.2006;(7):79-81. 22... ivkovic. SA,. Medsger.TA,. Jr.. Myasthenia. gravis. and. Z scleroderma:.Two.cases.and.a.review.of.the.literature.. Clin.Neurol.Neurosurg.2007;109():388-91. 23... urukawa. Y,. Yoshikawa. H,. Yachie. A,. Yamada. M.. F Neuromyelitis. optica. associated. with. myasthenia. gravis:. characteristic. phenotype. in. Japanese. population..Eur.J.Neurol.2006;13(6):6-8. 2... ister.I,.Gulati.S,.Boz.C,.Bergamaschi.R,.Piccolo.G,. K Oger. J,. et. al.. Neuromyelitis. optica. in. patients. with. myasthenia. gravis. who. underwent. thymectomy.. Arch.Neurol.2006;63(6):81-6. 2... ukushima.K,.Sato.T,.Mitsuhashi.S,.Kaneko.K,.Yazaki. F M,.Matsuda.M,.et.al..Isaacs'.syndrome.associated. with. myasthenia. gravis,. showing. remission. after. cytoreductive. surgery. of. pleural. recurrence. of. thymoma..Neuromuscul.Disord.2006;16(11):763-.
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... rob.D,.Brunner.NG,.Namba.T..The.natural.course.of. G myasthenia. gravis. and. effect. of. therapeutic. measures..Ann.N.Y.Acad.Sci.1981;377:62-69. 6... rgov.Z,.Kaminski,.H,.Al-Mudallal,.A,.Ruff,.RL..Toxic. A and.iatrogenic.myopathies.and.neuromuscular.transmission. disorders.. In:. Karpati. G,. Hilton-Jones,. D,. Griggs,. RC,. editor.. Disorders. of. voluntary. muscle.. 7th. ed.. Cambridge:. Cambridge. University. Press;. 2001..p..677-88. 7 . ichman. DP Agius. MA..Treatment. of. autoimmune. .. R ,. myasthenia.gravis..Neurology.2003;61(12):162-61.
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8... ronseth. GS,. Barohn. RJ.. Practice. parameter:. G thymectomy.for.autoimmune.myasthenia.gravis.(an. evidence-based. review):. report. of. the. Quality. Standards.Subcommittee.of.the.American.Academy. of.Neurology..Neurology.2000;(1):7-1.
Albers. JW.. Randomized. trial. of. azathioprine. or. prednisone.for.initial.immunosuppressive.treatment. of. myasthenia. gravis.. J. Neurol. Sci. 1997;10(1):962. 8... alace.J,.Newsom-Davis.J,.Lecky.B..A.randomized. P
9... ronseth. GS,. Barohn. RJ.. Thymectomy. for. G Myasthenia. Gravis.. Curr. Treat. Options. Neurol. 2002;(3):203-209. 0... uckingham.JM,.Howard.FM,.Jr.,.Bernatz.PE,.Payne. B WS,.Harrison.EG,.Jr.,.O'Brien.PC,.et.al..The.value.of. thymectomy. in. myasthenia. gravis:. a. computerassisted. matched. study.. Ann. Surg. 1976;18():. 3-8. 1.. . erlo. VP Poskanzer. DC,. Schwab. RS,. Viets. HR,. P ,. Osserman. KE,. Genkins. G.. Myasthenia. gravis:. evaluation.of.treatment.in.1,3.patients..Neurology. 1966;16():31-9. 2... edlack. RS,. Sanders. DB.. Steroid. treatment. for. B myasthenia.gravis:.steroids.have.an.important.role.. Muscle.Nerve.2002;2(1):117-21. 3... ascuzzi.RM,.Coslett.HB,.Johns.TR..Long-term.corP ticosteroid.treatment.of.myasthenia.gravis:.report.of. 116.patients..Ann.Neurol.198;1(3):291-8.
double-blind.trial.of.prednisolone.alone.or.with.azathioprine. in. myasthenia. gravis.. Myasthenia. Gravis. Study.Group..Neurology.1998;0(6):1778-83. 9... indall.RS,.Phillips.JT,.Rollins.JA,.Wells.L,.Hall.K..A. T clinical.therapeutic.trial.of.cyclosporine.in.myasthenia. gravis..Ann.N.Y.Acad.Sci.1993;681:39-1. 60... iafaloni. E,. Nikhar. NK,. Massey. JM,. Sanders. DB.. C Retrospective.analysis.of.the.use.of.cyclosporine.in. myasthenia.gravis..Neurology.2000;(3):8-0. 61.. . erez. MC,. Buot. WL,. Mercado-Danguilan. C,. P Bagabaldo. ZG,. Renales. LD.. Stable. remissions. in. myasthenia.gravis..Neurology.1981;31(1):32-7 . 62... iakan. E,. Harati.Y,. Rolak. LA.. Immunosuppressive. N drug. therapy. in. myasthenia. gravis.. Arch. Neurol. 1986;3(2):1-6. 63... e.Feo.LG,.Schottlender.J,.Martelli.NA,.Molfino.NA.. D Use. of. intravenous. pulsed. cyclophosphamide. in. severe,. generalized. myasthenia. gravis.. Muscle. Nerve.2002;26(1):31-6.
63
6... haudhry. V,. Cornblath. DR,. Griffin. JW,. O'Brien. R,. C Drachman. DB.. Mycophenolate. mofetil:. a. safe. and. promising. immunosuppressant. in. neuromuscular. diseases..Neurology.2001;6(1):9-6. 6... iafaloni.E,.Massey.JM,.Tucker-Lipscomb.B,.Sanders. C DB..Mycophenolate.mofetil.for.myasthenia.gravis:.an. open-label.pilot.study..Neurology.2001;6(1):97-9. 66... eriggioli. MN,. Ciafaloni. E,. Al-Hayk. KA,. Rowin. J,. M Tucker-Lipscomb.B,.Massey.JM,.et.al..Mycophenolate. mofetil.for.myasthenia.gravis:.an.analysis.of.efficacy,. safety,. and. tolerability.. Neurology. 2003;61(10):. 138-0. 67 . eriggioli. MN,. Rowin. J,. Richman. JG,. Leurgans. S.. .. M Mycophenolate. mofetil. for. myasthenia. gravis:. a. double-blind,.placebo-controlled.pilot.study..Ann.N.Y. Acad.Sci.2003;998:9-9. 68... akata. N,. Saito. T,. Tanaka. S,. Hirano. T,. Oka. K.. W Tacrolimus.hydrate.(FK06):.therapeutic.effects.and. selection. of. responders. in. the. treatment. of. myasthenia. gravis.. Clin. Neurol. Neurosurg. 2003;106(1):-8. 69... onishi.T,.Yoshiyama.Y,.Takamori.M,.Yagi.K,.Mukai.E,. K Saida. T.. Clinical. study. of. FK06. in. patients. with. myasthenia.gravis..Muscle.Nerve.2003;28():70-. 70... awaguchi.N,.Yoshiyama.Y,.Nemoto.Y,.Munakata.S,. K Fukutake.T,.Hattori.T..Low-dose.tacrolimus.treatment. in.thymectomised.and.steroid-dependent.myasthenia. gravis..Curr.Med.Res.Opin.200;20(8):1269-73. 71.. . agane. Y,. Utsugisawa. K,. Obara. D,. Kondoh. R,. N Terayama. Y.. Efficacy. of. low-dose. FK06. in. the. treatment. of. Myasthenia. gravis--a. randomized. pilot. study..Eur.Neurol.200;3(3):16-0.
72... onishi.T,.Yoshiyama.Y,.Takamori. M,. Saida.T.. LongK term. treatment. of. generalised. myasthenia. gravis. with. FK06. (tacrolimus).. J. Neurol. Neurosurg. Psychiatry.200;76(3):8-0. 73... ada.M,.Shimohata.T,.Oyake.M,.Igarashi.S,.Onodera. T O,. Naruse. S,. et. al.. Long-term. therapeutic. efficacy. and. safety. of. low-dose. tacrolimus. (FK06). for. myasthenia.gravis..J.Neurol.Sci.2006;27(1):17-20. 7.. . imon. HU,. Spath. PJ.. IVIG--mechanisms. of. action.. S Allergy.2003;8(7):3-2. 7... ajdos. P Chevret. S,.Toyka. K.. Plasma. exchange. for. G ,. myasthenia. gravis.. Cochrane. Database. Syst. Rev. 2002():CD00227. 76... ajdos.P G ,.Chevret.S,.Clair.B,.Tranchant.C,.Chastang. C.. Clinical. trial. of. plasma. exchange. and. high-dose. intravenous. immunoglobulin. in. myasthenia. gravis.. Myasthenia.Gravis.Clinical.Study.Group..Ann.Neurol. 1997;1(6):789-96. 77 . ureshi.AI,.Choudhry.MA,.Akbar.MS,.Mohammad.Y,. .. Q Chua.HC,.Yahia.AM,.et.al..Plasma.exchange.versus. intravenous.immunoglobulin.treatment.in.myasthenic. crisis..Neurology.1999;2(3):629-32. 78... onager. J,. Ravnborg. M,. Hermansen. I,.Vorstrup. S.. R Immunoglobulin.treatment.versus.plasma.exchange. in. patients. with. chronic. moderate. to. severe. myasthenia.gravis..Artif.Organs.2001;2(12):967-73. 79... ewsom-Davis.J..Therapy.in.myasthenia.gravis.and. N Lambert-Eaton.myasthenic.syndrome..Semin.Neurol. 2003;23(2):191-8. 80... ajdos.P G ,.Tranchant.C,.Clair.B,.Bolgert.F ,.Eymard.B,. Stojkovic. T,. et. al.. Treatment. of. myasthenia. gravis. exacerbation. with. intravenous. immunoglobulin:. a. randomized. double-blind. clinical. trial.. Arch. Neurol. 200;62(11):1689-93.
6
MYASTHENIA GRAVIS
81.. . inman. L,. Ng. E,. Bril. V.. IV. immunoglobulin. in. Z patients. with. myasthenia. gravis:. a. randomized. controlled.trial..Neurology.2007;68(11):837-1. 82... olfe.GI,.Barohn.RJ,.Foster.BM,.Jackson.CE,.Kissel. W JT,. Day. JW,. et. al.. Randomized,. controlled. trial. of. intravenous. immunoglobulin. in. myasthenia. gravis.. Muscle.Nerve.2002;26():9-2. 83... chiron. A,. Barak. Y,. Miron. S,. Sarova-Pinhas. I.. A Immunoglobulin.treatment.in.refractory.Myasthenia. gravis..Muscle.Nerve.2000;23():1-. 8... ilkevich.O,.Drory.VE,.Chapman.J,.Korczyn.AD..The. H use.of.intravenous.immunoglobulin.as.maintenance. therapy.in.myasthenia.gravis..Clin.Neuropharmacol. 2001;2(3):173-6. 8... ajdos.P G ,.Chevret.S,.Toyka.K..Intravenous.immunoglobulin.for.myasthenia.gravis..Cochrane.Database. Syst.Rev.2006(2):CD002277 .
6
AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic 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.
66
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. breakthrough. was. the. finding. of. mutations. within. the. gene. encoding.Cu,.Zn.superoxide.dismutase.(SOD1).in.some.
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.polyneuropathies.which.may.be.treatable...High.titer.of.antiGM1. antibodies. are. detected. in. up. to. 8%. of. MMN. patients
10,11
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.
sUMMaRY
Evidence.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 CONsENsUs
IVIG. is. not. indicated. in. the. treatment. of. patients. . with.ALS.
REfERENCEs
1.. . ictor.M,.Ropper.AH...Amyotrophic.lateral.sclerosis.. V . In.Victor.M,.Ropper.AH.(eds):.Principal.of.Neurology,. 7th.ed...New.York,.McGraw-Hill,.2001,.pp.113-. 2.. . othstein. JD,. Martin. LJ,. Kuncl. RW.. . Decreased. R glutamate. transport. by. the. brain. and. spinal.cord. in. amyotrophic. lateral. sclerosis.. . N. Engl. J. Med. 1992;. 326:.16-8... 3.. .Gunnarsson .LG...Motor.neuron.disease.and.exposure. to.chemicals.-.aetiological.suggestions.from.a.casecontrol.study...J.Neurol.Sci.199;.12.(Suppl.62-3). .. . asui. M,.Yase.Y,. Ota. K,. Garruto. RM.. . Evaluation. of. Y magnesium,. calcium. and. aluminum. metabolism. in. rats. and. monkeys. maintained. on. calcium-deficient. diets...Neurotoxicology.1991;.12:.603-1.
...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. fatal .. . Patients. usually. develop. respiratory. failure. that.
1
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.
OBJECtIVE
To.examine.the.efficacy.of.IVIG.in.ALS.
IVIG as MaINtENaNCE thERapY

Dalakas. et. al. treated. 9. patients. with. classic. ALS. who. had.a.rapidly.progressive.course.with.IVIG.in.an.open-
67
.. . arruto.RM,.Shankar.SK,.Yanakihara.R,.Salazar.AM,. G Amyx.HL,.Gajusek.DC...Low-calcium,.high-aluminum. diet-induced.motor.neuron.pathology.in.cynomolgus. Monkeys...Acta.Neuropathol.(Berlin).1989;.78:.210-9. 6.. . ppel. SH,. Engelhardt. JI,. Garcia. J,. Stefani. E.. A . Autoimmunity. and. ALS:. a. comparison. of. . animal. models. of. immune-mediated. motor. neuron. destruction.and.human.ALS...Adv.Neurol.1991;.6:. 0-12.
12... ouche. P Moulonguet. A,. Younes-Chennoufi. AB,. B ,. 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... aperstein. DS,. Katz. JS,. Amato. AA,. Barohn. R.. S . Clinical. spectrum. of. acquired. demyelinating. polyneuropathies...Muscle.Nerve.2001;.2.;.311-2. 1... alakas.MC,.Stein.DP D ,.Otero.C,.Sekul.E,.Cupler.EJ,.
7 . anders. KA,. Rowland. LP Murphy. PL,.Younger. DS,. .. S ,. Latov.N,.Sherman.WH,.Pesce.M,.Lange.DJ....Motor. neuron. diseases. and. amyotrophic. lateral. sclerosis:. GM1. antibodies. and. . paraproteinemia.. . Neurology. 1993;.3:.18-20.
McCrosky. S.. . Effect. of. high-dose. intravenous. immunoglobulin. on. amyotrophic. lateral. sclerosis. and. multifocal. motor. neuropathy.. . Arch. Neurol. 199;.1:861-. 1... uecci.N,.Nobile-Orazio.E,.Scarlato.G...Intravenous. M
8.. . osen. DR,. Siddique.T,. Patterson. D,. Figlewics. DA,. R 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(61):. 9-62.. . Erratum. in. Nature. 1993;. 36. (63):.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... aylor. BV,. Gross. L,.Windebank. AJ.. .The. sensitivity. T and. specificity. of. anti-GM1. antibody. testing.. . Neurology.1996;.7:.91-. 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.
immunoglobulin. therapy. in. amyotrophic. lateral. sclerosis...J.Neurol.1996;.23:.117-20.
68
LAMBERT-EATON MYASTHENIC SYNDROME

. Lambert-Eaton. myasthenic. syndrome. (LEMS). is. a.
1,. 2
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
disorder.of.neuromuscular.transmission.first.recognized. clinically. in. association. with. lung. cancer . and. subsequently. 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.acetylcholine.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. PLEMS..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,.
.. Dermatomyositis. has. also. been. reported. to. occur. LEMS.is.an.uncommon.condition.and.patients.with.
together.with.LEMS13. . 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. potentia69
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.
with. a. therapeutic. IVIG. preparation,. the. inhibitory. activity. of. LEMS. IgG. was. diminished. in. a. dosedependant. 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. IVIG VERSuS PLACEBo Bain. 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)... he.study.showed.a.significant.improvement. T 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. IVIG AS MAINtENANCE tHERAPy Muchnik.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.
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. treatment .. .
21
Azathioprine. can. be. added. as. corticosteroid. sparing. medication19.. . Cyclosporine. should. be. considered. in. patients.who.fail.to.respond.to.azathioprine8.
OBJECtIVEs
To. 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. dosedependant.manner...When.LEMS.IgG.was.coincubated.
70
(SCLC).who.was.treated.with..courses.of.chemotherapy.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.
Rich.et.al.treated.6.patients.with.LEMS.(3.women.
ADVERSE EffECtS:. (from. the. RCT). headache,. . aseptic.meningitis.
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. electrophysiological.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.
EXpERt CONsENsUs
1.. Treat.the.underlying.tumor.in.P-LEMS . 2.. . ,-diaminopyridine. is. effective. but. not. always. 3 available. 3.. . yridostigmine. is. of. some. benefit. although. not. as. P effective.as.3,-diaminopyridine .. .f. 3,-diaminopyridine. and. pyridostigmine. are. not. I effective,. immunosuppressants. can. be. added.. Prednisolone. and. azathioprine. are. the. most. frequently.used.immunosuppressants.and.they.are. given.alone.or.together27. .. .VIG. or. PE. produces. temporary. improvement.. I Therefore,.each.has.a.role.as.second.line.therapy. 6.. . here.is.a.theoretical.concern.that.immunosuppresT sion. may. reduce. the. immunologic. suppression. of. tumor.growth..Therefore,.aggressive.immunotherapy.in.LEMS.may.be.more.justified27.
sUMMaRY
IVIG.treatment.may.be.useful.short-term.therapy.particularly. 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,-diaminopyridine.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.administering.over..days.rather.than.2.days.
REfERENCEs
1.. . nderson. H,. Churchill-Davidson. H,. Richardson. A.. A Bronchial. neoplasm. with. myasthenia:. prolonged. apnoea. after. administration. of. succinylcholine.. Lancet.193;ii:1291-3. 2.. . enson.R..Discussion.of.unusual.manifestations.of. H bronchial. carcinoma.. Proceedings. of. the. Royal. Society.of.Medicine.193;6:89-61. 3.. . 'Neill. JH,. Murray. NM,. Newsom-Davis. J.. The. O Lambert-Eaton. myasthenic. syndrome.. A. review. of. 0.cases..Brain.1988;111.(.Pt.3):77-96. .. . otomura. M,. Johnston. I,. Lang. B,. Vincent. A,. M Newsom-Davis.J..An.improved.diagnostic.assay.for. Lambert-Eaton. myasthenic. syndrome.. J. Neurol. Neurosurg.Psychiatry.199;8(1):8-7 .
71
.. . ennon.VA,.Kryzer.TJ,.Griesmann.GE,.O'Suilleabhain. L PE,. Windebank. AJ,Woppmann. A,. et. al.. Calciumchannel.antibodies.in.the.Lambert-Eaton.syndrome. and.other.paraneoplastic.syndromes..N.Engl.J.Med. 199;332(22):167-7. 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;21(10):12-9. 7 . rgov. Z,. Shapira. Y,. Averbuch-Heller. L,. Wirguin. I.. .. A Lambert-Eaton. myasthenic. syndrome. (LEMS). in. association. with. lymphoproliferative. disorders.. Muscle.Nerve.199;18(7):71-9. 8.. . ewsom-Davis.J..Therapy.in.myasthenia.gravis.and. N Lambert-Eaton.myasthenic.syndrome..Semin.Neurol. 2003;23(2):191-8.
1... undh.H,.Nilsson.O,.Rosen.I..Treatment.of.LambertL Eaton. syndrome:. 3,-. diaminopyridine. and. pyridostigmine..Neurology.198;3(10):132-30. 1... cEvoy. KM,. Windebank. AJ,. Daube. JR,. Low. PA.. M 3,-Diaminopyridine. in. the. treatment. of. LambertEaton. myasthenic. syndrome.. N. Engl. J. Med. 1989;321(23):.167-71. 16... undh.H,.Nilsson.O,.Rosen.I,.Johansson.S..Practical. L aspects. of. 3,-diaminopyridine. treatment. of. the. Lambert-Eaton. myasthenic. syndrome.. Acta. Neurol. Scand.1993;88(2):136-0. 17 . anders.DB,.Massey.JM,.Sanders.LL,.Edwards.LJ.. .. S A.randomized.trial.of.3,-.diaminopyridine.in.LambertEaton.myasthenic.syndrome..Neurology.2000;(3):. 603-7 . 18... ain. PG,. Motomura. M,. Newsom-Davis. J,. Misbah. B
9.. . ewsom-Davis. J.. Lambert-Eaton. myasthenic. N syndrome..Rev.Neurol.(Paris).200;160(2):177-80. 10... oberts. A,. Perera. S,. Lang. B,.Vincent. A,. NewsomR 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.
SA,.Chapel.HM,.Lee.ML,.et.al..Effects.of.intravenous. immunoglobulin.on.muscle.weakness.and.calciumchannel. autoantibodies. in. the. Lambert-Eaton. myasthenic. syndrome.. Neurology. 1996;7(3):67883. 19... ewsom-Davis. J,. Murray. NM.. Plasma. exchange. N and. immunosuppressive. drug. treatment. in. the. Lambert-Eaton. myasthenic. syndrome.. Neurology. 198;3():80-. 20... halk.CH,.Murray.NM,.Newsom-Davis.J,.O'Neill.JH,. C
12... ha.SJ,.Layzer.RB..Myasthenia.gravis.and.LambertS Eaton. myasthenic. syndrome. in. the. same. patient.. Muscle.Nerve.2007 . 13... ossner. R,. Tings. T,. Beckmann. I,. Neumann. C,. M 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-.
Spiro. SG.. Response. of. the. Lambert-Eaton. myasthenic. syndrome. to. treatment. of. associated. small-cell. lung. carcinoma.. Neurology. 1990;0(10):12-6. 21.. . treib.EW,.Rothner.AD..Eaton-Lambert.myasthenic. S syndrome:. long-term. treatment. of. three. patients. with.prednisone..Ann.Neurol.1981;10():8-3.
72
22... uchwald. B,. Ahangari. R,. Weishaupt. A,.Toyka. KV.. B Presynaptic. effects. of. immunoglobulin. G. from. patients.with.Lambert-Eaton.myasthenic.syndrome:. their. neutralization. by. intravenous. immunoglobulins..Muscle.Nerve.200;31():87-9. 23... uchnik. S,. Losavio. AS,.Vidal. A,. Cura. L,. Mazia. C.. M Long-term. follow-up. of. Lambert-. Eaton. syndrome. treated. with. intravenous. immunoglobulin.. Muscle. Nerve.1997;20(6):67-8. 2... ird.SJ..Clinical.and.electrophysiologic.improvement. B in.Lambert-Eaton.syndrome.with.intravenous.immunoglobulin. 122-3. 2... akano.H,.Tanaka.M,.Koike.R,.Nagai.H,.Arakawa.M,. T Tsuji. S.. Effect. of. intravenous. immunoglobulin. in. Lambert-Eaton. myasthenic. syndrome. with. smallcell. lung. cancer:. correlation. with. the. titer. of. antivoltage-gated. calcium. channel. antibody.. Muscle. Nerve.199;17(9):1073-. 26... ich.MM,.Teener.JW,.Bird.SJ..Treatment.of.LambertR Eaton.syndrome.with.intravenous.immunoglobulin.. Muscle.Nerve.1997;20():61-. 27 . anders.DB..Lambert-Eaton.myasthenic.syndrome:. .. S diagnosis. and. treatment.. Ann. N. Y. Acad. Sci. 2003;998:00-8. therapy.. Neurology. 1992;2(7):.
73
NEUROMYOTONIA (ISAACS SYNDROME)

BaCKGROUNd
Neuromyotonia.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 .
,.
scranial.magnetic.stimulation...In.addition,.there.has.been. no.evidence.of.a.direct.defect.in.neuromuscular.transmission. as. measured. by. single-fiber. electromyography7.. . Neuromyotonia. has. been. seen. in. patients. with. chronic. inflammatory. demyelinating. polyneuropathy. and. incomplete.recovery.from.Guillain-Barr.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.paraneoplastic. 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...
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.neurophysiological. evidences. of. abnormality. in. the. cortical. motor. axon. and. central. motor. conduction. as. studied. by. tran7
NEUROMYOTONIA (ISAACS SYNDROME)
The. diagnosis. of. neuromyotonia. is. made. on. 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.
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. anticonvulsant.drugs.that.block.sodium.channels,.e.g.,.carbamazepine.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.
sUMMaRY
The. limited. information. available. on. IVIG. use. in. neuromyotonia.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.
CONsENsUs
There. is. insufficient. evidence. of. benefit. of. IVIG. . in.neuromyotonia.
REfERENCEs INtRaVENOUs IMMUNOGLOBULIN fOR NEUROMYOtONIa

IVIG AS MAINtENANCE tHERAPy Alessi.et.al.reported.a.patient.with.neuromyotonia.who. had.failed.to.respond.to.anticonvulsants,.benzodiazepine. and.plasma.exchange.(PE)23...Corticosteroid.and.azathioprine.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. 6weekly. intervals. with. substantial. improvement. after. 6. months.of.therapy23. . van.den.Berg.et.al.reported.a.patient.with.two.paraneoplastic.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.manifestations...Three.weeks.later,.PE.(.times.a.week,.2..l,.for. 2. weeks). resulted. in. a. dramatic. improvement.. . Subsequently,.immunosuppressive.treatment.(prednisolone. and. azathioprine). was. associated. with. disappearance.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.
7
1.. . ictor. M,. Ropper. A.. . Continuous. muscle. activity. V . (Isaacs.Syndrome)...In:.Victor.M,.Ropper.A,.editors.. . Principal.of.Neurology...7th.ed...New.York:.McGrawHill;.2001...p...168-9. 2.. . ewsom-Davis.J,.Mills.KR...Immunological.associaN tions.of.acquired.neuromyotonia.(Isaacs'.syndrome).. . Report. of. five. cases. and. literature. review.. . Brain. 1993;116.(.Pt.2):3-69. 3.. . uger. RG.. . AAEM. minimonograph. #:. diseases. A associated.with.excess.motor.unit.activity...Muscle. Nerve.199;17(11):120-63. .. . arber. PA,. Anderson. NE,. Vincent. A.. . Morvan's. B syndrome.associated.with.voltage-.gated.K+.channel. antibodies...Neurology.2000;(3):771-2. .. . iguori. R,. Vincent. A,. Clover. L,. Avoni. P Plazzi. G,. L ,. 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):217-26.
6.. . addison. P . Neuromyotonia.. . Clin. Neurophysiol. M .. 2006;117(10):2118-27 . 7 . addison.P .. M ,.Mills.KR,.Newsom-Davis.J...Clinical.electrophysiological.characterization.of.the.acquired.neuromyotonia.phenotype.of.autoimmune.peripheral.nerve. hyperexcitability...Muscle.Nerve.2006;33(6):801-8. 8.. . ewsom-Davis.J...Neuromuscular.junction.channelopN 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... cta.Neurol.Scand.1980;61():216A 26. 10.. . aerness.E...Neuromyotonia.and.bronchial.carcinoma.. W . Electromyogr.Clin.Neurophysiol.197;1(-6):27-3.
16.. . albach. M,. Homberg.V,. Freund. HJ.. . Neuromuscular,. H autonomic. and. central. cholinergic. hyperactivity. associated.with.thymoma.and.acetylcholine.receptor-. binding.antibody...J.Neurol.1987;23(6):33-6. 17 . an. Parijs. V,. Van. den. Bergh. PY,. Vincent. A.. .. V . Neuromyotonia. and. myasthenia. gravis. without. thymoma.. . J. Neurol. Neurosurg. Psychiatry. 2002;73(3):3-. 18.. . ntelli.A,.Spengos.K,.Zambelis.T,.Pandis.D,.Tsivgoulis. A G,.Zis.V...Neuromyotonia.and.myasthenia.gravis.in.the. absence.of.thymoma...Eur.J.Neurol.2006;13(7):e. 19.. . hillito. P Molenaar. PC,.Vincent.A,. Leys. K,. Zheng.W,. S ,. 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... art.IK,.Waters.C,.Vincent.A,.Newland.C,.Beeson.D,. H
11.. . alsh.JC...Neuromyotonia:.an.unusual.presentation.of. W intrathoracic.malignancy...J.Neurol.Neurosurg.Psychiatry. 1976;39(11):1086-91. 12.. . eidenreich. F Vincent. A.. . Antibodies. to. ion-channel. H ,. proteins.in.thymoma.with.myasthenia,.neuromyotonia,. and.peripheral.neuropathy...Neurology.1998;0():183.
Pongs.O,.et.al...Autoantibodies.detected.to.expressed. K+. channels. are. implicated. in. neuromyotonia.. . Ann. Neurol.1997;1(2):238-6. 21.. .saacs. H,. Heffron. JJ.. .The. syndrome. of. 'continuous. I muscle-fibre.activity'.cured:.further.studies...J.Neurol. Neurosurg.Psychiatry.197;37(11):1231-. 22...shii. A,. Hayashi. A,. Ohkoshi. N,. Oguni. E,. Maeda. M,. I
13.. . an. den. Berg. JS,. van. Engelen. BG,. Boerman. RH,. de. v Baets. MH.. . Acquired. neuromyotonia:. superiority. of. plasma. exchange. over. high-dose. intravenous. human. immunoglobulin...J.Neurol.1999;26(7):623-. 1.. . ayat.GR,.Kulkantrakorn.K,.Campbell.WW,.Giuliani.MJ.. H . Neuromyotonia:. autoimmune. pathogenesis. and. response.to.immune.modulating.therapy...J.Neurol.Sci. 2000;181(1-2):38-3. 1.. . arcia-Merino. A,. Cabello. A,. Mora. JS,. Liano. H.. G . Continuous.muscle.fiber.activity,.peripheral.neuropathy,. and.thymoma...Ann.Neurol.1991;29(2):21-8.
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):80-2. 23... lessi.G,.De.Reuck.J,.De.Bleecker.J,.Vancayzeele.S.. A . Successful.immunoglobulin.treatment.in.a.patient.with. neuromyotonia...Clin.Neurol.Neurosurg..2000;102(3):. 173-.
76
INFLAMMATORY MYOPATHIES
BaCKGOUNd
The.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.
77
Table.1:.Key.distinguishing.features.of.DM,.PM.and.IBM Dermatomyositis Mean.age.at.onset.symptoms Mode.of.onset.symptoms Sex.differences Occurrence.in.childhood Distribution.of.weakness Rash Association.with.malignancy Creatine.kinase Autoimmune.aetiology T.cell-mediated.myocytotoxicity Prominent.rimmed.vacuoles Complement-mediated.depletion.. of.capillaries Perifascicular.atrophy Good.response.to.corticosteroids <0.years. Subacute.. (weeks.to.months) F>M Yes Proximal.>.distal Yes Yes Usually...or Yes No No Yes.(early). Yes.(inconstant). Yes.(usually). Polymyositis <0.years. Subacute.. (weeks.to.months) F>M Yes.(very.rare) Proximal.>.distal No Yes.(weak). Usually...or Yes Yes No No No Yes.(usually). Inclusion.body.myositis <0.years. Slow.(years). M>F No Proximal.&.distal No No Usually Unclear Yes Yes No No No
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. dystrophy . and. occasionally. myophosphory3
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.
lase. deficiency. can. mimic. PM.. . IBM. should. not. be. confused.with.hereditary.inclusion.body.myopathy.due. to.mutations.in.the.gene.encoding.UDP-N-acetylglucosamine-2-epimerase./.N-acetylmannosamine.kinase .

78
tREatMENt Of dM aNd pM
A) DRuG tREAtMENt The.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. diagnosis .. . Azathioprine. is. an.
8
patients. was. extended18,19.. . Nine. of. nine. patients. with. treatment-resistant.juvenile.DM.and.corticosteroid.sideeffects.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.
effective.second-line.immunosuppressive.agent,.but.at. least. 3. months. is. required. for. a. significant. effect

9,. 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) IVIG tREAtMENt Level. 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.placebotreated. 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.corticosteroid.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.
tREatMENt Of IBM
A) DRuG tREAtMENt Corticosteroids. and. second-line. immunosuppressive. drugs. may. produce,. at. most,. modest. benefit. in. some. patients.with.IBM6,.39,.0...Monotherapy.with.oral.methotrexate.did.not.seem.effective.in.a.RCT1. B) IVIG tREAtMENt Three. 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. treatment2...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.
79
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.. .n. a. double-blind. crossover. RCT,. 19. patients. with. I IBM.received...IVIG..(2G/kg.monthly).or.placebo.for. . 6. months,. followed. by. the. alternative. treatment3.. . 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.
sUMMaRY
DM and PM There. 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.secondline. 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.corticosteroids. 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. immunosuppressive.agents,.IVIG.cannot.be.recommended.as. the. first-line. or. sole. therapy.. . Recent. reviews. discuss. the.use.of.IVIG.in.DM0,.1.
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. scores6.. . An. extended. course. of. IVIG.increased.knee.strength.in.one.patient7...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.patient8...Monthly.courses.of.IVIG.for.6-8.months. produced. sustained. improvement. of. dysphagia. in. . four.patients9.
2. IBM There. 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.
80
EXpERt CONsENsUs
IVIG. 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.
8. . Wiles. CM,. Brown. P. Chapel. H,. et. al.. Intravenous. immunoglobulin.in.neurological.disease:.a.specialist. review..JNNP.2002:72:0-8. 9.. . unch.TW.Prednisone.and.azathioprine.for.polymyoB sitis:. long-term. followup.. Arthritis. Rheum.. 1981:2:-8. 10... astaglia.FL,.Phillips.BA,.Zilko.P M ,.et.al..Relapses.in. idiopathic. inflammatory. myopathies.. Muscle. Nerve. 1999:22:1160-61. 11.. . ilke.WS.Methotrexate.use.in.miscellaneous.inflamW
REfERENCEs
1.. . alakas.MC,.Hohlfeld.R.Polymyositis.and.dermatoD myositis..Lancet.2003;362:971-82.
matory. diseases.. Rheum. Dis. Clin. North. Am.. 1997:23:8-82. 13... encovsky. J,. Jarosova. K,. Machacek. S,. et. al.. V
2.. Griggs. RC,. Askanas. V,. DiMauro. S,. et. al.. Inclusion. . body. myositis. and. myopathies. Ann. Neurol. 199:38:70-13. 3.. Gallardo.E,.Rojas-Garcia.R.&.de.Luna.N..Inflammation. . in. dysferlin. myopathy:. immunohisto-chemical. characterization. of. 13. patients.. Neurology. . .. Horneff.G,.Paetzke.I.&.Neuen-Jacob.E..Glycogenosis. . type. V. (McArdle's. disease). mimicking. atypical. myositis..Clin.Rheumatol.2001:20:7-60. .. Eisenberg. I,. Avidan. N,. Potikha. T,. et. al.. The. UDP. Nacetylglucosamine. 2-epimerase/N-acetylman2001:7:2136-8.
Cyclosporine.A.versus.methotrexate.in.the.treatment. of. polymyositis. and. dermatomyositis.. Scand. J. Rheumatol.2000:29:9-102. 1... iller.FW,.Leitman.SF M ,.Cronin.ME,.et.al..A.randomised. double-blind.controlled.trial.of.plasma.exchange.and. leukapheresis.in.patients.with.polymyositis.and.dermatomyositis..NEJM.1992:326:1380-8. 1... alakas.MC,.Ilia.I,.Dambrosia.JM,.et.al..A.controlled. D trial. of. high-dose. intravenous. immune. globulin. infusions. as. treatment. for. dermatomyositis.. NEJM. 1993;329:1993-2000. 16... ang.BA,.Laxer.RM,.Murphy.G,.et.al..Treatment.of. L dermatomyositis. with. intravenous. gammaglobulin.. Am.J.Med.1991:91:169-72. 17 . herin. P. &. Herson. S. Indications. for. intravenous. .. C
nosamine. kinase. gene. is. mutated. in. recessive. hereditary. inclusion. body. myopathy. Nat. Genet. 2001;29:83-87 . 6.. . alakas. MC. Controlled. studies. with. high-dose. D intravenous. immunoglobulin. in. the. treatment. of. dermatomyositis,.inclusion.body.myositis,.and.polymyositis..Neurology.1998;1(Supplement):S37-.. 7 Houser.SM,.Calabrese.LH,.&.Strome.M..Dysphagia. .. . in. patients. with. inclusion. body. myositis.. Laryngoscope.1998:108:1001-.
gammaglobulin.therapy.in.inflammatory.myopathies.. JNNP.199:7(Supplement):0-. 18... herin.R.Intravenous.immunoglobulins.in.polymyoC sitis. and. dermatomyositis.Ann. Med. Interne. (Paris).. 2000:11.(Supplement.1):1S8-0.
81
19... herin. P. Pelletier. S,.Teixeira. A,. et. al.. Results. and. C long-term. followup. of. intravenous. immunoglobulin. infusions. in. chronic,. refractory. polymyositis:. an. open. study. with. thirty-five. adult. patients.. Arthritis. Rheum.2002:6:67-7.
28... toll.T,. Michel. BA,. Neidhart. M,. et. al.. Polymyositis:. S disease. course. and. therapy. with. intravenously. administered. immunoglobulins. Schweiz. Med. Wochenschr.1992:122:18-6. 29... origuchi.M,.Suzuki.T,.Tateishi.M,.et.al..Intravenous. M
20... ansome.A.&.Dubowitz.V.Intravenous.immunoglobS ulin.in.juvenile.dermatomyositis-four.year.review.of. nine.cases.Arch.Dis.Child.199:72:2-8. 21.. Tsai.MJ,.Lai.CC,.Lin.SC,.et.al..Intravenousimmunogl . obulin. therapy. in. juvenile. dermatomyositis.. Chung. Hua. Min. Kuo. Hsiao. Erh. Ko. I. Hsueh. Hui.Tsa. Chih.. 1997:38:111-. .
immunoglobulin. therapy. for. refractory. myositis.. Intern.Med.1996:3:663-7 . 30... arie.I,.Hachulla.E,.Levesque.H,.et.al..Intravenous. M immunoglobulins. as. treatment. of. life. threatening. esophageal.involvement.in.polymyositis.and.dermatomyositis..J.Rheumatol.1999:26:2706-9. 31.. Saito. M,. Saito.Y,. Endo. K,. et. al.. A. case. of. steroid. .
22... astaglia.FL,.Phillips.BA,.Zilko.PJ..Immunoglobulin. M therapy. in. inflammatory. myopathies. JNNP. 1998:6:107-110. 23... I-Mayouf. SM,. Laxer. RM,. Schneider. R,. et. al.. A Intravenous. immunoglobulin. therapy. for. juvenile. dermatomyositis:. efficacy. and. safety.. J. Rheumatol. 2000:27:298-03. 2... ottfried. I,. Seeber. A,. Anegg. B,. et. al.. High. dose. G intravenous. immunoglobulin. (IVIG). in. dermatomyositis:. clinical. response. and. effect. on. slL -2R.levels..EurJ.Dermatol.2000;10:29-3. . 2... anieli.MG,.Malcangi.G,.Palmieri.C,.et.al..Cyclosporin. D A. and. intravenous. immunoglobulin. treatment. polymyositis/dermatomyositis. 2002:61:37-1. 26... herin. P. Peitte. JC,.Wechsler. B,. et. al.. Intravenous. C gamma.globulin.as.first.line.therapy.in.polymyositis. and. dermatomyositis:. an. open. study. in. 11. adult. patients..J.Rheumatol.199:21:1092-7 . 27 Jann.S,.Beretta.S,.Moggio.M.High-dose.intravenous. .. . human.immunoglobulin.in.polymyositis.resistant.to. treatment..JNNP.1992::60-62. Ann. Rheum. Dis.
resistant. polymyositis. who. made. a. good. response. to. high. dos. intravenous. immunoglobulins. (IVIG).. Rinsho.Shinkeigaku.2000:0:181-3. 32... enevay.S,.Saudan-Kister.A,.Guerne.PA..Intravenous. G gammaglobulins. in. refractory. polymyositis:. lower. dose. for. maintenance. treatment. is. effective.. Ann. Rheum.Dis.2001:60:6. 3... edanarayanan. V,. Subramony. SH,. Ray. LI,. et. al.. V Treatment. of. childhood. dermatomyositis. with. high. dose. intravenous. immunoglobulin. Pediatr. Neurol. 199:13:336-9. 3... abroe. RA,. Wellington. TB,. Kennedy. CT.. S Dermatomyositis.treated.with.high-dose.intravenous. immunoglobulins. and. associated. with. panniculitis.. Clin.Exp.Dermatol..199;20:16-7 . 36... aleazzi.M,.Bellucci.AM,.Girardelli.CR,.et.al..Efficacy. G of.intravenous.immunoglobulin.therapy.in.a.case.of. juvenile. dermatomyositis. Clin. Rheumatol. 1996:1:21-6. 37 . uruyaY,.TakahashiT,.Hamamoto.H,.et.al..High-dose. .. F immunoglobulin.therapy.for.a.patient.with.dermato. myositis.Intern.Med.1998:37:62-.
82
38... okori. H,. Fotoulaki. M,. Giannakopoulou. C,. et. al.. K Intravenous.immunoglobulin.treatment.in.a.girl.with. juvenile.dermatomyositis.Pediatr.Int.1999:1:696-7 . 39... eff. RL,. Miller. FW,. Hicks. J,. et. al.. The. treatment. L ofinclusion. body. myositis:. a. retrospective. review. and. a. randomized,. prospective. trial. of. immunosuppressive. therapy.. Medicine. (Baltimore). 1993:72:22-3. 0... ayers.ME,.Chou.SM,.Calabrese.LH.Inclusion.body. S 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... alakas.MC,.Sonies.B,.Dambrosia.J,.et.al..Treatment. D of.inclusion-body.myositis.with.IVIg:.a.double-blind,. placebo-. controlled. study.. Neurology. 1997;8:712-716. 3... alter. MC,. Lochmuller. H,.Toepfer. M,. et. al.. HighW dose. immunoglobulin. therapy. in. sporadic. inclusion. body. myositis:. a. double-blind,. placebo-controlled. study..J.Neurol.2000;27:22-8. ... alakas.MC,.Koffman.B,.Fujii.M,.et.al..A.controlled. D study. of. intravenous. immunoglobulin. combined. with.prednisone.in.the.treatment.of.IBM..Neurology. 2001:6:323-7 . ... oueidan. SA,. Dalakas. MC..Treatment. of. inclusion. S body.myositis.with.high-dose.intravenous.immunoglobulin..Neurology.1993:3:876-879. 6... mato.AA,.Barohn.RJ,.Jackson.CE,.et.al..Inclusion. A body.myositis:.treatment.with.intravenous.immunoglobulin..Neurology.199::116-118.
7 . asque. F Laroche. M,. Marque. P et. al.. Isokinetic. .. D ,. ,. strength. testing. for. evaluating. the. efficacy. of. intravenous. immune. globulin. therapy. for. inclusion. body. myositis.. Rev. Rhum. Engl. Ed.. 199:62:98-601. 8... ukunda. BN,. Kumar. DP. Smith. HR. Long-lasting. M effectiveness. of. intravenous. immunoglobulin. in. patient. with. inclusion-body. myositis.. Ann. Int. Med.. 2001:13:116.(letter). 9... herin. P. Pelletier. S,. Teixeira. A,. et. al. Intravenous. C immunoglobulin. for. dysphagia. of. inclusion. body. myositis..Neurology.2002:8:326-7 . 0... alakas.MC..The.role.of.high-dose.immune.globulin. D intravenous.in.the.treatment.of.dermatomyositis..Int. Immunopharmacol.2006;6:0-6. 1.. . ul. R,. Stangel. M.. Using. immunoglobulins. in. P muscular. disease. treatment.. Expert. Opin. Biol.Ther. 2008;8:113-110.
83
CHRONIC FATIGUE SYNDROME

BaCKGROUNd
Chronic. 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. features
7 9,. 13,. 2 ,.
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.
.. .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. research .. . This. case. definition. requires. at. least. 6.
7
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.flulike. illness.. . Fatigue. exacerbated. by. exertion. is. preeminent,.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,.
8
EtIOLOGY, pathOphYsIOLOGY aNd LaBORatORY OBsERVatIONs

The. etiology. of. CFS. remains. unknown. and. unclear. despite. many. years. of. study.. . However,. there. are. numerous.reports.of.the.association.of.CFS.with.abnormalities. or. dysfunction. of. diverse. organ. systems,. including.neuroendocrine,.psychiatric,.sleep.and.immunological. systems,. and. with. infections.. .The. interrelationships.between.these.associations.are.unclear...This. has. given. rise. to. the. concept. that. CFS. is. a. complex. disorder.with.multi-factorial.etiology1,.6,.17.
ChRONIC fatIGUE sYNdROME

Neuropsychiatric. symptoms. of. impaired. memory. or. concentration,.depression.and.anxiety.often.manifest.in. CFS...However,.studies.have.suggested.that.neuropsychiatric. disorders,. especially. depression,. are. not. the. primary.process.because.of.the.absence.of.neuroendocrine.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.hypothalamic-pituitary-adrenal. axis. and. disturbances. in. serotoninergic. 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,.enteroviruses. and. retroviruses,. and. others
1,. 6,. 17 27 ,.
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.. GF-beta,.raised.antinuclear. T 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. cosponsored.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.technologies. 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...
.. . 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. .. . Besides. suggesting. the. association. of. certain.
31
thERapY IN Cfs
While.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.
8
infections.with.CFS,.these.reports.also.suggest.that.the. host. response. to. infection. may. be. relevant. to. pathophysiology.in.CFS.
addition. to. IVIG,. these. include. other. immunological. or. anti-infectious.therapies.such.as.steroids,.anti-inflammatory. 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.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. time-point. . up. till. the. final. 6. months. .
IVIG IN Cfs
There.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.trial .involving.9.CFS.patients.compared.
1
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.investigator.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.contradictory. 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.
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.
86
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. VollmerConna.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). . he.question.whether.subsets.of.CFS.may.respond. T to. IVIG,. namely. those. that. have. evidence. of. association. with. specific. infections. or. disordered. immune.regulation,.remains.unresolved.and.merits. further.investigation.
EXpERt CONsENsUs
a). .VIG.AS.TREATMENT.IN.CLINICAL.MANAGEMENT. I OF.CFS. . I .VIG.cannot.be.recommended.as.routine.therapy.for. CFS. b). IVIG.AS.AN.INVESTIGATIONALTHERAPY . I .f.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.
REfERENCEs
1.. . fari.N.and.Buchwald.D...Chronic.fatigue.syndrome:. A A.review...Am.J.Psychiatry.2003;.60:.221-236. 2.. . leare. AJ.. . The. neuroendocrinology. of. chronic. C fatigue. syndrome.. . Endocrine. reviews. 2003;. 2:. 236-22. 3.. . e.Lange.FP d ,.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:.198-197 . .. . uBois. RE.. . Gamma. globulin. therapy. for. chronic. D mononucleosis.syndrome...AIDS.Res.1986;.2.Suppl. 1:.S191-19. .. . dmonds.M,.McGuire.H,.Price.J...Exercise.therapy. E for. chronic. fatigue. syndrome.. . Cochrane. Database. Syst.Rev.200;.(3):CD003200. 6.. . vengard.B.and.Klimas.N...Chronic.fatigue.syndrome:. E Probable. pathogenesis. and. possible. treatments.. . Drugs.2002;.62:233-26. 7 . ukuda.K,.Straus.SE,.Hickie.I,.Sharpe.MC,.Dobbins. .. F JG,. Komaroff. A.. .The. chronic. fatigue. syndrome:. a. comprehensive.approach.to.its.definition.and.study.. . Ann.Intern.Med.199;.121:.93-99.
87
8.. . errity. TR,. Papanicolaou. DA,. Amsterdam. JD,. G 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:.31-37 .
16... oss-Morris. R,. Sharon. C,. Tobin. R,. Baldi. JC.. . A. M randomized. controlled. graded. exercise. trial. for. chronic. fatigue. syndrome:. outcomes. and. mechanisms. of. change.. . J. Health. Psychol.. . 200;. 10:2-29. 17 . atelson. BH. and. Lange. G.. . A. status. report. on. .. N chronic.fatigue.syndrome...Environ.Health.Perspect. 2002;110:673-677 . 18... atelson. BH,. Weaver. SA,. Tseng. CL,. Ottenweller. N
9.. . olmes. GP. Kaplan. JE,. Gantz. NM,. et. al.. . Chronic. H fatigue.syndrome:..a.working.case.definition...Ann. Intern.Med.1988;.108:387-389. 10... ason. LA,. Corradi. K,. Torres-Harding. S,. Taylor. RR,. J King. C.. . Chronic. fatigue. syndrome:. the. need. for. subtypes...Neuropsychol.Rev...200;.1:29-8.
JE.. . Spinal. fluid. abnormalities. in. patients. with. chronic.fatigue.syndrome...Clin.Diagn.Lab.Immunol. . 200;.12:2-. 19... atarca.R...Cytokines.and.chronic.fatigue.syndrome.. P . Ann.NY.Acad.Sci.2001;.933:18-200. 20... eterson. PK,. Shepard. J,. Macres. M,. Schenck. C,. P
11.. . ason.LA,.Richman.JA,.Rademaker.AW,.Jordan.KM,. J et.al...A.community-based.study.of.chronic.fatigue. syndrome...Arch.Intern.Med.1999;.19:2129-2137 . 12... err. JR,. Cunniffe. VS,. . Kelleher. P. Bernstein. RM,. K Bruce.IN....Successful.intravenous.immunoglobulin. therapy. in. 3. cases. of. parvovirus. B19-associated. chronic.fatigue.syndrome...Clin.Infect.Dis.2003;36:. 61000-106. 13... loyd.AR,.Hickie.I,.Boughton.CR,.et.al....Prevalence. L of. chronic. fatigue. syndrome. in. an. Australian. population...Med.J.Aust.1990;.3:.22-28. 1... loyd.A,.Hickie.I,.Wakefield.D,.Boughton.C,.Dwyer.J.. L . A.double-blind,.placebo-controlled.trial.of.intravenous. immunoglobulin. therapy. in. patients. with. chronic. fatigue.syndrome...Am.J.Med.1990;89:.61-68 1... cGhee. SA,. Kaska. B,. Liebhaber. M,. Stichm. ER.. M . Persistent. parvovirus-associated. chronic. fatigue. treated.with.high.dose.intravenous.immunoglobulin.. . Pediatr.Infect.Dis.J...200;.2:.272-27.
Crosson.J,.Rechtman.D,.Lurie.N...A.controlled.trial. of.intravenous.immunoglobulin.G.in.chronic.fatigue. syndrome...Am.J.Med.1990;89:-60. 21.. . eid.S,.ChalderT,.Cleare.A,.Hotopf.M.and.Wessely. R S.. . Chronic. fatigue. syndrome.. . Clin.. . Evid. 2002;. 8:107-1088. 22... eynolds. KJ,.Vernon. SD,. Bouchery. E. and. Reeves. R WC.. . The. economic. impact. of. chronic. fatigue. syndrome...Cost.Eff.Resour.Alloc.200;.2:. 23... imes.KA,.Chalder.T...Treatments.for.chronic.fatigue. R syndrome...Occp.Med.(Lond)...200;.:32-39. 2... owe.KS...Double-blind.randomized.controlled.trial. R to.assess.the.efficacy.of.intravenous.gammaglobulin.for.the.management.of.chronic.fatigue.syndrome. in.adolescents...J.Psychiatr.Res.1997;31:.133-17 . 2... harpe. MC,. Archard. LC,. Banatvala. JE,. et. al.. . A. S report. -. chronic. fatigue. syndrome:. guidelines. for. research...JR.Soc.Med.1991;8:.118-121.
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26... tulemeijer.,.de.Jong.LW,.Fiselier.TJ,.Hoogveld.SW,. S Bleijenberg. G.. . Cognitive. behaviour. therapy. for. adolescents. with. chronic. fatigue. syndrome:. randomized.controlled.trial...BMJ.200;.330:1. 27 . an.EM,.Sugiura.K.and.Gupta.S...The.case.definition. .. T of. chronic. fatigue. syndrome.. . J. Clin. Immun. 2002;22:8-12. 28... ernon.SD,.Reeves.WC...Evaluation.of.autoantibodies. V to. common. and. neuronal. cell. antigens. in. chronic. fatigue.syndrome...J.Autoimmune.Dis...200;.2:2-. 29... ollmer-Conna.U,.Hickie.I,.Hadzi-Pavlovic.D,.Tymms. V 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... hiting. P. Bagnall. A-M,. Sowden. AJ,. Cornell. JE,. W Mulrow. CD,. Ramirez. G.. . Interventions. for. the. treatment. and. management. of. chronic. fatigue. syndrome...JAMA.2001;286:.1360-1368. 31.. . ickie.I,.Davenport.T,.Wakefield.D,.Vollmer-Conna.U,. H Cameron.B,.Vernon.SD,.Reeves.WC,.Lloyd.A...Postinfective.and.chronic.fatigue.syndromes.precipitated. by.viral.and.non-viral.pathogens:.prospective.cohort. study...BMJ.2006;333:7. 32... err.JR,.Christian.P K ,.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... ernon.SD,.Whistler.T,.Aslakson.E,.Rajeevan.M,.Reeves. V WC.. . Challenges. for. molecular. profiling. of. chronic. fatigue.syndrome.Pharmacogenomics.2006;.7:211-8.
89
PARANEOPLASTIC NEUROLOGICAL DISORDERS

INtROdUCtION
Paraneoplastic. 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. understanding.of.basic.neuroscience.and.neuropathogenesis. of. PNDs. .These. antigens. are. ascribed. as. onconeural.
3
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 fEatUREs
PND.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). ENCEPHALItIS Cortical.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.encephalitis.. . Paraneoplastic. limbic. encephalitis. is. characterized.
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.manifestations.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.manifestations.precede.the.detection.of.the.tumour...Hence.early.
90
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.abnormalities.. . 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 MyELItIS This.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. . The. patient.
1
CEREBELLARAtAxIA Patients. 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. paraneoplastic.autoantibodies. associated. include. anti-Ri,16. antiTr.(associated.with.Hodgkin's.lymphoma),.anti-Ma/Ta,11. PCA2,1.anti-CRMP.and.ANNA-36. SENSoRy AND SENSoRIMotoR NEuRoPAtHy Prominent.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. antiCRMP.and.ANNA-3.6 . Sensorimotor.polyneuropathy.is.a.common.presentation. of. PND.. . Associated. tumours. include. haematological.malignancy.such.as.myeloma.and.Waldenstrom. macroglobulinemia. with. monoclonal. gammopathy,. SCLC,. thymoma. and. breast. cancer.. . Associated. paraneoplastic.autoantibodies.are.anti-Hu,".anti-amphiphysin19. and.CRMP-.antibodies. AutoNoMIC NEuRoPAtHy
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-AtAxIA Opsoclonus. is. characterized. by. chaotic. involuntary. eye. movements.(dancing.eyes)...The.syndrome.was.initially. recognized. in. children. with. neuroblastoma 1.. . 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. antiHu,.anti-Ri.and.anti-Ta/Ma.16
It. is. important. to. consider. PND. in. patients. with. autonomic. 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. antiHu.and.CRMP-.antibodies. REtINoPAtHy Patients. present. with. visual. symptoms. including. impaired.visual.acuity,.photosensitivity,.abnormal.color. vision,. ring. scotomas. and. prolonged. dark. adaptation.
91
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 MyAStHENIC SyNDRoME (LEMS) The. well. known. association. of. autoimmune. MG. with. thymoma.and.LEMS.with.SCLC.have.been.discussed.in. other.parts.of.the.consensus.statements. INfLAMMAtoRy MyoPAtHy Dermatomyositis.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.
tREatMENt fOR paRaNEOpLastIC NEUROLOGICaL dIsORdERs GENERAL 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. tuMoR tHERAPy - 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.degeneration.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,. corticosteroids,.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.antiHu.or.anti-Yo.antibodies.and.concluded.that.the.efficacy. of. PE. with. other. immunosuppressants. in. the. stabilization.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. KeimeGuibert.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
pathOGENEsIs
The. discovery. of. anti-neuronal. antibodies. in. PND. that. also.bind.to.the.associated.tumours.suggest.an.underlying. autoimmune.pathogenesis...The.paraneoplastic.autoantibodies.probably.do.not.cause.the.inflammatory.response. and. neuronal. damage. directly,2. although. anti-recoverin. antibody.may.be.the.exception.2.Both.Hu-specific.CDT. 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.histologically. 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.proinflammatory. 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.
92
Blaes. et. al.. . reported. efficacy. of. IVIg. in. 2. patients.
sUMMaRY
CNS INVoLVEMENt:.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. methylprednisolone. (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
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.deteriorated...It.was.suggested.that.improvement.and.stabilization. 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...
Table 1. Paraneoplastic anti-neuronal autoantibodies and their associated oncological and neurological features in PND. Paraneoplastic anti-neuronal Autoantibodies ANNA-1.(anti-Hu) ANNA-2.(anti-Ri) ANNA-3.PCA-1.(anti-Yo) (anti-Yo) .PCA-2.Anti-CRMP
Neurological features CA/PEM/LE/SN/SMN/OMA. .OMA.(children) CA/OMA CA/PEM/LE/SN/SMN CA CA/PEM/LE/AD CA/PEM/LE/SN/CN/EPS
Common tumours associated SCLC.(adult).neuroblastoma. (children) breast.cancer SCLC,.lung.adenocarcinoma breast,.ovarian.cancers,.Cancers lung.cancer SCLC,.thymoma Hodgkin's.lymphoma Testicular.cancers.Others SCLC,.ovarian.cancer
Anti-Tr Anti-Ma/Ta Anti-amphiphys
CA CA/BE/LE SMS/SN/SMN/OMA
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.
93
Patients. with. PND. who. fulfill. clinical. and. electro-
paraneoplastic. cerebellar. degeneration. and. anti-Yo. antibodies. where. early. high. dose. IVIg. with. or. without. other.therapies.may.be.of.benefit.
physiological. criteria. of. Guillain-Barr. syndrome. (GBS). or.chronic.inflammatory.demyelinating.polyradiculoneuropathy.(CIDP).should.be.treated.according.to.standard. regimens...Patients.with.LEMS.tend.to.response.well.to. IVIg. and. PE,. but. immunosuppressants. such. as. azathioprine.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.crossover.study. Paraneoplastic. necrotizing. myopathy. presents. with. subacutely. evolving,. symmetric. proximal. weakness. associated.with.gastrointestinal.adenocarcinoma,.transitional. cell. carcinoma,. prostatic. carcinoma,. and. nonsmall. 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.
REfERENCEs
1.. . osner. JB.. Paraneoplastic. syndromes.. In:. Posner. P JB.. Neurologic. complications. of. cancer.. Contemporary. Neurological. Series,. FA. Davis. 199;33:-38. 2.. . ennon. VA.. The. case. for. a. descriptive. generic. L nomenclature:. clarification. of. immunostaining. criteria. for. PCA-1,. ANNA-1,. and. ANNA-2. autoantibodies..Neurology.199;:212-21. 3.. . arnell. RB.. Onconeural. antigens. and. the. paraneoD plastic. neurologic. disorders:. at. the. intersection. of. cancer,.immunity,.and.the.brain..Proc.Natl.Acad.Sci. USA.1996:93:29-36. .. . ucchinetti. CF,. Kimmel. DW,. Lennon. VA.. L Paraneoplastic. and. oncologic. profiles. of. patients. seropositive.for.type.1.antineuronal.nuclear.autoantibodies..Neurology.1998;0:62-67 . .. . u. Z,. KryzerTJ,. Griesmann. GE,. et. al.. CRMP-. Y neuronal. autoantibody:. marker. of. lung. cancer. and. thymoma-related. autoimmunity.. Ann. Neurol. 2001;9:16-1. 6.. . han. KH,.Vernino. S,. Lennon.VA.. ANNA-3. anti-neuC ronal. nuclear. antibody:. marker. of. lung. cancer-related.autoimmunity..Ann.Neurol.2001;0:301-311. 7 . ierley. JB,. Corsellis. JAN,. Hierons. R,. Nevin. S.. .. B Subacute. encephalitis. of. later. adult. life. mainly. affecting.the.limbicarea..Brain.1960;83:38-368. 8.. . orsellis. JAN,. Goldberg. GJ,. Norton. RA.. "Limbic. C encephalitis". and. its. association. with. carcinoma.. Brain.1968;91:81-96.
EXpERt CONsENsUs
IVIg. is. useful. in. children. with. opsoclonus-myoclonusataxia. 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. 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). . 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.
9
9.. . arr. I.. The. Ophelia. syndrome:. memory. loss. in. C Hodgkin's.disease..Lancet.1982;.1:8-8. 10... ultekin. SH,. Rosenfeld. MR,. Voltz. R,. et. al.. G Paraneoplastic. limbic. encephalitis:. neurological. symptoms,. immunological. findings. and. tumour. association. in. 0. patients.. Brain. 2000;. 123:. 181-19. 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;30:.1788-179. 12... all. JA.,. Warner. T,. Reid. P et. al.. Central. alveolar. B ,. hypoventilation. associated. with. paraneoplastic. brainstem. encephalitis. and. anti-Hu. antibodies.. J. Neurol.199;21:61-66. 13... orsyth.PA,.Dalmau.J,.Graus.F F ,.et.al..Motor.neuron. syndromes. in. cancer. patients.. Ann. Neurol. 1997;1:722-730. 1... ernino. S,. Lennon. VA.. New. Purkinje. cell. antibody. V (PCA-2):. marker. of. lung. cancer-related. neurological. autoimmunity..Ann.Neurol.2000:7:297-30. 1... udnick.E,.Khakoo.Y,.Antunes.NL,.et.al..OpsoclonusR 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... udde-Steffen.C,.Anderson.NE,.Rosenblum.MK,.et. B al.. An. anti-neuronal. autoantibody. in. paraneoplastic. opsoclonus..Ann.Neurol.1988;23:28-31. 17 . ojas. I,. Graus. F Keime-Guibert. F et. al.. Long-term. .. R ,. ,. clinical. outcome. of. paraneoplastic. cerebellar. . degeneration. and. anti-Yo. antibodies.. Neurology. 2000::713-71.
18... raus.F G ,.Keime-Guibert.F ,.Rene.Rad,.et.al..Anti-Huassociated. paraneoplastic. encephalomyelitis:. analysis.of.200.patients..Brain.2001;12:1138-118. 19... ennon.VA,.Manley.HA,.Kim.K-K,.et.al..Amphiphysin. L autoantibodies:. a. paraneoplastic. serological. marker. of. breast. and. lung. cancer-related. encephalomyelo-. radiculoneuritides. but. not. classical. stiffman. syn-. drome..Neurology.1997;8:A3. 20... ennon.VA,.Sas.DF L ,.Busk.MF ,.et.al..Enteric.neuronal. autoantibodies.in.pseudo-obstruction.with.small-.cell. lung.carcinoma..Gastroenterology.1991;100:137-12. 21.. . hirkill. CE,. FitzGerald,. Sergott. RC,. et. al.. CancerT associated. retinopathy. (CAR. syndrome). with. antibodies. reacting. with. retinal,. optic-nerve,. and. cancer.cells..N.Eng.J.Med.1989;321:189-19. 22... ichen.JG,.Dalmau.J,.Demopoulos.A,.et.al..The.phoE toreceptor. cell-specific. nuclear. receptor. is. an. autoantigen. of. paraneoplastic. retinopathy.. J. Neuroopthalmol.2001;21:168-172. 23... damus.G,.Amundson.D,.Siegel.GM,.Machnicki.M.. A Anti-enolase-alpha. autoantibodies. in. cancer-associated.retinopathy:.epitope.mapping.and.cytotoxicityon.retinal.cells..J.Autoimmun.1998;11:671-677 .. 2... erschuuren. JJ,. Dalmau. J,. Hoard. R,. Posner. JB.. V Paraneoplastic.anti-Hu.serum:.studies.on.human.cell. lines..J.Neuroimmunol.1997;79:202-210. 2... aeda.T,.Maeda.A,.Maruyama.I,.et.al..Mechanisms. M of. photoreceptor. cell. death. in. cancer-associated. retinopathy.. Invest. Ophthalmol. Vis. Sci. . 2001;2:70-710. 26... enyahia. B,. Liblau. R,. Merle-Beral. H,. et. al.. CellB mediated.autoimmunity.in.paraneoplastic.neurological.syndromes.with.anti-Hu.antibodies..Ann.Neurol. 1999;:162-167 .
9
27 . anaka. K.Tanaka. M,. InuzukaT,. et. al.. Cytotoxic. T. .. T lymphocyte-mediated. cell. death. in. paraneoplastic. sensory. neuronopathy. with. anti-Hu. antibody.. J. Neurol.Sci.1999;163:19-162. 28... osenblum.MK..Paraneoplasia.and.autoimmunologR ic. injury. of. the. nervous. system:. the. anti-Hu. syndrome..Brain.Pathol.1993:3:199-212. 29... almau. J,. Graus. F Cheung. NK,. et. al.. Major. histoD ,. compatibility.proteins,.anti-Hu.antibodies,.and.paraneoplastic. encephalomyelitis. in. neuroblastoma. and. small.cell.lung.cancer..Cancer.199:7:99-109. 30... eime-Guibert.F K ,.Graus.F ,.Broet.P ,.et.al..Clinical.outcome.of.patients.with.anti-Hu.associated.encephalomyelitis.after.treatment.of.the.tumour..Neurology. 1999:3:1719-1723. 31.. . raus. F G ,.Vega. F Delattre. JY,. et. al.. Plasmapheresis. ,. and.antineoplastic.treatment.in.CNS.paraneoplastic. syndromes. with. antineuronal. autoantibodies.. Neurology.1992:2:36-0. 32... tarke.E,.Wurster.U,.Patzold.U,.et.al..Immunological. S and. clinical. response. to. immunosuppressive. treatment.in.paraneoplastic.cerebellar.degeneration.. Arch.Neurol.199:2:81-818. 33... eime-Guibert.F K ,.Graus.F ,.Fleury.A,.et.al..Treatment. of.paraneoplastic.neurological.syndromes.with.antineuronal. antibodies. (anti-Hu,. anti-Yo). with. a. combination. of. immunoglobulins,. cyclophosphamide,.and.methylprednisolone..J.Neurol.Neurosurg. Psychiatry.2000:68:79-82. 3... laes. F Strittmatter. M,. Merkelbach. S,. et. al.. B ,. Intravenous. . immunoglobulins.. in. .the. . therapy. . of. paraneoplastic. neurological. disorders.. J. Neurol. 1999;26:299-303.
3... chuya...M,..Graus..F U ,.Vega..F ,..et.al....Intravenous. immunoglobulin.treatment.in.paraneoplastic.neurological. syndromes. with. antineuronal. autoantibodies..J.Neurol.Neurosurg.Psychiatry.1996:60:388-392. 36... oltz. R.. Paraneoplastic. neurological. syndromes:. an. V update. on. diagnosis,. pathogenesis,. and. therapy.. Lancet.Neurology.2002:1:29-30. 37 . ubhadra. C,. Dudek. AZ,. Rath. PP Lee. MS.. .. S ,. Improvement. in. visual. fields. in. a. patient. with. melanoma-associated. retinopathy. treated. with. intravenous. immunoglobulin.. J. Neuroophthalmol. 2008;28:23-26. 38... ampson. JB,. Smith. SM,. Smith. AG,. Singleton. JR,. S Chin. S,. Pestronk. A,. Flanigan. KM.. Paraneoplastic. myopathy:. response. to. intravenous. immunoglobulin..Neuromuscul.Disord.2007;17:0-08. 39... oltz. R.. Intravenous. immunoglobulin. therapy. in. V paraneoplastic. neurological. syndromes.. J. Neurol. 2006;23.Suppl.:V33-V38.. 0... huphanich. S,. Brock. C.. Neurologic. improvement. P after.high-dose.intravenous.immunoglobulin.therapy. in.patients.with.paraneoplastic.cerebellar.degeneration. associated. with. anti-Purkinje. cell. antibody.. J. Neurooncol.2007;81:67-69.
96
STIFF-PERSON SYNDROME
BaCKGROUNd
Stiff.person.syndrome.(SPS).is.a.disorder.first.described.in. 196.by.Moersh.and.Woltman1...It.occurs.mainly.in.adult. life.and.can.be.paraneoplastic.in.20-30% ...It.presents.with.
2
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.autoimmune.disorders. . The. differential. diagnosis. includes. chronic. tetanus,. extrapyramidal. syndromes. with. dystonia. and. rigidity,. neuromyotonia.and.psychogenic.disorders3.
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.
NEUROphYsIOLOGY
The. 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.
97
aUtO-aNtIBOdIEs aNd IMMUNOpathOGENEsIs

In. 1988. it. was. found. that. about. 6%. of. SPS. patients. have. auto-antibodies. to. GAD-6. or. GAD-67. the. ratelimiting.enzyme.for.GABA.synthesis ...The.titers.in.SPS.

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). .mmunomodulatory. treatments.. . The. initial. focus. I 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.
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.polymyositis .
3
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. MRS ...The.serum.and.CSF.of.SPS.patients.inhibit.GAD.
3
activity. affecting. GABA. synthesis. in. vitro .. . However.

3
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. antigephryn.and.anti-Ri.antibodies. . Some. patients. with. SPS. have. no. associated. malignancy.or.anti-GAD.antibodies.
IVIG IN sps
Early.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.
thERapIEs
Considering.the.pathogenesis.of.SPS.two.main.therapies. have.been.in.use. 1). . rugs. enhancing. GABA. activity.. . High. doses. of. D diazepam.up.to.100.mg/day.are.most.widely.used.. .
98
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. doubleblind,. 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.-distribution-of-stiffness. index. (DSI). and. heightenedsensitivity. 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.significantly.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.
EXpERt CONsENsUs
Considering.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.
REfERENCEs
1.. . oersh. FP. Woltman. HW.. Progressive. fluctuating. M muscular. rigidity. and. spasm. (stiff-man. syndrome);. report.of.a.case.and.some.observations.in.13.other. cases..Mayo.Clin.Proc.196;.31:21-7 . 2.. . ataller. L,. Dalmau. J.. Paraneoplastic. Neurologic. B Syndromes:.Approaches.to.diagnosis.and.treatment.. Seminars.Neurol..2003;.23.(2):21-2. 3.. . evy.LM,.Dalakas.MC,.Floeter.MK...The.stiff-person. L syndrome:. an. autoimmune. disorder. affecting. neurotransmission. of. gamma-aminobutyric. acid.. . Ann. Internal.Med.1999;.131.(7);.22-30. .. . alakas. MC,. Fuji. M,. Li. M,. et. al.. High-dose. D intravenous. immune. globulin. for. stiff-person. syndrome..N.Engl.J.Med.2001;.3.(26):.1870-76. .. . olimena. M,. Folli. F,. Denis-Donini. S,. et. al.. S 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.. . mato. AA,. Cornman. EW,. Kissel. JT..Treatment. of. A stiff-man.syndrome.with.intravenous.immunoglobulin..Neurology.199;.(9):.162-. 7 . arlson. EW,. Sudarsky. L,. Ruderman. E,. et. al.. .. K Treatment.of.stiff-man.syndrome.with.IVIG..Arthritis. Rheum.199;.37(6):.91-18.
sUMMaRY
There.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.paraneoplastic. forms. of. SPS;. however. the. probable. autoimmune. nature. of. this. syndrome. suggests. that. IVIG.should.be.used.here.as.well.
99
8.. . arker. RA,. Marsden. CD.. Successful. treatment. of. B stiff-man. syndrome. with. IVIG.. J. Neurol. Neurosurg. Psychiatry.1997;.62:26-7 . 9.. . ikaeloff.Y,.Jambaque.I,.Mayer.M,.et.al..Benefit.of. M intravenous. immunoglobulin. autoimmune. stiffperson.syndrome.in.a.child..J.Pediatr.2001;.139(2).:30. 10. . erschlager. W,. Brown. P Effect. of. treatment. with. G .. 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. . evy.LM,.Dalakas.MC,.Fleeter.MK..The.stiff-personL syndrome:.an.autoimmune.disorder.affecting.neurotransmission. 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.
100
EPILEPSY
EPILEPSY
BaCKGROUNd
The.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.demonstrated).epilepsies. WESt SyNDRoME (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.developmental. 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-GAStAut SyNDRoME (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.develop101
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.
INtRaCtaBLE EpILEpsIEs
About. 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.. .
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. felbamate12.,.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'S ENCEPHALItIS (RE) Rasmussen's. encephalitis. (RE). is. a. rare. condition. occurring.usually.in.children.and.adolescence,.characterized.by.progressive.unilateral.hemispheric.dysfunction,. intractable. focal. epilepsy. including. epilepsia. partialis. continua,.cognitive.and.behavioural.changes,.and.inflammatory.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.autoantibodies. against. the. GluR3. receptor. was. highlighted .. .
19
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. LANDAu kLEffNER SyNDRoME (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.
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.
102
BasIs fOR UsING IMMUNOMOdULatION

There. 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. autoantibodies.and.immunomodulatory.treatments.have.been.at.least. partially.effective30.
EPILEPSY
Recent.case.reports.have.focused.on.several.auto-
In. the. only. large. multi-center. double. blind.
antibodies. in. some. epilepsy. syndromes. including. antiGAD. antibodies. in. myoclonic. seizures. and. refractory. partial.seizures.with.or.without.cerebellar.ataxia.as.well. as. anti-voltage. gated. potassium. channels. in. non-paraneoplastic. limbic. encephalitis,. where. seizures. are. part. of. a. subacute. neuropsychiatric. syndrome. of. amnesia,. confusion.and.sometimes.psychosis...
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.significantly.after.treatment2. IVIG IN WS IVIG. 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
IVIG IN EpILEpsY
There. has. been. an. interest. in. IVIG. in. epilepsy. since. Prichard.demonstrated.a.benefit.of.intramuscular.immunoglobulins.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.highlighting. the. use. of. IVIG. in. IE.. . Most. of. these. were. uncontrolled,. unblinded. and. often. retrospective.. . Up. until. 1996,.a.total.of.29.studies.had.used.IVIG.in.373.patients. with.a.benefit.in.17.patients ...In.a.critical.review .Van.
30 31
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.
. 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.
103
Van. Engelen. conducted. a. well-designed. add-on.
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. IVIG IN LkS Initially.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.dependent0.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...
study.in.1.patients.where.3.had.WS.and.demonstrated. efficacy.in.only.one.of.these3...A.more.recent.retrospective. 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. disappearance.and.only.clinical.reports.were.relied.upon. IVIG IN LGS Initial.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.study ... hough.different.dosage.and.regimens. T
37
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.multicenter. study. with. use. both. in. recently. diagnosed. and. refractory.cases.would.be.useful. IVIG IN RE Hart. initially. reported. a. multi-center. prospective. open. label.study.of.steroids.or.IVIG.or.both.in.mostly.biopsy. proven. RE .. .The. treatment. protocol. was. variable. and.
23
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.
10
EPILEPSY
sUMMaRY
Intractable. 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.
REfERENCEs
1.. . ingel. U,. Pinter. JD,. Sotero. de. Menezes. M,. et. al.. B Intravenous. immunoglobulin. as. adjunctive. therapy. for. juvenile. spasms.. J. Child. Neurol.. 2003;. 18. (6):379-82. 2.. . antala. H,. Putkonen. I. Occurrence,. outcome,. andR prognostic. factors. of. infantile. spasms. and. LennoxGastaut. syndrome.. Epilepsia.. 1999. Mar;0(3):286-9. 3.. . anagaki.S,.Oguni.H,.Hayashi.K,.et.al..A.comparative. Y study. of. high-dose. and. low-dose.ACTH. therapy. for. West.syndrome..Brain.Dev..1999;.21(7):.61-7 . .. Baram.TZ,.Mitchell.WG,.Tournay.A,.et.al..High-dose. corticotropin. (ACTH). versus. prednisone. for. infantil. spasms:. a. prospective,. randomized,. blinded. study.. Pediatrics..1996;.97(3):.37-9. .. . igevano. F Cilio. MR.. Vigabatrin. versus. ACTH. as. V ,. first-line.treatment.for.infantile.spasms:.a.randomized,. prospective. 38(12):1270-127. 6. Driefuss. F,. Farwell. J,. . Holmes. G,. et. al.. . . study.. Epilepsia.. 1997;.
EXpERt CONsENsUs
1).. . he. evidence. for. the. use. of. IVIG. as. a. standard. T 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.
Infantile. spasms.. Comparative. trial. of. nitrazepam. and. corticotropin.. Arch. Neurol.. 1986;. 3(11):. 1107-1110. 7 . yken.PR,.DuRant.RH,.Minden.DB,.et.al..Short.term. .. D effects. of. valproate. on. infantile. spasms.. Pediatr. Neurol..198;.1(1):.3-37 . 8.. Glauser.TA,.Clark.PO,.Strawsburg.R..A.pilot.study.of. .
2).. .n.adult.Rasmussen's.syndrome.there.seems.to.be. I a. role. for. periodic. IVIG. therapy. before. surgical. treatment. is. considered,. especially. in. the. patient. without.deficits. 3).. .n. the. Landau-Kleffner. syndrome,. IVIG. might. be. I considered.especially.in.steroid.failures.
topiramate. in. the. treatment. of. infantile. spasms. Epilepsia..1998;.39(12).:132-1328. 9.. . lauser..TA,.Clark.PO,.McGee.K..Long-term.response. G to. topiramate. in. patients. with. West. syndrome.. Epilepsia..2000;.1.Suppl.1:.S91-9.
10
10... ossoff.EH,.Pyzik.PL,.McGrogan.JR,.et.al..Efficacy. K of.the.ketogenic.diet.for.infantile.spasms..Pediatrics.. 2002;.109():.780-3. 11.. . riizumi. A M,. Baba. K,. Hibio. S,. et. al..
19... ogers. SW,. Andrews. PI,. Gahring. LC. et. al.. R Autoantibodies. to. glutamate. receptor. GluR3. in. Rasmussen's. encephalitis.. Science.. 199. 29;. 26:68-1.
Immunoglobulintherapy. in. the. West. syndrome.. Brain.Dev.1987;9():.22-2. 12... he. Felbamate. Study. Group. in. Lennox-Gastaut. T Syndrome.. Efficacy. of. Felbamate. in. childhood. epileptic. encephalopathy. (Lennox-Gastaut. syn. drome)..N.Engl.J.Med..1993.7;.328:29-33. 13... riksson.AS,. Nergardh.A,. Hoppu. K..The. efficacy. of. E lamotrigine. in. children. and. adolescents. with. refrac. tory. generalized. epilepsy:. a. randomized,. doubleblind,. crossover. study.. Epilepsia.. 1998;. 39():. 9-01. . 1... achdeo. RC,. Glauser.TA,. Ritter. F et. al.. A. double. S ,. blind,. randomized. trial. of. topiramate. in. LennoxGastaut. syndrome.. Topiramate. YL. Study. Group. Neurology..1999.10;.2(9):.1882-87 . 1... odson.WE..Felbamate.in.the.treatment.of.LennoxD Gastaut.syndrome:.results.of.a.12-month.open-label. study. following. a. randomized.clinical. trial.Epilepsia.. 1993;.3.(Suppl.7):S18-2. 16... lauser.TA,.Levisohn.PM,.Ritter.F G ,.et.al..Topiramate. in. Lennox-Gastaut. syndrome:. open-label. treatment. of.patients.completing.a.randomized.controlled.trial.. Topiramate. L.Study.Group..Epilepsia..2000;1(Suppl. Y 1):S86-90. 17 . chmidt.D,.Bourgeois.B..A.risk-benefit.assessment. .. S of.therapies.for.Lennox-Gastaut.syndrome..DrugSaf.. 2000;.22(6):67-77 . 18... illani. F Spreafico. R,. Farina. L,. et. al.. Positive. V ,. response.to.immunomodulatory.therapy.in.an.adultpatient. with. Rasmussen's. encephalitis.. Neurology.2001.23;6(2):28-0.
20... iendl. H,. Bien. CG,. Bernasconi. P et. al.. GluR3. W ,. antibodies:. prevalence. in. focal. epilepsy. but. no. specificity.for.Rasmussen's.encephalitis..Neurology.. 2001.23;7(8):111-. 21.. Bien. CG,. Widman. G,. Urbach. H,. et. al..The. natural. . history. of. Rasmussen's. encephalitis.. Brain.. 2002;12(Pt8):171-9. 22... ranata.T,.Fusco.L,.Gobby.G,.et.al..Experience.with. G immunomodulator y. 61(12):1807-10. 23... art. YM,. Cortez. M,. Andermann. F et. al.. Medical. H ,. treatment. of. Rasmussen's. syndrome. (chronic. encephalitis. and. epilepsy):. effect. of. high-dose. steroids. or. immunoglobulins. in. 19. patients.. Neurology..199;.(6):1030-6. 2... mith. MC,. Hoeppner.TJ.. Epileptic. encephalopathy. S of.late.childhood:.Landau-Kleffner.syndrome.and.the. syndrome. of. continuous. spikes. and. waves. during. slow-wave. sleep.. J. Clin. Neurophysiol.. 2003;20(6):62-72. 2... raline.J,.Hommet.C,.Barthez.MA,.et.al..Outcome.at. P adulthood. of. the. continuous. spike-waves. during. slow. sleep. and. Landau-Kleffner. syndromes. Epilepsia..2003.Nov;(11):13-0. 26... obinson. RO,. Baird. G,. Robinson. G,. et. al.. LandauR Kleffner.syndrome:.course.and.correlates.with.outcome.. Dev.Med.Child.Neurol..2001;.3():.23-7 . 27 . ikati. MA,. Saab. R.. Successful. use. of. intravenous. .. M immunoglobulin.as.initial.monotherapy.in.LandauKleffner. syndrome..Epilepsia..2000.Jul;1(7):880-6. . treatments. in. Rasmussen'sencephalitis.. Neurology.. 2003. 23;.
106
EPILEPSY
28...Tsuru Mori. M,. Mizuguchi. M,. et. al.. Effects. of. high.T,. dose. intravenous. corticosteroid. therapy. in. LandauKleffner.syndrome..Pediatr.Neurol..2000;.22(2):1-7 . 29...rwin.K,.Birch.V,.Lees.J,.et.al..Multiple.subpial.tranI section.in.Landau-Kleffner.syndrome..Dev.MedChild. Neurol..2001;.3():28-2. 30... use.M,.Notarangelo.LD.Tiberti.S,.et.al..IVIG.in.the. D treatment. of. intractable. childhood. epilepsy.. Clin. ExpImmunol.1996;.10.(Suppl.1):.71-76. 31.. . an. Engelen. BG,. Renier.WO,.Weemaes. CM,. et. al.. V Immunoglobulin. treatment. in. human. and. experimental.epilepsy..J.Neurol.Neurosurg.Psychiatry.199;. 7.(Suppl):.72-7.. . 32... echadre. JC,. Sauvezie. B,. Osier. C,. et. al.. The. P treatment.of.epileptic.encephalopathies.with.gamma. globulin. in. children. (authors. translation). Rev. Electroencephalogr. Neurophysiol. Clin.. 1977;. 7. ():3-7 .. 33... an. Rijckevorsel-Harmant. K,. Delire. M,. Schmitzv morrman.W,. et. al..Treatment. of. refractory. epilepsy. with. intravenous. immunoglobulins.. Results. of. the. first.double-.blind./.dose.finding.clinical.study..Int.J. ClinLab.Res.199.2:.162-166. 3... chenne. B,. Dulac. 0,. Parayre-Chanez. MJ,. et. al.. E Treatment.of.infantile.spasms.with.IVIG..Brain.Dev. 1991;.13:313-319. 3... an. Engelen. BG,. Renier.WO,.Weemaes. CM,. et. al.. v High-dose. intravenous. immunoglobulin. treatment. in. cryptogenic.West.and.Lennox-Gastaut.syndrome;.an. add-on.study..Eur.J.Pediatr..199;.13(10):762-9. 36... ross-Tsur..V,.Shalev.RS,.Kazir.E,.et.al..Intravenous. G high-dose.gammaglobulins.for.intractable.childhood. epilepsy..Acta.Neurol.Scand..1993;.88(3):20-9.
37 .lium. N,.Taudorf. K,. Heilmann. C,. et. al.. Intravenous. .. I immunoglobulin:. a. single-blind. trial. in. children. with. Lennox-Gastaut. 1990;21(2):87-90. 38... each.JP.Chadwick.DW,.Miles.JB,.et.al..Improvement. L in. adult-onset. Rasmussen'sencephalitis. with. longterm. immunomodulatory. therapy.. Neurology.. 1999. 10;.2():738-2. 39... ayad. MN,. Choueiri. R,. Mikati. M.. Landau-Kleffner. F syndrome:. consistent. response. to. repeated. intravenous. gamma-globulin. doses:. a. case. report. Epilepsia..1997;.38():89-9. 0... agae. LG,. Silberstein. J,. Gillis. PI,. et. al.. Successful. L use. of. intravenous. immunoglobulins. in. LandauKleffner. syndrome.. Pediatr. Neurol.. 1998;. 18(2):16-68. 1.. Mikati. MA,. Saab. R,. Fayad. MN,. et. al.. Efficacy. of. . intravenous. immunoglobulin. in. Landau-Kleffner. syndrome..Pediatr.Neurol..2002;.26():298-300. 2... illiau. AD,. Witters. P Ceulemans. B,. Kasran. A,. B ,. Wouters. C,. Lagae. L.. Intravenous. immunoglobulins. in. refractory. childhood-onset. epilepsy:. effects. on. seizure. frequency,. EEG. activity,. and. cerebrospinal. fluid.cytokine.profile..Epilepsia.2007;8:1739-179. . syndrome.. Neuropediatrics..
107
OPSOCLONUS-MYOCLONUS-ATAXIA
BaCKGROUNd
Opsoclonus-myoclonus-ataxia. (OMA). is. an. immune. mediated.monophasic.or.multiphasic.disorder.affecting. both.children.and.adults....It.is.a.rare.and.is.either.paraneoplastic.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. imaging ....The.pathogenesis.of.OMA.was.thought.to.be.
1
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.neuroblastomas.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....
antibody.mediated....Anti-Ri,.anti-.Hu.and.other.antineuronal. antibodies. are. sometimes. found. in. adult. onset. paraneoplastic. OMA .. . . In. childhood. anti-Purkinje. cell.
2
and.anti-neurofilament.antibodies.have.been.reported .. .
1-3
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,.

108
Longer. follow-ups. have. suggested. continued. improvement. with. about. half. the. children. achieving. average.intelligence1.
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.immunotherapies.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. (10. mg/kg. over. 3. days). though. this. response. was. gradual.and.may.suggest.a.natural.remission....BorgnaPignatti. 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.
CONVENtIONaL MaNaGEMENt
The. first. line. treatment. of. the. immune. syndrome. has. been.ACTH./.oral.steroids6.with.or.without.pulse.methylprednisolone. therapy .. . . Other. immunomodulatory.
9
treatments.like.plasma.exchange10.and.immunoadsorption11. 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. Rituximab . led. to. a.
2
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 OMa
It. 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.methylprednisolone.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.
sUMMaRY
1).. . here. is. Level. IIIb. evidence. supporting. the. use. of. T 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.
109
2).. .t. is. possibly. less. useful. in. adult. paraneoplastic. I OMA.where.tumor.control.seems.more.crucial. 3).. . ost. successes. were. continuing. other. therapies. M like. ACTH. /. chemotherapy. and. this. may. have. influenced.the.results.
.. . ranzatelli. MR,.Tate. ED,.Wheeler. A,. Bass. N,. Gold. P AP.Griebel.ML,.Gumbinas.M,.Heydemann.PT,.Holt. PJ,. Jacob. P. Kotagal. S,. Minarcik. CJ,. Schub. HS. Screening.for.autoantibodies.in.children.with.opsoclonus-myoclonus-ataxia.. 2002;27():.38-87 . . .. Pranzatelli. MR,.Travelstead. AL,.Tate. ED,. Allison.TJ,. . Moticka.EJ,.Franz.DN,.Nigro.MA,.Parke.JT,.Stumpf. DA,.Verhulst.SJ...B-.and.T-cell.markers.in.opsoclonusmyoclonus.syndrome:.immunophenotyping.of.CSF. lymphocytes...Neurology...200;.62(9):.126-32. 6.. . udnick. E,. Khakoo. Y,. Antunes. NL,. Seeger. RC,. R Brodeur. GM,. Shimada. H,. Gerbing. RB,. Stram. DO,. Matthay. KK.. . Opsoclonus-myoclonus-ataxia. syndrome. in. neuroblastoma:. clinical. outcome. and. anti-neuronal. antibodies. -. a. report. from. the. Children's.Cancer.Group.Study...Med.Pediatr.Oncol.. . 2001;36(6):612-22. . Pediatr. Neurol.. .
).. . he. dosage. of. IVIG. used. has. been. variable. from. T 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 CONsENsUs
IVIG. 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. 8.. . usso. C,. Cohn. SL,. Petruzzi. MJ,. de. Alarcon. PA.. R . 7 . ammer. MS,. Larsen. MB,. Stack. CV.. Outcome. of. .. H children. with. opsoclonus-myoclonus. regardless. of. etiology...Pediatr.Neurol.199.I;.13(1):21-.
REfERENCEs
1.. . ayward. K,. Jeremy. RJ,. Jenkins. S,. Barkovich. AJ,. H Gultekin. SH,. Kramer. J,. Crittenden. M,. Matthay. KK. Long-term. neurobehavioral. outcomes. in. children. with. neuroblastoma. and. opsoclonus-myoclonusataxia. syndrome:. relationship. to. MRI. findings. and. anti-neuronal. antibodies.. . J. Pediatr.. . 2001;. 139():2-9. 2.. . ataller. L,. Graus. F Saiz. A,. Vilchez. JJ;. Spanish. B ,. Opsoclonus-Myoclonus. Study. Group.. Clinical. outcome. in. adult. onset. idiopathic. or. paraneoplasticopsoclonus-myoclonus.Brain..2001;.12(Pt.2):.37-3. 3.. Petruzzi.MJ,.de.Alarcon.PA...Neuroblastoma-associ. ated. opsoclonus-myoclonus. treated. with. intravenously. administered. immune. globulin. G.. . JPediatr.. . 199;.127(2):.328-9.
110
Long-term. neurologic. outcome. in. children. with. opsoclonus-myoclonus. associated. with. neuroblastoma:.a.report.from.the.Pediatric.Oncology.Group. Med.Pediatr.Oncol...1997;28():28-88. 9.. . mir.S,.Akyuz.C,.Buyukpamukcu.M...Treatment.of. E the. neuroblastoma-associated. opsoclonusmyoclonus-ataxia.syndrome.with.high.dose.methylprednisolone...Med...Pediatr...Oncol...2003;.0:139.. 10... iu. VW,. Kovithavongs. T,. McGonigle. LF Ferreira. Y ,. . P Plasmapheresis. as. an. effective. treatment. for. .. opsoclonus-myoclonus. syndrome.. . Pediatr. Neurol.. . 2001;2(1):.72-7.
11.. Batchelor. TT,. .
Platten.
M,.
Hochberg.
FH.. .
19... een.WG,.Weemaes.CM,.Verbeek.MM,.Willemsen. L MA,.Rotteveel.JJ...Rituximab.and.intravenous.immunoglobulins.for.relapsing.postinfectious.opsoclonusmyoclonus. syndrome.. . Pediatr. Neurol. 2008;39:213-217 . 20... rtle.F E ,.Behnisch.W,.Al.Mulla.NA,.Bessisso.M,.Rating. D,.Mechtersheimer.G,.Hero.B,.Kulozik.AE...Treatment. of. neuroblastoma-related. opsoclonus-myoclonusataxia. syndrome. with. high-dose. dexamethasone. pulses...Pediatr.Blood.Cancer.2008;0:683-687 .
Immunoadsorption. therapy. for. paraneoplastic. syndromes...J.Neurooncol...1998;.0(2):131-36. . 12... ichael. R.. . Pranzatelli,. Elizabeth. D.. . Tate,. Anna. M 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... ugie.H,.Sugie.Y,.Akimoto.H,.Endo.K,.Shirai.M,.Ito. S M...High-dose.IV.human.immunoglobulin.in.a.case. with. infantile. opsoclonus-polymyoclonia. syndrome.. . Acta.Paediatr...1992;.81():.371-2. 1... less. M,. Ronthal. M.. . Treatment. of. opsoclonusP myoclonus. with. high-dose. intravenous. immunoglobulin...Neurology.1996;.6(2):.83-. 1... latz. G K,. Meinck. HM,. Wildemann. B.. .
21.. . ranzatelli. MR,.Tate. ED,.Travelstead.AL,. Barbosa. J,. P 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... urke. MJ,. Cohn. SL.. . Rituximab. for. treatment. of. B opsoclonus-myoclonus.syndrome.in.neuroblastoma.. . Pediatr.Blood.Cancer.2008;0:679-680. 23... ell.J,.Moran.C,.Blatt.J...Response.to.rituximab.in.a. B child.with.neuroblastoma.and.opsoclonus-myoclonus.. . Pediatr.Blood.Cancer.2008;0:370-371. 2... ranzatelli. MR,.Tate. ED,.Travelstead.AL,. Longee. D.. P . Immunologic.and.clinical.responses.to.rituximab.in.a. child. with. opsoclonus-myoclonus. syndrome.. . Pediatrics.200;11:e11-e119.83.
Parainfectiousopsoclonus-myoclonus. syndrome:. high. dose. intravenous. immunoglobulins. are. . effective.. . J. Neurol. Neurosurg. Psychiatry.. . 2003;.7(2):.279-80. 16... ranzatelli.MR,Tate.ED,.Kinsbourne.M,.Caviness,.VS. P 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... orgna-Pignatti. C,. Baiter. R,. Marradi. P. Colamaria.V.. B Treatment. with. intravenously. administered. . immunoglobulins. of. the. neuroblastoma-associated. opsoclonus-myoclonus.. . J. Pediatr.1996;. 129(1):. 179-80.
111
ACUTE DISSEMINATED ENCEPHALOMYELITIS

CLINICaL fEatUREs
Acute. 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. neurological.signs...Optic.neuritis,.which.is.often.bilateral,.and. paraparesis.or.tetraparesis.with.a.sensory.level.due.to. transverse.myelitis.can.also.occur. antirabies. (Murthy. 1998). and. Japanese. encephalitis. (Plesner.et.al.,.1998)...In.this.era.of.organ.transplantation. with.use.of.immunosuppressants,.post-organ.transplantation.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.reactivation. 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).
EtIOLOGY
Post-infectious. ADEM. in. infants. and. children. mostly. commonly. followed. viral. infections. by. measles. (Litvak. et.al...193)...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).. . Postimmunization.ADEM.is.most.commonly.associated.with. measles,.mumps.and.rubella.vaccinations.(Nalin.1989),. and. has. reported. with. vaccination. against. Semple.
112
pathOGENEsIs
Histological. examinations. of. affected. brain. or. cord. lesions. showed. areas. of. demyelination. and. inflammation.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.. .
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.Theilers.murine.encephalomyelitis. 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.glycoprotein. can. induce. ADEM. after. immunization. in. Freunds. 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)...
tREatMENt
The. aim. of. treatment. in. ADEM. is. to. suppress. the. autoimmune.inflammatory.demyelinating.response.that. damage. the. CNS. and. optic. neuritis.. . Hence. immunomodulatory.treatments.are.employed...Intravenous.corticosteroids.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. methylprednisolone. (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.neurological.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. plasmapheresis. should. be. considered. for. ADEM. when. the. disease. course. is. aggressive. or. severe. without. . satisfactory. improvement. to. corticosteroids. and. IVIG. (Khurana.et.al.,.200).
dIaGNOsIs
In. the. appropriate. clinical. context,. one. should. suspect. ADEM.. . MRI. scans. are. useful. for. demonstrating. disseminated.lesions.of.inflammatory.demyelination,.but.a. temporal.delay.of..to.1.days.between.onset.of.neurological.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. fluidattenuated. 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.
ROLE Of IVIG IN adEM

IVIG.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.
113
mild.lymphocytic.pleocytosis.usually.without.oligoclonal. bands... here.is.no.diagnostic.test...Electroencephalogram. T may. be. normal. or. consistent. with. an. encephalopathy. (Apak.et.al.,.1999).
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. methylprednisolone.. . 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.corticosteroids.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)...
3.. . mbler.M,.Stoll.J,.Tzamaloukas.A,.Abala.MM..Focal. A 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.. 1997;20:2-26. .. . hurana.DS,.Melvin.JJ,.Kothare.V,.et.al..Acute.disK 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.disseminated. encephalomyelitis.. Neurology. 1996;6:1173-117. 7 . art. MN,. Earle. KM.. Hemorrhagic. and. perivenous. .. H Bone. Marrow. Transplant.
EXpERt CONsENsUs
1.. . here.are.no.controlled.trials.to.confirm.the.benefits. T of. IVIG. in. ADEM,. but. anecdotal. reports. and. case. series. suggest. that. IVIG. may. be. efficacious. in. ADEM. 2.. .VIG. can. be. used. in. ADEM. patients. who. do. not. I respond. to. high. dose. corticosteroids. or. in. patients. where.steroids.are.contraindicated.(e.g..suspicion.of. CNS.infection).
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;1:187-180. 9.. . aji.M,.Kusuhara.T,.Ayabe.M,.et.al..Survey.of.herpes. K simplex. virus. infection. of. the. central. nervous. system,. including. acute. disseminated. encephalomyelitis,. in. the. Kyushu. and. Okinawa. regions. of. Japan..Mult.Scler.1996;2:83-87 . 10... leiman. M,. Brunquell. P Acute. disseminated. K .. encephalomyelitis:. response. to. intravenous. immunoglobulin?.J.Child.Neurol.199;10:81-83.
REfERENCEs
1.. . llen. IV.. Demyelinating. diseases.. In:. Greenfields. A neuropathology,. th. ed. Adams. JH,. Corsellis. JAN,. Duchen.LW.(editors)..London:.Edward.Arnold;.198. pp..338-38. 2.. . ssa. A,. Watemberg. N,. Bujanover. Y,. et. al.. A Demyelinative.brainstem.encephalitis.responsive.to. intravenous. immunoglobulin. therapy.. Pediatrics. 1998;10:301-30.
11.. . axmi. SN,. Takahashi. S,. Matsumoto. K,. et. al.. L Treatment-related. disseminated. necrotizing. leukoencephalopathy. with. characteristic. contrast. enhancement. of. the. white. matter.. Radiat. Med. 1996;1:303-307 .
11
12... ipton. HL.. Theilers. virus. infection. in. mice:. an. L unusual.biphasic.disease.process.leading.to.demyelination..Infect.Immun.197;11:117-11. 13... itvak. AM,. Sands. IJ,. Gibel. H.. Encephalitis. compliL cating. measles:. report. of. 6. cases. with. follow-up. studies.in.32..Am.J.Dis.Child.193;6:26-29. 1... archioni. E,. Marinou. Aktipi. K,. Uggetti. C,. et. al.. M Effectiveness. of. intravenous. immunoglobulin. treatment. in. adult. patients. with. steroid-resistant. monophasic. or. recurrent. acute. disseminated. encephalomyelitis. 1... urray.PD,.Pavelko.KD,.Leibowitz.J,.et.al..CD+.and. M CD8+.T.cells.make.discrete.contributions.to.demyelination. and. neurologic. disease. in. a. viral. model. of. multiple.sclerosis..J.Virol.1998;72:7320-7329. 16... ishikawa.M,.Ichiyama.T,.Hayashi.T,.et.al..Intravenous. N immunoglobulin. therapy. in. acute. disseminated. encephalomyelolitis.. 1999;21:83-86. 17 Pellegrini.M,.OBrien.TJ,.Hoy.J,.Sedal.L..Mycoplasma. .. . pneumoniae. infection. associated. with. an. acute. brainstem. syndrome.. Acta. Neurol. Scand. 1996;93:203-206. 18... ilver.B,.McAvoy.K,.Mikesell.S,.Smith. W..Fulminating. S T encephalopathy. with. periventricular. demyelination. and. vacuolar. myelopathy. as. the. initial. presentation. of. human. immunodeficiency. virus. infection.. Arch. Neurol.1997;:67-60. 19... pieker.S,.Petersen.D,.Rolfs.A,.et.al..Acute.dissemiS nated.encephalomyelitis.following.Pontiac.fever..Eur. Neurol.1998;0:169-172. 20... traussberg. R,. Schonfeld. T,. Weitz. R,. et. al.. S Improvement. of. atypical. disseminated. encephalomyelitis.with.steroids.and.intravenous.immunoglobulins..Pediatr.Neurol.2001;2:139-13. Pediatr. Neurol.
21.. . olley.ND,.Tsunoda.I,.Fujinami.RS..DNA.vaccination. T against. Theilers. murine. encephalomyelitis. virus. leads.to.alteratons.in.demyelinating.disease..J.Virol. 1999;73:993-1000. 22... einshenker. BG,. OBrien. PC,. Patterson. TM,. W 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.
11
MULTIPLE SCLEROSIS
CLINICaL fEatUREs
Multiple. 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,.opticospinal.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.neuromyelitis.optica.(NMO),.which.has.a.different.pathogenesis. . 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.
116
such. as. paresthesia,. Lhermittes. 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.corticosteroid...Fatigue.is.common.in.many.patients...Worsening. of. symptoms. with. increase. of. body. temperature. (Uhthoffs. 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.misdiagnosed.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.
MULTIPLE SCLEROSIS
EtIOLOGICaL faCtORs aNd pathOGENEsIs

Classical. 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.susceptibility.to.develop.MS.(Jersild.et.al.,.1973)...Candidategenes.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. histological.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, . antibody-mediated. demyelin2
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.inflammatory.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-associatedglycoprotein,. 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. autoantibodies.. . 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.
ation.likely.with.complement.activation, distal.oligoden3.
drogliopathy. and. apoptosis. possibly. related. to. toxins,. ischemia.and.viruses.and.primary.oligodendrogliopathy.. . Interestingly.individual.patients.were.different.in.the.histological.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.oligodendrocyte. dystrophy.. .This. hypothesis. can. explain. the. variable.clinical.severity.and.response.to.immunomodulatory. treatments. among. different. MS. patients,. and. . was. supported. by. report. that. patients. with. antibodymediated. demyelination. on. histology. might. respond. . to. plasmapheresis. better. than. other. groups.. . (Keegan. .et.al.,.200).
dIaGNOsIs
MS. remains. to. be. a. clinical. diagnosis. supported. by. investigation. findings. with. exclusion. of. other. diseases. that. can. mimic. MS.. . Posers. 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.diseasemodifying.agents.such.as.-interferon,.MRI.criteria.were. employed.to.facilitate.earlier.diagnosis.of.MS.especially. for. patients. who. presented. after. a. single. attack. of.
117
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.
IV. corticosteroid. group.. . At. . years. there. was. no. difference... 2. Long term disease-modifying agents Agents.that.reduce.relapse.rate
BEta-INtERfERONs
Beta-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.2th.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. 21. 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.
tREatMENt
General principles MS.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: .. educe.relapse.rate r .. revent.fixed.disability.directly.attributable.to.relapse p .symptomatic.treatment.of.fixed.neurological.deficits . .prevent.disability.acquired.through.progression . .treat.established.progression.. . General measures Medications.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 tREatMENts
1. Acute phase During. 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.
118
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.
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...
CORtICOstEROIds
Zivadinov. et. al. studied. 90. RRMS. patients. who. were. randomized. to. corticosteroid. only. during. relapses. OR. regular. pulsed. CS. (g. MP. over. . days. Qm. for. 3. yrs,. then.Q6m.for.2.yrs)...The.annual.relapse.rate.were.the. same.among.the.2.groups.but.the.regular.pulsed.corticosteroid. 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.
OthER EMERGING tREatMENts

. Natalizumab. is. a. humanized. monoclonal. antibody. against. 1. 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.transendothelial. 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-CD2),. which. reduces. cerebral. inflammation.in.SPMS.and.reduce.number.of.relapses.
BEta-INtERfERONs
For. 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. >. 10mg/m2. and. hence. use. is. limited. for. maximum. of. 3. years. at. current. dose,. birth.
ROLE Of IVIG IN Ms
Acute attacks Visser.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.IVIGIVMP.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,.
119
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.
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...
RRMs
Fazekas.et.al,.studied.18.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. neurological.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. .
120
pROGREssIVE Ms
The.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 CONsENsUs
According.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.
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.corticosteroid.for.acute.attacks.of.MS... . IVIG.may.be.considered.as.an.optional.treatment.to. reduce. the. incidence. of. pregnancy. and. postpartumrelated.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.
Challoner.PB,.Smith.KT,.Parker.JD,.et.al..Subacute.leukoencephalitis. caused. by. CNS. infection. of. human. herpesvirus.6.in.multiple.sclerosis..Proc.Natl.Acad.Sci.U. S.A.199;92:70-7. Dean.G..Annual.incidence,.prevalence,.and.mortality.of. multiple. sclerosis. in. white. South-African. born. and. in. white.immigrants.to.South.Africa..BMJ. Fazekas. F Deisenhammer. F Strasser-Fuchs. S,. et. al.. ,. ,. Randomized. placebo-controlled. trial. of. monthly. intravenous. immunoglobulin. therapy. in. relapsingremitting.multiple.sclerosis..Austrian.Immunoglobulin.in. Multiple. Sclerosis. Study. Group.. Lancet. 1997;39:8993. European. Study. Group. on. Interferon. Beta-1b. in.
REfERENCEs
Achiron.A,.Gabbay.U,.Gilad.R,.et.al..Intravenous.immunoglobulin. treatment. in. multiple. sclerosis.. Effect. on. relapses..Neurology.1998;0:398-02.. Achiron.A,.Kishner.I,.Sarova-Pinhas.I,.et.al..Intravenous. immunoglobulin.treatment.following.the.first.demyelinating.event.suggestive.of.multiple.sclerosis..Arch.Neurol. 200;61:11-120. 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;21:1133-1137 . Beck. RW,. Cleary. PA,. Anderson. MM. Jr,. et. al.. A. randomized,. controlled. trial. of. corticosteroids. in. the. treatment. of. acute. optic. neuritis.. N. Eng. J. Med. 1992;326:81-88. Comi. G,. Filippi. M,. Barkhof. F et. al.. Interferon. beta. 1a. ,. (Rebif). in. patients. with. acute. neurological. syndromes. suggestive. of. multiple. sclerosis:. a. multi-center,. randomized,. double-blinded,. placebo-controlled. study.. Neurology.2000;:Suppl.3:A8-86. Compston. A,. Coles. A.. Multiple. sclerosis.Lancet. 2002;39:1221-1231.
Secondary. Progressive. MS.. Placebo-controlled. multicenter. randomized. trial. of. interferon. beta-1b. in. treatment. of. secondary. progressive. multiple. sclerosis.. Lancet.1998;32:191-197 . Fazekas. F Sorenson. PS,. Filippi. M,. et. al.. MRI. results. ,. from.the.European.study.on.intravenous.immunoglobulin.in.secondary.progressive.multiple.sclerosis.(ESIMS).. Mult.Scler.200;11():33-0. Goodin. DS,. Frohman. EM,. Garmany. GP et. al.. Disease. ,. modifying.therapies.in.multiple.sclerosis..Report.of.the. Therapeutics.and. echnology.Assessment.Subcommittee. T of. the. American. Academy. of. Neurology. and. the. MS. Council. for. Clinical. Practice. Guidelines.. Neurology. 2002;8:169-178. Goodin. DS,. Arnason. BG,. Coyle. PK,. et. al..The. use. of. mitoxantrone.(Novantrone).for.the.treatment.of.multiple. sclerosis:. report. of. the. Therapeutics. and. Technology. Assessment. Subcommittee. of. the.American.Academy. of.Neurology..Neurology.2003;61:1332-1338.
121
Hommes.OR,.Sorenson.PS,.Fazekas.F ,.et.al..Intravenous. immunoglobulin. in. secondary. progressive. multiple. sclerosis:. randomized. placebo-controlled. trial.. Lancet. 200;36:119-116.
Lucchinetti.CF ,.Bruck.W,.Parisi.J,.et.al..Heterogeneity.of. multiple.sclerosis.lesions:.implications.for.the.pathogenesis.of.demyelination..Ann.Neurol.2000;7:707-717 . McDonald.. I,.Compston.A,.Edan.G,.et.al..Recommended. W
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;33:898-90. 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;8:13-6. Keegan. M,. Konig. F Bitsch. A,. et. al.. Multiple. sclerosis. ,. pathological. subtype. predicts. response. to. therapeutic. plasma.exchange..Neurology.200(Suppl.):A29. 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.immunoglobulins. in. MS:. clinical. and. MRI. assessment.. Eur. J. Neurol.2002;9:6-72.
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;33:938-92. 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.demyelinating. potential. of. antibodies. to. myelin. oligodendrocyte. glycoprotein. is. related. to. their. ability. to. fix. complement..Am.J.Pathol.1993;13:-6. Prevention.of.Relapses.and.Disability.by.Interferon.beta. -1a. Subcutaneously. in. Multiple. Sclerosis. (PRISMS). Study. Group.. Randomized. double-blind. placebocontrolled. study. of. interferon. beta-1a. in. relapsing/ remitting. multiple. sclerosis.. Lancet. 1998;32:19810. . Rieckmann. P Toyka. KV,. Bassetti. C,. et. al.. Multiple. ,. Sclerosis.Therapy. Consensus. Group.. Escalating. immunotherapy. of. multiple. sclerosis. . new. aspects. and. practical.application..J.Neurol.200;21:1329-1339.
122
MULTIPLE SCLEROSIS
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;6:196-10. 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.immunological. 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.complementmediated.demyelination..Ann.Neurol.1998;3:6-71. Trapp. BD,. Peterson. J,. Ransohoff. RM,. et. al.. Axonal. transaction.in.the.lesion.of.multiple.sclerosis..N.Eng.J. Med.1998;338:278-28. The. IFNB. Multiple. Sclerosis. Study. Group.. Interferon. beta-1b. is. effective. in. relapsing-remitting. multiple. sclerosis..I..Clinical.results.of.a.multicenter,.randomized,. double-blind,. placebo-controlled. trial.. Neurology. 1993;3:6-661. Weinshenker. BG,. Bass. B,. Rice. GP et. al..The. natural. ,. history. of. multiple. sclerosis:. a. geographically. based. study..I..Clinical.course.and.disability..Brain.1989;112:1336. Weinshenker.BG,.OBrien.PC,.Patterson. M,.Noseworthy. T 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.
123
NEUROMYELITIS OPTICA
INtROdUCtION
Neuromyelitis. optica. (NMO). is. an. idiopathic. inflammatory.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*101. allele. while. OSMS. is. associated. with. HLA-DPB1*001. 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.
12
with. fulminant. attacks. were. clinically. and. immunogenetically. 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 fEatUREs
Typical.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. centralenhancing,. 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.
(CSF). oligoclonal. bands. (OCB). and. worse. neurological. prognosis.(de.Seze.et.al.,.2003;.Ghezzi.et.al.,.200).
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)...
pathOLOGY aNd pathOGENEsIs

Pathologically. NMO. is. characterized. by. presence. of. necrosis.of.grey.and.white.matter,.perivascular.immunoglobulin.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.specifically.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.perivascular. 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.longitudinally. or. recurrent. optic. neuritis. without. myelitis,. were. seropositive. for. the. NMO-IgG. (Lennon. et. al.,. 200)...Together.with.patients.with.recurrent.longitudinally.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. predominantly. 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. ..
tREatMENt
Acute. 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.demyelination. 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.insufficiency.(Wingerchuk.et.al.,.2007)... . Maintenance. immunosuppressive. therapy. is. recommended.for.reducing.relapse.frequency.in.NMO.. . Systemic. corticosteroids. in. combination. with. azathioprine. 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.immunosuppressants.therapy.
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RoLE of IVIG IN NMo There. 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.neurological. 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).
3.. . erman.M,.Feldman.S,.Alter.M,.Zilber.N,.Kahana.E.. B . Acute. transverse. myelitis:. incidence. and. etiologic. considerations...Neurology.1981;31:966-71. .. . han. KH,. Tsang. KL,. Fong. GCY,. et. al.. . Idiopathic. C severe. recurrent. transverse. myelitis:. a. restricted. variant.of.neuromyelitis.optica...Clin.Neuro.Neurosurg. 200;107(2):132-. .. . ordonnier. D,. de. Seze. J,. Breteau. G,. Ferriby. D,. C Michelin. E,. Stojkovic. T,. Pruvo. JP Vermersch. P . ,. .. Prospective.study.of.patients.presenting.with.acute. partial. transverse. myelopathy.. . J. Neurol. 2003;10(12):17-2. 6.. . ree. BA,. Lamb. S,. Morgan. K,. et. al.. .An. open. label. C study. of. the. effects. of. rituximab. in. neuromyelitis. optica...Neurology.200;12:6(7):1270-1272. 7 . orge.Correate,.Marcela.Fiol...Activation.of.humoral. .. J immunity. and. eosinophils. in. neuromyelitis. optica.. . Neurology.200;63:2263-70. 8.. . e.Seze.J,.Lebrun.C,.Stoikovic.T,.Ferriby.D,.Chatel.M,. d Vermersch. P . Is. Devics. neuromyelitis. optica. a. .. separate.disease?.A.comparative.study.with.multiple. sclerosis...Mult.Scler.2003;9:21-2. 9.. . alcini. F Trapani. S,. Ricci. L,. et. al.. . Sustained. F ,. improvement.of.a.girl.affected.with.Devics.disease. over. 2. years. of. mycophenolate. mofetil. treatment.. . Rheumatology.2006;:913-91. 10... ukazawa.T,.Kikuchi.S,.Niino.M,.Yabe.I,.Miyagishi.R,. F Fukaura. H,. Hamada.T,.Tashiro. K,. Sasaki. H.. .Attackrelated. severity:. a. key. factor. in. understanding. the. spectrum. of. idiopathic. inflammatory. demyelinating. disorders...J.Neurol.Sci.200;22(1-2):71-8. 11.. . hezzi. A,. Bergamaschi. R,. Martinelli. V,.Trojano. M,. G Tola. MR,. Merelli. E,. Mancardi. L,. Gallo. P Filippi. M,. ,. Zaffaroni.M,.Comi.G...Clinical.characteristics,.course. and. prognosis. of. relapsing. Devics. Neuromyelitis. Optica...J.Neurol.200;21(1):7-2.
EXpERt CONsENsUs
Without. 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. azathioprine,. IVIG. might. reduce. relapse. rate. and. promote. neurological.recovery.
REfERENCEs
1.. . akker. J,. Metz. L.. . Devics. neuromyelitis. optica. B treated. with. intravenous. gamma. globulin. (IVIG).. . Can.J.Neurol.Sci.200;31(2):26-7 . 2.. . akshi.R,.Kinkel.PR,.Mechtler.LL,.Bates.VE,.Lindsay. B 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.
126
12... inson. SR,. Pittock. SJ,. Lucchinetti. CF Roemer. SF H ,. ,. 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... effery. DR,. Mandler. RN,. Davis. LE.. . Transverse. J myelitis:.retrospective.analysis.of.33.cases,.with.differentiation. of. cases. associated. with. multiple. sclerosis. and. parainfectious. events.. . Arch. Neurol. 1993;0:32-3. 1... un-ichi. Kira.. . Multiple. sclerosis. in. the. Japanese. J population...Lancet.Neurology.2003;2:117-27 . 1... kada.K,.Tsuji.S,.Tanaka.K...Intermittent.intravenous. O immunoglobulin. successfully. prevent. relapses. of. neuromyelitis. optica.. . Intern. Med. 2007;6:16711672. 16... eegan. M,. Pineda. AA,. McClelland. RL,. Darby. CH,. K Rodriguez. M,.Weinshenker. BG.. . Plasma. exchange. for.severe.attacks.of.CNS.demyelination:.predictors. of.response...Neurology.2002;8:13-6. 17 . idd. D,.Thorpe. JWm.Thompson. AJ,. et. al.. . Spinal. .. K cord.MRI.using.multi-array.coils.and.fast.spin.echo. II.. . Findings. in. multiple. sclerosis.. . Neurology. 1993;3:2632-7 . 18... ennon.VA,.Wingerchuk. DM,. Kryzer.TJ,. Pittock. SJ,. L Lucchinetti. CF Kazuo. Fujihara,. Ichiro. Nakashima,. ,. Weinshenker.BG...A.serum.autoantibody.marker.of. neuromyelitis. optica:. distinction. from. multiple. sclerosis...Lancet.200;36:2106-12.. 19... ucchinetti. CF Mandler. RN,. McGavern. D,. et. al.. .A. L ,. role.for.humoral.mechanisms.in.the.pathogenesis.of. Devics. neuromyelitis. optica.. . Brain. 2002;12:. 10-61. 20... andler.RN,.Ahmed.N,.Dencoff.JE...Devics.neuroM myelitis.optica:.a.prospective.study.of.seven.patients. treated. with. prednisolone. and. azathioprine.. . Neurology.1998;1:1219-20.
21.. . cDonald. WI,. Compston. A,. Edan. G,. et. al.. M . Recommended. diagnostic. criteria. for. multiple. sclerosis:.guidelines.from.the.international.panel.on. the. diagnosis. of. multiple. sclerosis.. . Ann. Neurol. 2001;0:121-127 .. 22... irsattari.SM,.Johnston.JB,.McKenna.R,.Del.Bigio. M MR,. Orr. P Ross. RT,. Power. C.. . Aboriginals. with. ,. multiple.sclerosis:.HLA.types.and.predominance.of. neuromyelitis.optica...Neurology.2001;6:317-23. 23... isra. UK,. Kalita. J,. Kumar. S.. . A. clinical,. MRI. and. M neurophysiological. study. of. acute. transverse. myelitis...J.Neurol.Sci.1996;138:10-6. 2... isu.T,.Fujihara.K,.Nakashima.I,.et.al...Pure.opticoM spinal. form. of. multiple. sclerosis. in. Japan.. . Brain. 2002;12:260-68. 2... oser. CM,. Paty. DW,. Scheinberg. L,. et. al.. . New. P diagnostic. criteria. for. multiple. sclerosis:. guidelines. for. research. protocols.. . Ann. Neurol. 1983;133:22731. 26... atsuoka.T,.Matsushita.T,.Kawano.Y,.Osoegawa.M,. M Ochi.H,.et.al...Heterogeneity.of.aquaporin-.autoimmunity.and.spinal.cord.lesions.in.multiple.sclerosis. in.Japanese...Brain.2007;130:1206-1223. 27 . ransverse. myelitis. consortium. working. group.. .. T . Proposed. diagnostic. criteria. and. nosology. of. acute. transverse.myelitis...Neurology.2002;9():99-0. 28... ippet. DS,. Fishman. PS,. Panitch. HS.. . Relapsing. T transverse.myelitis...Neurology.1991;1:703-6. 29... einshenker. BG,. OBrien. PC,. Patterson. TM,. W 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.
127
30... einshenker. BG.. . Neuromyelitis. optica:. what. is. it. W and.what.it.might.be...Lancet.2003;361:889-90. 31.. . einstock-Guttmann. B,. Ramanathan. M,. Lincoff. N,. W et. al.. . Study. of. mitoxantrone. for. the. treatment. of. recurrent.neuromyelitis.optica.(Devic.disease)...Arch. Neurol.2006;63:97-963. 32... ingerchuk. DM,. Hogancamp. WF OBrien. PC,. W ,. Weinshenker.BG...The.clinical.course.of.neuromyelitis. optica. (Devics. syndrome).. . Neurology. 1999;3:1107-1. 33... ingerchuk.DM,.Lennon.VA,.Lucchinetti.CF W ,.Pittock. SJ,.Weinshenker.BG...The.spectrum.of.neuromyelitis.optica...Lancet.Neurol.2007;6:80-81. 3... amasaki. K,. Horiuchi. I,. Minohara. M,. Kawano. Y,. Y Ohyagi.Y,.Yamada.T,.Mihara.F ,.Ito.H,.Nishimura.Y,.Kira. J.. . HLA-DPB1*001-associated. with. opticospinal. multiple.sclerosis:.clinical,.neuroimaging.and.immunogenetic.studies...Brain.1999;122:1689-96. 3... u.YL,. Hawkins. BR,. Ho. HC,. Huang. CY.. . Multiple. Y sclerosis. among. Chinese. in. Hong. Kong.. . Brain. 1989;112:1-67 .
128
APPENDICES
APPENDICES
appENdIX a
Terms. of. reference. and. membership. of. the. . Scientific.Committee.. tERMS of REfERENCE The.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.worlds.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. 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.
129
appENdIX B
In. 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.
appENdIX C
Literature.Review.on.the.use.of.IVIg.in.Neurology Search.Strategy.and.Results . Asia.Pacific.Immunoglobulins.in.Neurology.Advisory. Board. members. of. INDAPS. undertook. the. literature. review.on.which.the.Consensus.Statements.are.based. 2.1 SEARCH StRAtEGy The. 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 2.2 SEARCH tERMS Over.0016.abstracts.obtained.with.search.terms.. Terms.used.to.identify.relevant.citations.included: Immunoglobulins.-.Intravenous Immunoglobulin Immunoglobulin.-.Drug.Administration Immunoglobulin.-.Adverse.Drug.Reaction Immunoglobulin.-.Clinical.Trial. Immunoglobulin.-.Drug.Dose Immunoglobulin.-.Intravenous.Drug.Administration Demyeliating.Autoimmune.Diseases,.CNS.or. Dymelinating.Disease Lambert.Eaton.Myasthenic.Syndrome.or.Eaton. Lambert.Syndrome Leukoencephalitis,.Acute.Haemmorrhagic.or.Eaton. Lambert.Syndrome Leukoencephalitis,.Acute.Haemorrhagic.or. Encephalomyelitis Myasthenia.Gravis. Polyradiculoneuropathy Stiff-Person.Syndrome Stiff.Man.Syndrome Brain.Disease Brain.Diseases Central.Nervous.System.Infections Central.Nervous.Infection Encephalomyelitis
Spinal.Cord.Diseases Spinal.Cord.Disease Paraneoplastic.Syndromes Nervous.System Paraneoplastic.Syndrome Fatigue.Syndrome Chronic. Chronic.Fatigue.Syndrome Motor.Neurone.Disease Neuromuscular.Junction.Disease Neuromuscular.Junction.Disorder Peripheral.Nervous.System.Disease Peripheral.Neuropathy Isaacs.Syndrome Myokymia Vasculitis Central.Nervous.System Brain.Vasculitis. Uveomeningoencephalitic.Syndrome Meningoencephalitis Autoimmune.Disease Immunoglobulins 2.3 SEARCH fINDINGS Citations.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.
130
MEMBERSHIP OF SCIENTIFIC COMMITTEE
MEMBERSHIP OF SCIENTIFIC COMMITTEE

a/prof andrew J Kornberg (Chair)
Director.of.Neurology. Royal.Childrens.Hospital. Flemington.Road. Parkville. Victoria,.Australia.302
a/prof Ching-piao tsai

President,.Taiwan.Neurological. Society,.Neurological.Institute National.Yang-Ming.University.and.Taipei. Veterans.General.Hospital.Taipei. Taiwan
prof Marinos C dalakas, M.d.

Chair,.Clinical.Neuroscience.. Neurouomuscular.Diseases Imperial.College. London,.U.K
dr Koon ho Chan
Specialist.Neurologist University.Department.of.Medicine Queen.Mary.Hospital The.University.of.Hong.Kong
dr Woon Chee Yee

Consultant.Neurologist National.Neuroscience.Institute Singapore
dr Rawiphan Witoonpanich
Consultant.Neurologist Division.of.Neurology Ramathibodi.Hospital. Mahidol.University. Bangkok,.Thailand
prof Edward Byrne

Executive.Dean. Faculty.of.Biomedical.Sciences University.College London,.U.K..
131
dr david hutchinson
Consultant.Neurologist Department.of.Neurology Auckland.District.Health.Board. Auckland,.New.Zealand
prof John pollard

Director.of.Neurology Brain.Mind.Research.Institute. University.of.Sydney NSW,.Australia
dr Vrajesh Udani
Consultant.Neurologist Paediatrics.&.Neurology. PD.Hinduja.National.Hospital Mumbai,.India
dr santhi datuk puvanarajah.

Consultant.Neurologist. Division.of.Neurology Kuala.Lumpur.Hospital Kuala.Lumpur,.Malaysia . . .
132
COMMENTARY ON INTERPRETATION OF PUBLICATIONS REVIEWED

The.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.
133
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
WAIVER OF LIABILITY
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The Second Edition Expert Consensus Statements On The Use of IVIg in Neurology

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The Second Edition Expert Consensus Statements On The Use of IVIg in Neurology

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SECOND EDITION

BRINGING CONSENSUS TO THE USE OF IVIG IN NEUROLOGY

Chronic Inflammatory Demyelinating Polyneuropathy.......................................................................................31

Multifocal Motor Neuropathy................................................................................................................................39.. .

IgM Paraproteinemic Neuropathies........................................................................................................................

Myasthenia Gravis. ................................................................................................................................................. .

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

Neuromyotonia (Isaacs Syndrome)...................................................................................................................... 7

Chronic Fatigue Syndrome.....................................................................................................................................8

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

Acute Disseminated Encephalomyelitis.............................................................................................................. 112.

Neuromyelitis Optica............................................................................................................................................ 12.

A/Prof.Andrew.J..Kornberg Chairman,. Asia. Pacific. Immunoglobulins. in. Neurology. Advisory.Board November.2008

COMMENtaRY ON thE INtERpREtatION Of pUBLICatIONs REVIEWEd

aCRONYMs aNd aBBREVIatIONs tERMINOLOGY

NHMRC. National.Health.and.Medical.Research.Council PE. . PM.. Plasma.exchange Polymyositis

BIBLIOGRaphY aNd LItERatURE REVIEW

a). . yasthenia.gravis;.b).LEMS;.c).stiff-person. M syndrome;.d).autoimmune.demyelinating.neuropathies.(CIDP ,.GBS,.MMN)

assessments. based. on. controlled. treatment. trials. in. patients.with.neurological.diseases...Muscle.Nerve.20,. 1102-1107 .

subtypes. of. the. disease .. . The. most. common. form,. classic.GBS.(or.acute.inflammatory.demyelinating.polyneuropathy,.AIDP),.is.characterized.by.segmental.demy22

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.versions ,.updating.an.

beneficial.effect...However,.the.double-blind,.controlled. randomised. trial. did. not. show. a. significant. difference. between.the.two.treatments8.

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

Intravenous. immunoglobulin. for. Guillain-Barr. syndrome...Cochrane.Database.Syst.Rev...200;(1): CD002063..and.2006;.(1):CD002063. 2... ughes.RAC,.Rees.JH...Clinical.and.epidemiological. H

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

sUGGEstEd appROaCh tO MaNaGEMENt

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Occasional. patients. will. have. a. long. term. benefit.

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.

1...Dyck .PJ,.Lais.AC,.Ohta.M,.et.al..Chronic.inflammtory. polyradiculoneuropathy.. Mayo. Clinic. Proceedings.. . 197;.0:621-61.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

3... cCrone.P M ,.Chisholm.D,.Knapp.M,.et.al...Cost-utility. analysis.of.intravenous.immunoglobulin.and.prednisolone. for. chronic. inflammatory. demyelinating. polyradiculoneuropathy.Eur.J.Neurol...2003;.10:687-69.

therapy.in.chronic.inflammatory.demyelinating.polyneuropathy...A.double-blind,.sham-controlled,.crossover.study.Brain...1996;.119.(.Pt.):10-1066. ... ehndiratta. MM,. Hughes. RA,. Agarwal. P . Plasma. M ..

MULTIFOCAL MOTOR NEUROPATHY

MULTIFOCAL MOTOR NEUROPATHY

MULTIFOCAL MOTOR NEUROPATHY

.. . In. most. long.

continued. clinical. deterioration inadequate.dosage. DoSAGE

. but. may. reflect.

specific.T.lymphocytes.can.orchestrate.inflammatory. peripheral. neuropathy.. . Brain.. . 199;. 118. (. Pt. ):1263-1272.

MULTIFOCAL MOTOR NEUROPATHY

IGM PARAPROTEINEMIC NEUROPATHIES

IGM PARAPROTEINEMIC NEUROPATHIES

SyStEMIC DISoRDER Multiple.myeloma. Waldenstrms.macroglobulinemia. Osteosclerotic.myeloma. Primary.NF-amyloidosis. Cryoglobulinemia. POEMS.syndrome. CANOMAD.syndrome.

Axonal Demyelinating Demyelinating Axonal Axonal Mixed.demyelinating.&.axonal.picture Mixed.demyelinating.&.axonal.picture

IGM PARAPROTEINEMIC NEUROPATHIES

IVIG IN IGM paRapROtEINEMIC NEUROpathIEs

IGM PARAPROTEINEMIC NEUROPATHIES

OthER IMMUNOsUppREsaNts BEING CONsIdEREd

BRACHIAL AND LUMBOSACRAL PLEXOPATHIES

BRACHIAL AND LUMBOSACRAL PLEXOPATHIES

pathOGENEtIC MEChaNIsMs IN NEURaLGIC aMYOtROphY

dIaBEtIC LUMBOsaCRaL pLEXOpathY

tREatMENt Of NEURaLGIC aMYOtROphY

IMMUNE MOdULatING thERapY IN NEURaLGIC aMYOtROphY, INCLUdING IVIG

IdIOpathIC LUMBOsaCRaL pLEXOpathY

BRACHIAL AND LUMBOSACRAL PLEXOPATHIES

pathOGENEtIC MEChaNIsMs Of dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathY

thERapY IN dIaBEtIC aNd IdIOpathIC LUMBOsaCRaL pLEXOpathY

.. . yck.PJ,.Windebank.AJ...Diabetic.and.non-diabetic. D lumbosacral. radiculoplexus. neuropathies:. new. insights.into.pathophysiology.and.treatment...Muscle. Nerve.2002...2:77-91.

seronegative.generalized.MG.patients.in.one.series.and. 37 .%.of.32.such.patients.in.another.series ...Antibodies.

IgM Paraproteinemic Neuropathies........................................................................................................................

Myasthenia Gravis. ................................................................................................................................................. .

Neuromyotonia (Isaacs Syndrome)...................................................................................................................... 7

Chronic Fatigue Syndrome.....................................................................................................................................8

Neuromyelitis Optica............................................................................................................................................ 12.

beneficial.effect...However,.the.double-blind,.controlled. randomised. trial. did. not. show. a. significant. difference. between.the.two.treatments8.

Intravenous. immunoglobulin. for. Guillain-Barr. syndrome...Cochrane.Database.Syst.Rev...200;(1): CD002063..and.2006;.(1):CD002063. 2... ughes.RAC,.Rees.JH...Clinical.and.epidemiological. H

1...Dyck .PJ,.Lais.AC,.Ohta.M,.et.al..Chronic.inflammtory. polyradiculoneuropathy.. Mayo. Clinic. Proceedings.. . 197;.0:621-61.

3... cCrone.P M ,.Chisholm.D,.Knapp.M,.et.al...Cost-utility. analysis.of.intravenous.immunoglobulin.and.prednisolone. for. chronic. inflammatory. demyelinating. polyradiculoneuropathy.Eur.J.Neurol...2003;.10:687-69.

therapy.in.chronic.inflammatory.demyelinating.polyneuropathy...A.double-blind,.sham-controlled,.crossover.study.Brain...1996;.119.(.Pt.):10-1066. ... ehndiratta. MM,. Hughes. RA,. Agarwal. P . Plasma. M ..

specific.T.lymphocytes.can.orchestrate.inflammatory. peripheral. neuropathy.. . Brain.. . 199;. 118. (. Pt. ):1263-1272.

.. . yck.PJ,.Windebank.AJ...Diabetic.and.non-diabetic. D lumbosacral. radiculoplexus. neuropathies:. new. insights.into.pathophysiology.and.treatment...Muscle. Nerve.2002...2:77-91.

seronegative.generalized.MG.patients.in.one.series.and. 37 .%.of.32.such.patients.in.another.series ...Antibodies.

. and. serum. AChR. antibodies0.. . Five. to. ten. mg. of.

#2:. single-fiber. electromyography.. Muscle. Nerve. 1996;19(9):1069-83. 0... incent.A,.Newsom-Davis.J..Acetylcholine.receptor. V

30... ngel.AG..The.investigation.of.congenital.myasthenic. E syndromes..Ann.N.Y.Acad.Sci.1993;681:2-3. 31.. . eeson.D,.Palace.J,.Vincent.A..Congenital.myasthenic. B syndromes..Curr.Opin.Neurol.1997;10():02-7 .

immunoglobulin. therapy. in. amyotrophic. lateral. sclerosis...J.Neurol.1996;.23:.117-20.

study.in.1.patients.where.3.had.WS.and.demonstrated. efficacy.in.only.one.of.these3...A.more.recent.retrospective. study. in. the. very. refractory. "juvenile". spasms .

. reported. >. 7%. improvements. in. seizure. frequency.

Lucchinetti.CF ,.Bruck.W,.Parisi.J,.et.al..Heterogeneity.of. multiple.sclerosis.lesions:.implications.for.the.pathogenesis.of.demyelination..Ann.Neurol.2000;7:707-717 . McDonald.. I,.Compston.A,.Edan.G,.et.al..Recommended. W

(CSF). oligoclonal. bands. (OCB). and. worse. neurological. prognosis.(de.Seze.et.al.,.2003;.Ghezzi.et.al.,.200).